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David R. MATTHEWS,MA, DPhil, BM, BCh, FRCP
Oxford Centre for Diabetes, Endocrinology and Metabolism
Harris Manchester College Oxford; National Institute for Health Research (Senior Research Fellow);
and Oxford Biomedical Research Centre
Oxford, UNITED KINGDOM

Many decades ago, type 2 diabetes was already known to be associated with damaging complications. Although the symptoms of hyperglycemia could be prevented, there was continuing debate about how best to avoid the damaging long-term effects. Early observational data suggested that optimizing metabolic control could be advantageous, but findings from the Universities Group Diabetes Program (UGDP) trials suggested that the solution might not be straightforward. Was good control improving outcome or increasing dangers to the patient? A series of subsequent trials have thrown light on the question—suggesting that the answer depends on the selection of patients for different regimens. Taking care in the clinical appraisal of a patient allows the selection of optimum therapy, which the synthesis of trials suggests will reduce bothmicrovascular andmacrovascular disease. It is now apparent that early treatment of both glycemia and hypertension is beneficial, and the trials of lipid lowering suggest that the risk of cardiovascular disease can be significantly reduced. All the trial data suggest that hyperglycemia is a risk for cardiovascular disease and should be lowered if possible. The target for glycemia is for a glycated hemoglobin (HbA1c) level lower than 7.5%, and this may be nearer 6.5% if achieved slowly and without dangerous hypoglycemia. Early intervention is clearly beneficial. Late intervention to strict targets requires a careful incremental approach.

Background

Estimates from current epidemiology suggest that the number of those with type 2 diabetes will increase to 285 million people by the year 2010, and to more than 400 million by 2030.¹ The problem is not confined to country, race, or geographical location, and so an unprecedented challenge is one of provision of appropriate health care. Many decades ago, type 2 diabetes was already known to be associated with damaging complications.² Although the symptoms of hyperglycemia could be prevented, there was a continuing debate about how best to avoid the damaging long-term effects. Early observational data suggested that optimizing metabolic control could be advantageous, but until the Universities Group Diabetes Program (UGDP) trial³ no systematic trial evidence had been published. The UGDP results were not clear,⁴ however, and so, in the following decades, a variety of trials were undertaken. Astonishingly, not a single one of these trials was without controversy over its design, results, or interpretation. Nevertheless, the synthesis of the knowledge adduced from them all allows us a clear vision of the advantages and disadvantages of the pursuit of normoglycemia. Our understanding has been evolutionary—though perhaps a physician from 1985 transported a quarter of a century ahead in time would feel that there had been a revolution in attitudes and therapeutics.

Trials of glycemic control

_ UGDP
Throughout the 1950s and 1960s, there had been a growing awareness that diabetes complications—both of microvascular and macrovascular origin—were presenting the greatest challenge to the quality of life and longevity of type 2 diabetes patients. Clinical acumen and observation had demonstrated that patients with glycosuria and very high blood glucose levels had a poor quality of life, but some physicians thought that moderate glycosuria might be advantageous in terms of weight loss—a view now resurgent with the development of sodium-glucose cotransporter 2 (SGLT-2) inhibitors.⁵

UGDP3 was the first trial to attempt to optimize glycemia using a controlled trial approach. Launched in 1960, this placebocontrolled, multicenter clinical trial aimed to determine which, if any, of the treatments for type 2 diabetes was efficacious. Although the differences seen in cumulative total mortality were not statistically significant, a subgroup analysis suggested that cardiac deaths occurred more frequently in the tolbutamide group. The investigators terminated this limb of the study. However, the randomization was significantly skewed at baseline—there was 30% more electrocardiographic abnormality, 40% more angina, and 90% more hypercholesterolemia in the tolbutamide group.⁴ Randomization had failed to deliver equipoise in the outcome.

_ UKPDS
The United Kingdom Prospective Diabetes Study (UKPDS) was established to definitively answer the glycemic control controversy as well as to attempt to answer important questions about the class of agents used to achieve control.^6-8 UKPDS was one of very few trials that recruited newly diagnosed type 2 diabetes patients (5012 in total)—an important point, as it transpired, since only UKPDS had the capacity to answer the question of the suitability of early treatment before the onset of serious complications. Despite this criterion, it was nevertheless apparent that many had early signs of trouble ahead—background retinopathy and ECG abnormalities, in particular. The evolution of complications was meticulously recorded—the trial lasted a median of 10 years, with some patients having been followed for 20 years at closeout.

UKPDS had stringent aims for euglycemia on monotherapy, but allowed fasting glucose to rise to 15 mmol/L before adding additional agents. Because one of the aims was to address the question of which monotherapy should be used, glycemia rose progressively throughout the trial. In contrast with later trials, the aim was to persist with monotherapy for as long as possible rather than to achieve a predominant glycemic target. At closeout, the results showed that intensive glucose control was efficacious in reducing many complications. Metformin, used only in the overweight, reduced diabetes-related deaths (risk reduction [RR], 0.58; P=0.017) and myocardial infarction (RR, 0.61; P=0.01) compared with conventional treatment. This is the prime evidence base for the use of metformin. It has been criticized as being based on a UKPDS subset of low statistical power, but one should note that the effect demonstrated in small numbers increases our certainty that this is clinically, as well as statistically, useful. In the main study of sulfonylurea or insulin use, there were clear reductions in relative risk in the intensively treated group: a 12% risk reduction for any diabetes related end point (P=0.029); a 25% risk reduction for microvascular end points (P=0.0099); a 21%risk reduction for retinopathy at twelve years (P=0.015); and a 33% risk reduction for albuminuria at twelve years (P=0.000054). The 16% risk reduction for myocardial infarction had borderline significance (P=0.052).^7,8

The study compared intensive versus conventional treatment for blood glucose control and achieved a glycated hemoglobin (HbA_1c) level of 7% in the intensive groups of the study population compared with 7.9% in the conventional group (Figure 1). Nevertheless, questions remained—especially the question of how low an HbA_1c level one should aim for in glycemic control. Would more aggressive glucose control decrease macrovascular or microvascular disease further?

Figure 1. Diagram of the glycemic control achieved in UKPDS,
ADVANCE, and ACCORD showing differences in duration, duration
of diabetes at recruitment, and glycemic control achieved.

_ PROACTIVE
In 2005, PROACTIVE (PROspective pioglitAzone Clinical Trial In macroVascular Events)⁹ reported its results. PROACTIVE was a prospective, randomized controlled trial of 5238 patients with type 2 diabetes who had evidence of macrovascular disease. The median follow-up was just under 3 years. Patients were assigned to pioglitazone or placebo taken in addition to their glucose-lowering drugs and other medications. The primary end point was a composite of cardiovascular disease, including surgical intervention in the coronary or leg arteries and amputation above the ankle. The outcome of this was not significant (P=0.095). However, the main secondary end point—the composite of all-cause mortality, nonfatal myocardial infarction, and stroke—was, with a significant, favorable response to pioglitazone (P=0.027).

The trial was marred by the problem of the selection of a primary combined outcome that involved not only the onset of new pathology, but also surgical interventions relating to pathology. Surgical interventions are not emerging pathology— they are a response to emerging pathology and, as such, have many constraints on their timing. A decision about when an amputation is undertaken is as much a clinical decision as it is an emergent complication of diabetes. By contrast, the timing of a myocardial infraction is a direct measure of an agonal point in underlying pathology. A multiplicity of outcomes increases the event count, but can do so at the expense of specificity. Nevertheless, the secondary analyses in PROACTIVE were highly significant—a risk reduction of 28% for myocardial infarction (P=0.045) and 47% for fatal and nonfatal stroke (P=0.009).⁹

_ RECORD
In a remarkable coup-de-théâtre, Nissen et al¹⁰ produced a meta-analysis that seemed to demonstrate that rosiglitazone might have an adverse effect on cardiovascular outcome. This meta-analysis has been criticized,¹¹ especially on the grounds that it was not based on a comprehensive search of all the studies that might yield evidence of rosiglitazone’s cardiovascular effects and that the studies were combined on the basis of a lack of statistical heterogeneity, despite variability in study design and outcome assessment.¹¹ Then, in 2009, the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycemia in Diabetes (RECORD) trial reported.¹² This trial featured 4447 patients with type 2 diabetes on metformin or sulfonylurea monotherapy with a mean HbA_1c of 7.9%. They were randomly assigned to take additional rosiglitazone or a combination of metformin and sulfonylurea. In a 5.5 year follow-up, there was no difference in the primary outcome. There was an increase in heart failure causing admission to hospital or death in the rosiglitazone group (hazard ratio [HR], 2.10; 95% confidence interval [CI], 1.35 to 3.27), and upper and distal lower limb fracture rates increased, mainly in women. So, although rosiglitazone lowers glycemia, it seems that there is a significant increase in complications.

_ ACCORD
In 2008, three cardiovascular disease trials reported at the American Diabetes Association. These were ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation), ACCORD (Action to Control CardiOvascular Risk in Diabetes), and VADT (Veterans Affairs Diabetes Trial). ACCORD¹³ produced a startling headline result that mortality was worse in the group that was intensively treated to lower HbA_1c toward 6%. At one year, stable median HbA_1c levels of 6.4% and 7.5% were achieved in the intensive- therapy group and the standard-therapy group, respectively. During follow-up, the primary outcome (a composite of nonfatal myocardial infarction, stroke, or cardiovascular death) occurred in 352 patients in the intensive-therapy group, compared with 371 in the standard-therapy group (HR, 0.90; 95% CI, 0.78 to 1.04; P=0.16). However, 257 patients in the intensive-therapy group died, compared with 203 patients in the standard-therapy group (HR, 1.22; 95% CI, 1.01 to 1.46; P=0.04).¹³ This finding brought the main result from UKPDS into question again. Is intensive glucose lowering harmful? Here, however, the significant differences between ACCORD and UKPDS should be noted.

UKPDS recruited “healthy” new-onset type 2 diabetes patients (serious disease of any kind was a contraindication). In ACCORD, those recruited had been diagnosed a median of 10 years previously and were selected for preexisting cardiovascular disease or specific risk factors. Sudden changes in glycemia in such patients may not be advisable. In this trial, the reports show that the majority of the glucose-lowering effect had already been achieved within the first 4 months, by which time median HbA_1c was 6.6%. Although there was no explicit evidence that hypoglycemia was the precipitating cause of death, it remains the number one suspect for the increased death rate. Hypoglycemia rates were three times higher in the intensively treated group (death precludes con- temporaneous measurement of blood glucose). Many of the patients were receiving rosiglitazone (91% in the intensive arm and 57% in the standard therapy arm). The excess mortality was not simply cardiovascular; hypoglycemia can cause falls or nocturnal aspiration that leads to pneumonia. In the elderly, any significant medical event may be seriously life-threatening.

_ ADVANCE
ADVANCE¹⁴ is the largest trial of cardiovascular disease in type 2 diabetes to date, recruiting 11 140 patients with type 2 diabetes randomized to standard or intensive glucose control with the aim of using gliclazide (modified release) plus other drugs, as required, to achieve an HbA_1c value of 6.5% or less. After a median of 5 years’ follow-up, mean HbA_1c in the intensive-control group was 6.5% compared to 7.3% in the standard-control group. In the intensive-control group, there was a reduced incidence in the combined end point of major macrovascular and microvascular events (HR, 0.90; 95% CI, 0.82 to 0.98; P=0.01), as well as that of major microvascular events (9.4%vs 10.9%; HR, 0.86; 95%CI, 0.77 to 0.97; P=0.01), primarily because of a reduction in the incidence of nephropathy (HR, 0.79; 95%CI, 0.66 to 0.93; P=0.006). However, the type of glucose control had no significant effect on major macrovascular events (HR with intensive control, 0.94; 95% CI, 0.84 to 1.06; P=0.32), death from cardiovascular causes (HR with intensive control, 0.88; 95% CI, 0.74 to 1.04; P=0.12), or death from any cause (HR with intensive control, 0.93; 95% CI, 0.83 to 1.06; P=0.28), although the 12% decrease in cardiovascular death is worth noting given the significant 35% increase in ACCORD.

_ VADT
This trial¹⁵ randomized 1791 predominantly male military veterans (mean age, 60.4 years) to intensive or standard glucose control, achieving about a 1.5% HbA_1c difference over a median duration of 5.6 years. There was no significant difference between the two groups in any component of the primary outcome or in the rate of death from any cause—a finding unremarkable in that the trial was essentially underpowered (both in terms of numbers of subjects and duration). There was, however, a lessening of progression of albuminuria (P=0.01).

Table I. Relative risk reduction with sulfonylurea/insulin after 10
years’ follow-up in UKPDS.

_ UKPDS Post-Trial Monitoring
UKPDS monitored its patients for outcome after the study for a median of ten years— with biochemical indices for five of these. The study, published as UKPDS-PTM (UKPDS Post- Trial Monitoring),¹⁶ examined whether the effects of being in the intensively controlled group would dissipate with time. After the trial, everyone was given advice about intensive control. The 3277 patients remaining in the trial were asked to attend annual UKPDS clinics for 5 years, but no attempts were made to maintain their previously assigned therapies. Annual questionnaires were used to survey patients who were unable to attend the clinics, and all patients in years 6 to 10 were assessed using questionnaires. In the years that followed their inclusion in the trial, no glycemic differences were strived for, nor seen. The null hypothesis was that with no differences in treatment, the differences in outcome would be lost. But far from there being a diminution of the glycemic trial effect over the ten years, the lower incidence of pathological effects was maintained, and with the advent of more events the statistical probabilities of error declined. In the sulfonylurea-insulin group, relative reductions in risk persisted at 10 years for any diabetes-related end point (9%, P=0.04) and microvascular disease (24%, P=0.001), and risk reductions for myocardial infarction (15%, P=0.01) and death from any cause (13%, P=0.007) emerged over time as more events occurred (Table I).¹⁶ In the metformin group, significant risk reductions persisted for any diabetes-related end point (21%, P=0.01), myocardial infarction (33%, P=0.005), and death from any cause (27%, P=0.002). So, despite there being no glycemic differences, a continued reduction in microvascular risk and emergent risk reductions for myocardial infarction and death from any cause were observed during the 10 years of posttrial follow-up.

Evolution or revolution?

It has taken many years for a clear picture to emerge from the glycemic trials, and our understanding has evolved. Nevertheless, looking back on what we knew in 1997 and what we know now, the change in knowledge is a revolution. How do all the trials lock together into one cohesive pattern? The lessons learnt are summarized in Table II (page 26). Interestingly, it turns out that UKPDS⁷ and UKPDS-PTM¹⁶ hold the important core of what we need to know; the other trials color in the details. UKPDS established beyond any reasonable doubt that outcomes in those whose blood pressure and glycemic control were near normal were better, and it provided the major evidence base for the use of metformin.¹⁷ It laid to rest the old canard that it was somehow the “diabetes” causing the problems—perhaps by insulin resistance or some other arcane process. UKPDS-PTM¹⁶ went further. It established that the first ten years of treatment were crucial to outcome—that there was a glycemic legacy effect. There has been no suggestion from the authors that this was a “metabolic memory” effect— a term used by the Diabetes Control and Complications Trial (DCCT). The effects are most likely to be simply related to atherosclerosis. Higher blood glucose over ten years leads to more vascular damage, and the effect is permanent.

ACCORD taught us all a sharp lesson. Taking high-risk patients and imposing very tight glycemic control led to the perverse outcome of greater mortality in the intensive group. This shows that we need to use clinical care in those in whom hypoglycemia (the major suspect for the adverse outcome) may pose a problem. These patients were identified as general groups in the trial by the presence of preexisting high HbA_1c or by having been diagnosed at a younger age. Extra caution is needed in those in whom established pathology can be detected. The effects shown in the ADVANCE trial,¹⁸ whose duration of diabetes was similar to that of ACCORD (8 years), were mainly attributable to a 21% relative reduction in nephropathy, but unlike the ACCORD trial, there was no indication that achieving the target of 6.5% gradually over four years had any detrimental cardiovascular effects nor did it cause increased mortality. How can one explain the differences between these outcomes? ADVANCE used gliclazide (mainly gliclazide modified release) and metformin to lower glycemia in the intensive control group, which contrasts with ACCORD where rosiglitazone was used extensively (in both arms), as was insulin and sulfonylurea in combination. In ACCORD, glycemic targets were aggressively pursued and control of glycemia over time did not deteriorate (Figure 2).¹³ By contrast, in ADVANCE, the target HbA_1c of below 6.5% was achieved progressively over a period of 4 years—a much slower rate than that of the ACCORD patients, and the totality of the updated mean difference was much less. So, the differences between the two trials were a marked difference in the rate of achievement of target glycemia, a very high hypoglycemia rate in ACCORD (nearly 4 times greater than the rate in ADVANCE), and a clear difference in the choice of agents for the two trials. ACCORD suggests that intensive glycemic control achieved fast and late in diabetes using multiple agents might not be wise. ADVANCE suggests that the achievement of such targets over a period of several years should not be contraindicated and that there may be gains to be achieved in the prevention of renal disease. ACCORD teaches us that very sudden changes in glycemia in the elderly may do more harm than good, while ADVANCE suggests that even if cardiovascular disease cannot be diminished in the short term, one can at least gain from less renal pathology in the long term.

Table II. Lessons learnt from trials of glycemia in diabetes.

Figure 2. Glucose control at baseline and during follow-up in the ACCORD study.

What agents should one use? The peroxisome proliferator-activated receptor γ (PPAR-γ) agonist pioglitazone has emerged as being efficacious in the light of the PROACTIVE trial, but rosiglitazone still has to prove its effectiveness on cardiovascular outcomes. The evidence tends to point in the other direction. And what about sulfonylureas? Despite debates dating back to the days of UGDP and the fear that â-cell failure might be affected, sulfonylureas have continued to stand the test of time. There were no detrimental signals from UKPDS or from UKPDS-PTM,¹⁶ and ADVANCE shows that gliclazide modified release can be an effective late intervention. And what about insulin? UKPDS used insulin as one of its randomized interventions, and there was no suggestion that this policy was unsafe or had detrimental outcomes.

What about hypoglycemia? Here, I think we are closer to real answers. ACCORD had a very high rate of hypoglycemia, and there are many rational reasons to suppose this to be dangerous in the elderly. So, we need to take new stock of this as a real life-threatening risk as well as a threat to quality of life. Hypoglycemia in the elderly threatens events related to falls, aspiration pneumonia, accidents, forgetfulness, and other significant risks.

The trials reported here have focused on glycemic control, but type 2 diabetes cannot simply be treated as a disease of abnormal glucose. The trial data are strongly indicative that lipids and blood pressure^19,20 should be treated in parallel, and the Steno 2^21,22 trial—a trial of multiple intervention care-packages— suggests real benefits from this approach.

Conclusions

All the trial data suggest that hyperglycemia is a risk for cardiovascular disease and should be lowered if possible. The targets for glycemia are an HbA_1c lower than 7.5%, and this may be nearer 6.5% if achieved slowly and without dangerous hypoglycemia. Early intervention is clearly beneficial. Late intervention to strict targets requires a careful incremental approach. _

References
1. The Global Burden. IDF Diabetes Atlas. 4th ed. International Diabetes Federation: Brussels, Belgium; 2009:21-27.
2. Moss SE, Klein R, Klein BE. Cause-specific mortality in a population-based study of diabetes. Am J Public Health. 1991;81:1158-1162.
3. Meinert CL, Knatterud GL, Prout TE, Klimt CR. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. II. Mortality results. Diabetes. 1970;19(suppl):789-830.
4. Leibel B. An analysis of the University Group Diabetes Study Program: data results and conslusions. Can Med Assoc J. 1971;105:292-294.
5. Idris I, Donnelly R. Sodium-glucose co-transporter-2 inhibitors: an emerging new class of oral antidiabetic inhibitors. Diabetes Obesity Metabol. 2009;11:79-88.
6. UKPDS Group. UK Prospective Diabetes Study VIII: Study design, progress and performance. Diabetologia. 1991;34:877-890.
7. UKPDS Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.
8. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascu- lar and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405-412.
9. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366:1279-1289.
10. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457-2471.
11. Diamond GA, Bax L, Kaul S. Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death. Ann Intern Med. 2007;147:578- 581.
12. Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet. 2009;373:2125- 2135.
13. Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545-2559.
14. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358: 2560-2572.
15. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129-139.
16. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359: 1577-1589.
17. UKPDS Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-865.
18. Patel A, MacMahon S, Chalmers J, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370:829-840.
19. UKPDS Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854-865.
20. Adler AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ. 2000;321:412-419.
21. Gaede P, Valentine WJ, Palmer AJ, et al. Cost-effectiveness of intensified versus conventional multifactorial intervention in type 2 diabetes: results and projections from the Steno-2 study. Diabetes Care. 2008;31:1510-1515.
22. Gaede P, Pedersen O. Multi-targeted and aggressive treatment of patients with type 2 diabetes at high risk: what are we waiting for? Horm Metab Res. 2005;37(suppl 1):76-82.

Keywords: trials; type 2 diabetes; cardiovascular disease; gliclazide; insulin; rosiglitazone; pioglitazone; ADVANCE; ACCORD; UGDP; UKPDS; PROACTIVE; RECORD; VADT; Steno 2

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Antonio CERIELLO, MD, PhD
Insititut d’Investigacions Biomèdiques August Pi
i Sunyer (IDIBAPS)
Barcelona, SPAIN

Evidence implicates hyperglycemia-derived oxygen free radicals as mediators of diabetic complications. However, intervention studies with classic antioxidants, such as vitamin E, have failed to demonstrate any beneficial effect. Recent studies demonstrate that a single hyperglycemiainduced process of superoxide overproduction by the mitochondrial electron- transport chain seems to be the first and key event in the activation of all the other pathways involved in the pathogenesis of diabetic complications. These include increased polyol pathway flux, advanced glycation end product formation, and hexosamine pathway flux, and activation of protein kinase C. These processes result in acute endothelial dysfunction in diabetic blood vessels that, convincingly, also contributes to the development of diabetic complications. While waiting for more focused tools, we will have to use other options, particularly the oral hypoglycemic agent gliclazide, which reduces glycemia while exerting an antioxidant effect.

In the last few decades the occurrence of type 2 diabetes mellitus has rapidly increased internationally, and it has been estimated that the number of diabetic patients will more than double within 15 years.¹ As type 2 diabetes is mainly characterized by the development of increased cardiovascular disease (CVD) morbidity and mortality, it has been suggested that diabetes could be considered a CVD.¹ However, diabetes is also characterized by dramatic microangiopathic complications, such as retinopathy, nephropathy, and neuropathy.¹

Recent evidence suggests that glucose overload may damage cells through oxidative stress.² This is currently the basis of the “unifying hypothesis,” in which hyperglycemia- induced oxidative stress may account for the pathogenesis of all diabetic complications.²

The central role of oxidative stress in the pathogenesis of diabetic complications

It has been suggested that four key biochemical changes induced by hyperglycemia—( i) increased flux through the polyol pathway (in which glucose is reduced to sorbitol, lowering levels of both reduced nicotinamide adenine dinucleotide phosphate [NADPH] and reduced glutathione); (ii) increased formation of advanced glycation end products (AGEs); (iii) activation of protein kinase C (PKC) (with effects ranging from vascular occlusion to expression of proinflammatory genes); and (iv) in- creased shunting of excess glucose through the hexosamine pathway (mediating increased transcription of genes for inflammatory cytokines)— are all activated by a common mechanism: overproduction of superoxide radicals.²

Excess plasma glucose drives excess production of electron donors (mainly NADH/H⁺) from the tricarboxylic acid cycle; in turn, this surfeit results in the transfer of single electrons (instead of the usual electron pairs) to oxygen, producing superoxide radicals and other reactive oxygen species (instead of the usual end product, H₂O). The superoxide anion itself inhibits the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase, and consequently, glucose and glycolytic intermediates spill into the polyol and hexosamine pathways, as well as additional pathways that culminate in PKC activation and intracellular AGE formation (Figure 1).

Figure 1. Potential mechanism by which hyperglycemia-induced mitochondrial superoxide overproduction activates four pathways of hyperglycemic damage.

However, superoxide overproduction is also accompanied by increased nitric oxide (NO) generation, due to the uncoupled state of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS),³ a phenomenon favoring the formation of the strong oxidant peroxynitrite, which in turn damages DNA.³ DNA damage is an obligatory stimulus for the activation of the nuclear enzyme poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP).⁴ PARP activation in turn depletes the intracellular concentration of its substrate NAD+, slowing the rate of glycolysis, electron transport, and adenosine triphosphate formation, and producing ADP-ribosylation of the glyceraldehyde-3-phosphate dehydrogenase.⁴ These processes result in endothelial dysfunction (Figure 2).

These pathways have been confirmed by at least one study on the perfusion for 2 hours of isolated rat hearts with solutions of 11.1 mmol/L glucose, 33.3 mmol/L glucose, or 33.1 mmol/L glucose plus glutathione. In the hearts perfused with high glucose concentrations, coronary perfusion pressure increased significantly; there was a 40% increase in NO levels and an upregulation of iNOS, but a 300% increase in the production of superoxide species; nitrotyrosine and cardiac cell apoptosis also increased significantly.⁵ All these effects were substantially prevented by glutathione, which effectively removes reactive oxygen species, including peroxynitrite.⁵

However, more recently, evidence from in vitro studies suggests that marked fluctuations in glucose levels, as seen in diabetic patients, have consequences that are even more deleterious than those of continuous high glucose levels, and that oxidative stress is convincingly involved. For example, in cultures of human umbilical vein endothelial cells, levels of nitrotyrosine (a marker of oxidative stress), intercellular adhesion molecule 1 (ICAM-1), vascular cellular adhesion molecule 1, E-selectin, interleukin 6 (IL-6), and 8-hydroxydeoxyguanosine (a marker of oxidative damage of DNA) all increased after incubation in a medium containing 20 mmol glucose compared with incubation in a 5 mmol glucose medium, but alternating the two media caused even greater increases.^6-8 In addition, intermittent hyperglycemic conditions increased rates of cellular apoptosis, and stimulated the expression of caspase 3 (a proapoptotic protein), but decreased Bcl2 (an antiapoptotic protein). These effects were abolished by adding superoxide dismutase (SOD), which scavenges free radicals, or inhibitors of the mitochondrial electron-transport chain, suggesting that overproduction of free radicals in the mitochondria mediates the apoptotic effects of increased glucose concentrations and fluctuations.⁹

Figure 2. Intracellular hyperglycemia induces overproduction of superoxide
at the mitochondrial level.

Oxidative stress in diabetes: in vivo evidence

The response-to-injury hypothesis of atherosclerosis states that the initial damage affects the arterial endothelium, in terms of endothelial dysfunction. Notably, today’s evidence confirms that endothelial dysfunction, associated with oxidative stress, predicts CVD.¹⁰ Indeed, studies show that high glucose concentrations induce endothelial dysfunction in diabetic as well as normal subjects.3 The role of free radical generation in producing hyperglycemia-dependent endothelial dysfunction is also suggested by studies showing that the acute effects of hyperglycemia are counterbalanced by antioxidants.^11,12

Numerous studies have also noted the effect of hyperglycemia- induced oxidative stress on inflammation. A study in which insulin secretion was blocked, and subjects were maintained at plasma glucose levels of 15 mmol/L for 5 hours, found that levels of IL-6, tumor necrosis factor α (TNF-α), and the proinflammatory cytokine IL-18 rose significantly and returned to baseline within 3 hours in the control group.¹³ However, patients with impaired glucose tolerance had significantly higher TNF-α and IL-6 levels at baseline, and cytokine levels reached substantially higher peaks and stayed elevated for considerably longer than in the control subjects.¹³ All changes in plasma cytokine levels were abolished by infusion of the antioxidant glutathione, consistent with the hypothesis that hyperglycemia, especially in the form of spikes, is linked to immune activation via an oxidative mechanism.¹³ Another study matching diabetic patients and healthy controls found increases in circulating ICAM-1 in both groups during an oral glucose tolerance test (OGTT); these increases were also abolished by glutathione.¹⁴ Glutathione administered without a glucose load decreased circulating ICAM-1 levels in the diabetic group, but not in the control group, again suggesting that hyperglycemia increases ICAM-1 levels via an oxidative mechanism.¹⁴

More direct evidence for the central role of oxidative stress is derived from clinical studies that measured markers. For example, among 20 diabetic patients, either a low-carbohydrate or a high-carbohydrate meal increased levels of plasma glucose, insulin, triglycerides, and malondialdehyde (a marker for lipid peroxidation), and decreased nonsterified fatty acids and the total radical-trapping antioxidant parameter (TRAP), a global measure of antioxidant capacity in the plasma.¹⁵ However, the high-carbohydrate meal (designed to produce higher postprandial glucose levels) increased glucose and malondialdehyde more, decreased TRAP significantly more, and rendered low-density lipoprotein more susceptible to oxidation than the low-carbohydrate meal.¹⁵ The decrease in TRAP highlights the fact that oxidative stress may also ensue from the failure of normal antioxidant defenses: the same group found that during the OGTT, TRAP was reduced from baseline in both well-controlled, nonsmoking diabetic subjects and healthy age-matched subjects, as were levels of protein-bound thiol (-SH) groups, vitamins C and E, and uric acid.¹⁵

As aforementioned, a superoxide anion combines with NO to produce a peroxynitrite ion; this species is capable of peroxidating lipoproteins and damaging DNA, which then activates the nuclear enzyme poly(ADP-ribose) polymerase, depleting intracellular NAD+ and (among other effects) causing acute endothelial dysfunction.3 In one study involving 12 healthy subjects, infusion of L-arginine (to supply NO) reversed hyperglycemia-induced increases in systolic and diastolic blood pressure, heart rate, plasma catecholamine levels, ADPinduced platelet aggregation, and blood viscosity.¹⁶ However, infusing NG-monomethyl-L-arginine, which inhibits the synthesis of endogenous NO, produced effects that were very similar to those produced by hyperglycemia. Thus, decreased NO availability may be one mechanism by which hyperglycemia induces hemodynamic and rheological changes in blood.¹⁶ It has been shown, however, that unlike normal con- trols, patients with diabetes have significantly elevated fasting nitrotyrosine levels, as well as postprandial increases after eating a standard mixed meal; the effect was significantly normalized by insulin aspart (which targets postprandial glucose), but not by regular insulin.¹⁷

Finally, consistent with the recent emerging role of glucose fluctuations, a new study confirms that in type 2 diabetes, diurnal glucose fluctuations are the most powerful predictors of oxidative stress generation.¹⁸

New perspectives: oxidative stress and hyperglycemia- induced “metabolic memory”

Large randomized studies have established that early intensive glycemic control reduces the risk of diabetic complications, both micro- and macrovascular.¹⁹ Moreover, epidemiological and prospective data support the idea that early metabolic control has a long-term influence on clinical outcomes.¹⁹ This phenomenon has recently been defined as “metabolic memory.”¹⁹ Potential mechanisms for propagating this “memory” are the nonenzymatic glycation of cellular proteins and lipids and an excess of cellular reactive oxygen and nitrogen species, in particular those that originated at the level of glycated mitochondrial proteins, perhaps acting in concert with one another to maintain stress signaling.¹⁹

_ Experimental evidence supporting the concept of “metabolic memory” and its possible link with oxidative stress
Several years ago, there were preliminary reports of the possibility that “hyperglycemic memory” for hyperproduction of fibronectin and collagen in endothelial cells persists after glucose normalization.20 Using the same design, ie, 14 days in high concentration glucose followed by 7 days of culture in normal concentration glucose, it has been shown that the overproduction of free radicals in endothelial cells persists after normalization of glucose concentration, and this is accompanied by a prolongation of the induction of PKC-β, NAD(P)H oxidase, Bax, collagen, and fibronectin, in addition to 3-nitrotyrosine.²¹ This suggests that oxidative stress may be involved in the “metabolic memory” effect.

The effect of reinstitution of good glucose control on hyperglycemia- induced increased oxidative stress and nitrative stress has also been previously evaluated in the retina of rats maintained with poor glucose control before initiation of good control.²² In diabetic rats, 2 or 6 months of poor control (glycated hemoglobin [HbA_1c] >11.0%) was followed by 7months of good control (HbA_1c <5.5%). Reinstitution of good control after 2 months of poor control inhibited elevations in retinal lipid peroxide and NO levels by approximately 50%, but failed to have any beneficial effects on nitrotyrosine formation. However, reversal of hyperglycemia after 6 months of poor control had no significant effect on retinal oxidative stress and NO levels. In the same rats, iNOS expression and nitrotyrosine levels remained elevated by >80% compared with normal rats or rats with good glucose control for the duration.²² In a similar study, caspase 3 activity in diabetic rats with poor control for 13 months was higher than in normal rats.²³ Reinstitution of good glycemic control after 2 months of poor control partially normalized the hyperglycemia-induced activation of caspase 3 (to 140% of normal values), while reinstitution of good control after 6 months of poor control had no significant effect on the activation of caspase 3. In the same study, nuclear factor-κB (NFκB) activity was 2.5-fold higher in diabetic rats with poor glucose control than in normal rats.

Reinstitution of good control after 2 months of poor control partially reversed this increase, but good control after 6months of poor control had no effect. Initiation of good control soon after induction of diabetes in rats prevented activation of retinal caspase 3 and NFκB.²³ Similar results are available for the kidney. Diabetic rats were maintained with good glycemic control (HbA_1c = 5%) soon, or 6 months, after induction of diabetes, and were sacrificed after 13 months.²⁴ For rats in which good control was initiated soon after the induction of diabetes, oxidative stress (as measured by levels of lipid peroxides, 8- hydroxy-2´-deoxyguanosine, and reduced glutathione) and NO levels in urine and renal cortex were no different from those observed in normal control rats, but when the reinstitution of good control was delayed for 6 months after induction of diabetes, oxidative stress and NO remained elevated in both urine and renal cortex.²⁴ These data suggest that hyperglycemia- induced oxidative stress and NO, as well as activation of apoptosis and NFκB, can be prevented if good glycemic control is initiated very early, but are not easily reversed if poor control is maintained for longer durations. Therefore, these findings suggest the persistence of hyperglycemia-induced damage in such organs, even after glycemia normalization.

However, if excess reactive species are central to the development of hyperglycemia-related diabetic complications, could this excess explain the persistence of the risk of complications even when hyperglycemia is reduced or normalized?

The above reported studies suggest that long-lasting effects of hyperglycemia result in increased oxidative stress, while inhibiting oxidative stress has preliminarily been shown to reverse these effects.²¹ Mitochondrial overproduction of superoxide in hyperglycemia has been suggested as the “unifying hypothesis” for the development of diabetic complications.² Therefore, it is reasonable to assume that mitochondria are also important players in propagating “metabolic memory.” Chronic hyperglycemia is thought to alter mitochondrial function through glycation of mitochondrial proteins.²⁵ Levels of methylglyoxal, a highly-reactive alpha-dicarbonil byproduct of glycolysis, increase in diabetes.²⁶ Methylglyoxal readily reacts with arginine, lysine, and sulfhydryl groups of proteins,²⁶ in addition to nucleic acids,²⁶ inducing the formation of a variety of structurally identified AGEs in both target cells and plasma.²⁶ Methylglyoxal has an inhibitory effect on mitochondrial respiration and methylglyoxal-induced modifications are targeted to specific mitochondrial proteins.²⁶ These premises are important because a recent study has described, for the first time, a direct relationship between formation of intracellular AGEs on mitochondrial proteins and the decline in mitochondrial function and excess formation of reactive species.²⁵ Mitochondrial respiratory chain proteins that underwent glycation were prone to produce more superoxide, independent of the level of hyperglycemia. The glycation of mitochondrial proteins may be a contributing explanation for the phenomenon of “metabolic memory.” The glycation of mitochondrial proteins that overproduce free radicals, independent of actual glycemia, can also lead to a catastrophic cycle of mitochondrial DNA damage, as well as functional decline, cellular injury, further oxygen radical generation, and the continued activation of pathways involved in the pathogenesis of diabetic complications.²⁷ Furthermore, mitochondrial proteins become damaged or posttranslationally modified as a consequence of a major change in a cell’s redox status.²⁷ This may affect mitochondrially destined proteins that are imported into the mitochondrial outer membrane, inner membrane, or matrix space via specific import machinery transport components.²⁷

In other words, it may be postulated that the cascade of events in “metabolic memory” is the same as that proposed by Brownlee²; the source of superoxide is still the mitochondria, but, in addition, the production of reactive species is unrelated to the presence of hyperglycemia; it depends on the level of glycation of mitochondrial proteins.

How could oxidative stress be reduced with pharmacological intervention?

Antioxidant therapy may be of great value in diabetic patients. However, the classic antioxidants, like vitamins E and C, do not seem to be helpful. New insights into the mechanisms leading to the generation of oxidative stress indiabetes are now available. Presumably, these findings will lead to the discovery and evaluation of new antioxidant molecules, such as superoxide dismutase (SOD) and catalase mimetics, that may hopefully inhibit the mechanism leading to diabetic complications at an early stage. While waiting for these specific new compounds, it is reasonable to suggest that substances already available, such as statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers, should be used for their effectiveness as “causal and preventive” antioxidants (for an up-to-date review, see reference 28).

The availability of compounds that simultaneously decrease hyperglycemia, restore insulin secretion, and inhibit oxidative stress produced by high glucose is an interesting therapeutic prospect for the prevention of vascular complications of diabetes. Gliclazide, an oral hypoglycemic agent that belongs to the sulfonylurea class, has been demonstrated to be effective and safe in numerous clinical trials and in clinical practice. Several studies have demonstrated, both in vitro and in vivo, that gliclazide shows antioxidative potential, independent of its hyperglycemia-lowering effect.²⁹ Gliclazide is a general free radical scavenger in vitro—in contrast with glibenclamide, which fails to produce any effect below a concentration of 25 ìg/mL (gliclazide induced strong concentration-dependent inhibition of free radical generation at therapeutic concentrations).²⁹ Jennings et al confirmed these effects of gliclazide on oxidative stress in clinical conditions. They found that gliclazide-treated type 2 patients with retinopathy had a highly significant and sustained decrease in peroxidized lipids and an increase in erythrocyte SOD activity.³⁰ Interestingly, glucose control did not differ between therapeutic groups, which supports the hypothesis that the effect results from the molecule gliclazide itself, rather than from a general improvement in metabolic control.

The antioxidative property of gliclazide convincingly impacts the vascular system in diabetes. Fava et al studied both the antioxidative potential of gliclazide in vivo and its effect on vascular reactivity.³¹ In this experiment, blood glucose control remained unchanged from baseline and similar in both groups, as patients were already being treated, which excludes any glucose-related “bias effect.” Thirty type 2 diabetic patients received glibenclamide or gliclazide in a 12-week, randomized, observer-blinded, parallel study. Blood pressure responses to an intravenous bolus of L-arginine were measured pre- and posttreatment. Gliclazide, but not glibenclamide, significantly reduced systolic and diastolic blood pressure in response to intravenous L-arginine. This provided the first demonstration that gliclazide significantly enhances NO-mediated vasodilatation and thus improves vascular reactivity in type 2 diabetic patients.

Finally, and this could be of great relevance, in order to avoid the development of diabetic complications, it has been shown that gliclazide can block the “metabolic memory” effect.³² In my opinion, all these effects³³ may contribute to explaining why gliclazide prevented nephropathy in the Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE).³⁴ Conclusions

Our understanding of the molecular pathways activated inside the cell by hyperglycemia is growing, and evidence about the involvement of oxidative stress in the development of diabetic complications is becoming abundant, making the “unifying hypothesis” more persuasive every day. Against this background, the finding of unexpected protective effects of drugs intended for different uses or different pathologies has given us an intriguing opportunity to elucidate their underlying mechanisms, to tune up these “weapons” to be more and more effective, and to confirm the hypothesis formulated. These goals are becoming increasingly important due to the massive spread in diabetic pathology that is expected to occur in the coming years. _

References
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2. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414:813-820.
3. Ceriello A. New insights on oxidative stress and diabetic complications may lead to a “causal” antioxidant therapy. Diabetes Care. 2003;26:1589-1596.
4. Garcia Soriano F, Virag L, Jagtap P, et al. Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation. Nature Med. 2001;7:108-113.
5. Ceriello A, Quagliaro L, D’Amico M, et al. Acute hyperglycemia induces nitrotyrosine formation and apoptosis in perfused heart from rat. Diabetes. 2002; 51:1076-1082.
6. Piconi L, Quagliaro L, Da Ros R, et al. Intermittent high glucose enhances ICAM-1, VCAM-1, E-selectin and interleukin-6 expression in human umbilical endothelial cells in culture: the role of poly(ADP-ribose) polymerase. J Thromb Haemost. 2004;2:1453-1459.
7. Quagliaro L, Piconi L, Assaloni R, Martinelli L, Motz E, Ceriello A. Intermittent high glucose enhances apoptosis related to oxidative stress in human umbilical vein endothelial cells: the role of PKC and NAD(P)H-oxidase activation. Diabetes. 2003;52:2795-2804.
8. Quagliaro L, Piconi L, Assaloni R, et al. Intermittent high glucose enhances ICAM-1, VCAM-1 and E-selectin expression in human umbilical vein endothelial cells in culture: the distinct role of protein kinase C and mitochondrial superoxide production. Atherosclerosis. 2005;183:259-267.
9. Quagliaro L, Piconi L, Assaloni R, et al. Constant and intermittent high glucose enhances endothelial cell apoptosis through mitochondrial superoxide overproduction. Diabetes Metab Res Rev. 2006;22:198-203.
10. Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation. 2001;104:2673-2678.
11. Marfella R, Verrazzo G, Acampora R, et al. Glutathione reverses systemic hemodynamic changes by acute hyperglycemia in healthy subjects. Am J Physiol. 1995;268:E1167-E1173.
12. Ting HH, Timimi FK, Boles KS, Creager SJ, Ganz P, Creager MA. Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. J Clin Investig. 1996;97:22-28.
13. Esposito K, Nappo F, Marfella R, et al. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation. 2002;106:2067-2072.
14. Ceriello A, Falleti E, Motz E, et al. Hyperglycemia-induced circulating ICAM-1 increase in diabetes mellitus: the possible role of oxidative stress. Horm Metab Res. 1998;30:146-149.
15. Ceriello A, Bortolotti N, Motz E, et al. Meal-induced oxidative stress and lowdensity lipoprotein oxidation in diabetes: the possible role of hyperglycemia. Metabolism. 1999;48:1503-1508.
16. Giugliano D, Marfella R, Coppola L, et al. Vascular effects of acute hyperglycemia in humans are reversed by L-arginine. Evidence for reduced availability of nitric oxide during hyperglycemia. Circulation. 1997;95:1783-1790.
17. Ceriello A, Quagliaro L, Catone B, et al. Role of hyperglycemia in nitrotyrosine postprandial generation. Diabetes Care. 2002;25:1439-1443.
18. Ceriello A, Esposito K, Piconi L, et al. Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients. Diabetes. 2008;57:1349-1354.
19. Ceriello A, Ihnat MA, Thorpe JE. The “metabolic memory”: is more than just tight glucose control necessary to prevent diabetic complications? J Clin Endocrinol Metab. 2009;94:410-415.
20. Roy S, Sala R, Cagliero E, Lorenzi M. Overexpression of fibronectin induced by diabetes or high glucose: phenomenon with a memory. Proc Natl Acad Sci U S A. 1990;87:404-408.
21. Ihnat MA, Thorpe JE, Kamat CD, et al. Reactive oxygen species mediate a cellular ‘memory’ of high glucose stress signalling. Diabetologia. 2007;50:1523-1531.
22. Kowluru RA. Effect of reinstitution of good glycemic control on retinal oxidative stress and nitrative stress in diabetic rats. Diabetes. 2003;52:818-823.
23. Kowluru RA, Chakrabarti S, Chen S. Re-institution of good metabolic control in diabetic rats and activation of caspase-3 and nuclear transcriptional factor (NF-kappaB) in the retina. Acta Diabetol. 2004;41:194-199.
24. Kowluru RA, Abbas SN, Odenbach S. Reversal of hyperglycemia and diabetic nephropathy: effect of reinstitution of good metabolic control on oxidative stress in the kidney of diabetic rats. J Diabetes Complications. 2004;18:282-288.
25. RoscaMG,Mustata TG, KinterMT, et al. Glycation ofmitochondrial proteins from diabetic rat kidney is associated with excess superoxide formation. Am J Physiol Renal Physiol. 2005;289:F420-F430.
26. Yan SF, Ramasamy R, Schmidt AM. Mechanisms of disease: advanced glycation end-products and their receptor in inflammation and diabetes complications. Nat Clin Pract Endocrinol Metab. 2008;4:285-293.
27. Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial ROS-induced ROS release: an update and review. Biochim Biophys Acta. 2006;1757:509-517.
28. Ceriello A, Testa R. Antioxidant anti-inflammatory treatment in type 2 diabetes. Diabetes Care. 2009;32(suppl 2):S232-S236.
29. Jennings PE, Belch JJF. Free radical scavenging activity of sulfonylureas: a clinical assessment of the effect of gliclazide. Metabolism. 2000;49(S1):23-26.
30. Jennings PE, Scott NA, Saniabadi AR, Belch JJF. Effects of gliclazide on platelet reactivity and free radicals in type II diabetic patients: clinical assessment. Metabolism. 1992;41:36-39.
31. Fava D, Cassone-Faldetta M, Laurenti O, De Luca O, Ghiselli A, De Mattia G. Gliclazide improves anti-oxidant status and nitric oxide-mediated vasodilation in type 2 diabetes. Diabet Med. 2002;19:752-757.
32. Corgnali M, Piconi L, Ihnat M, Ceriello A. Evaluation of gliclazide ability to attenuate the hyperglycaemic ‘memory’ induced by high glucose in isolated human endothelial cells. Diabetes Metab Res Rev. 2008;24:301-309.
33. Ceriello A. Effects of gliclazide beyond metabolic control. Metabolism. 2006; 55(5 suppl 1):S10-S15.
34. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572.

Keywords: hyperglycemia; free radicals; antioxidants; superoxide; pathogenesis; polyol; advanced glycosylation end product; hexosamine pathway

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Erol CERASI,MD, PhD, DHC
Endocrine Services Department of Medicine
Hebrew University Hadassah Medical Centre
Jerusalem, ISRAEL

The idea that type 2 diabetes (T2DM) is mainly due to insulin resistance stems from the 1930s, but became dominating from the 1980s. However, evidence since the 1960s indicates that insulin response to glucose is markedly diminished from the earliest signs of glucose intolerance. Insulin pump treatment induces near-normoglycemia in T2DM with doses similar to type 1 diabetes, indicating that hyperglycemia is caused by lack of insulin, insulin resistance acting as an amplifier. Insulin secretion is genetically controlled. T2DM risk gene polymorphisms hint toward mechanisms of reduced insulin secretion in diabetes-prone subjects, in whominsulin response decreases as the number of diabetic alleles increases. I hypothesize that the genetic background of the β cell determines its adaptation capacity to increased insulin demand imposed by augmented caloric intake and insulin resistance; failure to adapt eventually leads to T2DM. Therefore, I regard the “prediabetic” β cell as a normal cell with limited adaptability, diabetes risk being entirely context-dependent (nutritional load and insulin sensitivity). Once hyperglycemia is established, β cells are exposed to continuous nutrient stimulation, with consequent oxidative and endoplasmic reticulum (ER) stresses. The result is increasing functional deficiencies and β-cell apoptosis, hence reduced β-cellmass. Some of itsmechanisms are discussed. An intriguing as yet unanswered question is whether the mechanisms of β-cell deficit in the diabetic environment operate before hyperglycemia in overfed, insulin-resistant subjects. Therapeutic agents preventing β-cell oxidative and ER stress could stop the progression and perhaps initiation of T2DM.

The formal separation of type 1 diabetes as an autoimmune entity is of relatively recent date¹; nevertheless, the heterogeneity of diabetes, as well as the fact that for some patients insulin treatment is a lifesaving procedure while others may more or less control their metabolic state with dietary or pharmacological means, has been known to clinicians and clinical investigators since long ago. As insulin became more widely used it also appeared that in many patients whom today we identify as typical type 2 diabetics, achieving metabolic control with insulin treatment was difficult, sometimes impossible. Thus, several decades before the insulin receptor and its signaling pathways were identified, an astute clinician such as H. P. Himsworth could write “…I would suggest the possibility of the existence of a type of diabetes due not to diminished secretion of insulin by the pancreas, but to a greater or less impairment of the organism’s susceptibility to insulin.”^2,3 In short, the idea that diabetes may be the result of insulin resistance is not new. Indeed, the presence of obesity in the vast majority of patients with type 2 diabetes (T2DM) makes it a reasonable assumption that some degree of insulin resistance must exist in this disorder.

The striking advancements over the past three decades in the field of insulin action, including the detailed understanding of the molecular biology of the insulin receptor and its signaling pathways as well as of the regulation of glucose transporters, have naturally further attracted the attention of investigators to insulin resistance as a main pathophysiological factor in type 2 diabetes, sometimes presented as the sole factor. Thus, as recently as 2000, the Journal of Clinical Investigation stressed this by publishing a “Perspective” series entitled On diabetes: insulin resistance.⁴ Yet, many investigators demonstrated as soon as insulin immunoassays became available in the early 1960s that the insulin response to a glucose challenge is markedly reduced in type 2 diabetics, including in normoglycemic subjects with glucose intolerance (IGT) only.^5-9 The adoption of dogmatic, monolithic views by many investigators of both “camps” did not facilitate the development of open-minded approaches to analyze the etiopathology of diabetes in its full physiological context, notwithstanding some balanced views^10-12 pointing to the fact that the biology of type 2 diabetes is not simple, and that pure β-cell deficit or exclusive insulin resistance are rare events since in fact these two factors are interlinked, as would be expected from any closed-loop feedback regulatory system.

Insulin resistance, plasma insulin levels, and β-cell function

The variability of the insulin response to glucose as well as that of the sensitivity to insulin is remarkably large in the normal population.13-15 he obese, while insulin sensitivity is reduced and insulin response is augmented, variation is as wide, with considerable overlap with the levels of lean subjects. Thus, there exist substantial numbers of subjects with either a markedly low insulin response or a low sensitivity to insulin who nevertheless retain normal glucose tolerance. Indeed, at least 2/3 of obese subjects never develop IGT or type 2 diabetes; yet they are insulin resistant and hyperinsulinemic. In type 2 diabetic patients, except in its very severe forms, both fasting and postprandial plasma insulin levels are normal or higher than normal. This observation provides the rationale for insulin resistance in diabetes: if blood glucose remains high despite substantial levels of insulin, hormone action must be defective. This is a static view of a highly dynamic regulatory system, confusing cause and effect: what are “substantial” levels of insulin, ie, what degree of hyperinsulinemia is adequate for a given degree of hyperglycemia? Glucose vs insulin dose-response curves have been constructed from acute experiments (eg, see reference 16); however, lacking data on long-term experimentally induced hyperglycemia in normal subjects, how can we determine whether a given plasma insulin value in a chronically hyperglycemic diabetic is higher or lower than normally expected?

Figure 1. Fasting plasma insulin levels in 15 type 2 diabetic patients
prior to and following 6-month treatment with the sulfonylurea
gliclazide. Data calculated from reference 17.

Two examples strikingly demonstrate how lack of consideration for physiological regulation leads to erroneous conclusion. The first relates to fasting insulin concentration. Many investigators, including our group, find that the fasting plasma insulin level in type 2 diabetic patients is higher than normal; however, fasting glucose also is higher: does it contribute to the fasting hyperinsulinemia of the patient? In 15 mildly obese type 2 diabetics treated with the sulfonylurea gliclazide for 6 months we found that, in parallel with the normalization of blood glucose, the initially high fasting plasma insulin levels fell to the range found in weight-matched normoglycemic controls despite the use of the β-cell stimulator gliclazide17; this is illustrated in Figure 1. Thus, fasting insulin is also under the control of ambient blood glucose concentration. The second example relates to the bell-shaped insulin curve often used to describe changes in β-cell function during the fall of glucose tolerance from normal to IGT and T2DM. This is an artefact due to the use of 120-minute plasma insulin values in the oral glucose tolerance test (OGTT): patients with IGT having higher glucose levels throughout the test generate a strong signal for amplifying the secretion of insulin at a time when blood glucose is still high enough to stimulate the β-cell, resulting in a typical late insulin peak. In fact, if earlier (eg, 30 min) time points are chosen, the insulin response to OGTT shows a linear fall from normal via IGT to T2DM.18-20 In short, provided the plasma insulin data are interpreted with full reference to the physiology of regulated insulin secretion, it becomes clear that β-cell responsiveness to glucose is lower than normal in IGT, and even less so in T2DM.

Table I. Effect of continuous subcutaneous insulin infusion (CSII) treatment on fasting and postprandial blood glucose control in moderately obese type 2 diabetic patients (calculated from references 17, 21, and 22; Mean ±SEM).

Figure 2. Schematic illustration of the plasma insulin response to a hyperglycemic clamp, showing the gradual decrease in firstphase as well as second-phase insulin secretion as glucose tolerance deteriorates from normal to IGT and further to mild and advanced diabetes.

The above discussion does not mean that I negate the existence of insulin resistance in type 2 diabetic patients; the scientific literature is replete with data convincingly showing that insulin resistance is part of the pathogenesis of T2DM. Nevertheless, I remain convinced that T2DM is a disorder of insulin deficit, the input of insulin resistance to its pathogenesis increasing with the severity of obesity. To my mind, the best demonstration of the above was achieved in mildly obese type 2 diabetic patients treated with continuous subcutaneous insulin infusion (CSII). In pilot studies in 23 white patients, we could achieve fasting and postprandial normoglycemia with a mean daily insulin dose around 0.6 units per kg body weight.^17,21 Similar results were obtained in a larger group of Chinese patients.²² The amounts of insulin administered through CSII in these studies were not strikingly higher than the doses routinely used in insulin pump–treated type 1 diabetic patients (Table I). Thus, a similar degree of insulin deficit seems to exist in both types of diabetes, which leads me to conclude that insulin resistance in T2DM is not the main factor inducing hyperglycemia.

β-Cell function during the development of type 2 diabetes

The earliest modifications of the insulin response to glucose that can be detected as glucose tolerance starts deviating from normal are the early or first-phase insulin response, and the physiological oscillations of secretion.^5,6,8,23,24 The latter requires numerous blood samplings, and therefore has not gained popularity among clinicians and investigators. In contrast, early insulin response to glucose can be measured during oral or IV glucose tolerance tests; however, glucose clamps allow the most detailed definition of the kinetics of the plasma insulin response to glucose. The first-phase response is markedly reduced in subjects with IGT, and further diminishes as fasting hyperglycemia appears. At these stages of the disease, the later or second-phase insulin response to glucose is normal, but with the progression of the severity of diabetes also this phase collapses. These changes are schematically illustrated in Figure 2.

Low first-phase insulin response is found also in some subjects with normal glucose tolerance.^5,6 Several studies over the past few years have demonstrated that a low insulin response is a predictor of future glucose intolerance and T2DM, both in lean and obese subjects belonging to various ethnic groups.^25-27 In our study, lean and physically active Swedish subjects with normal glucose tolerance were followed for a mean period of 25 years; the only initial parameter that was significantly correlated to later glucose intolerance was first-phase insulin response corrected for insulin sensitivity (disposition index).²⁵ These results are summarized in Table II (page 38).

What is the genetic/molecular basis of the low insulin response in nondiabetic subjects? Extensive studies over 4 decades in family members related or unrelated to diabetic patients, in-cluding in monozygotic twin pairs, have shown that several aspects of the insulin response to glucose in man are under strong genetic control.^28-31 However, it is only now that we are gaining some insight into the possible cellular mechanisms that may be responsible for the decrease of β-cell function in subjects at risk of developing diabetes. Indeed, the numerous whole genome association studies that have been performed over the past decade have identified allelic variants of several genes, mostly involved in β-cell development, function and survival, that collectively participate in the risk of diabetes development. As the number of risk alleles that a subject carries increases, several aspects of β-cell function deteriorate; most pertinently, the insulin response to oral or IV glucose decreases in proportion to the number of risk alleles.^32,33

Table II. Prediction of the 2-hour blood glucose concentration
during OGTT in 269 healthy lean subjects after a mean of 25 years.

By which cellular mechanisms these risk alleles impair insulin secretion is not known. However, recent findings from Gloyn et al suggest that, at least regarding the highest-risk gene, transcription factor 7–like 2 (TCF7L2), the association of insulin granules with the voltage-gated calcium channels in the β may be disturbed, thus reducing the efficiency of the insulin exocytotic machinery.³⁴ stands to reason that within a short space of time, the mechanisms of low insulin response to glucose, which is a strong risk factor for T2DM, will be fully clarified at the molecular level.

Progression of diabetes and deterioration of β-cell function: decrease in cell function or cell mass?

It has been the experience of most clinicians that as the duration of diabetes increases so does the severity of the disease. This old observation has received its scientific approval through the United Kingdom Prospective Diabetes Study (UKPDS): whatever the treatment modality chosen, the level of HbA_1c increases with time (for a review, see reference 35). However, it is also the experience of most clinicians that, whatever the treatment modality chosen, induction of strict normoglycemia throughout the day over a period of years in type 2 diabetics is nearly impossible; therefore, it is not clear whether T2DM is an inherently progressive disorder due to the nature of its pathogenesis, or whether progression is secondary to the unregulated metabolic state which reflects our inability to provide adequate treatment (the latter is my belief, entirely unproven). Whether primary or secondary, the progression of diabetes is paralleled by the progressive decline of β-cell function, as measured by the plasma insulin response to glucose³⁵ (see Figure 2 also). Plasma insulin may decrease either because β-cell function, ie, the function of individual β cells, is reduced, or because the number of β cells declines, ie, β-cell mass is reduced.

_ Is β-cell mass reduced in type 2 diabetes?

There is consensus that some degree of β-cell mass reduction does occur at some stage in T2DM,^36-38 but there is also considerable disagreement as to the extent of the reduction and its significance for diabetes development. Presently the dominating view, most strongly advocated by the Butler group in Los Angeles,³⁷ is that β-cell mass is markedly reduced already at the stage of IGT, a further deficit being apparent in overt diabetes even if treated only by diet. By contrast, studies in Europe^36,38 find considerably less reduction in β-cell mass. It has to be stressed that real β-cell mass was calculated only by Rahier et al,³⁸ while Butler et al³⁷ measured β-cell area, which reflects β-cell mass less adequately. Perhaps more importantly, the Rahier laboratory in Brussels points to the extraordinarily wide range of β-cell masses
both in the diabetic and nondiabetic groups, with the existence of major overlap between the hyperglycemic and normoglycemic subjects. These observations make it difficult to ascribe a definitive role to reduced β-cell mass in the genesis of hyperglycemia. Obviously, it may be argued that the hyperglycemia of the patient should have driven β-cell mass to increase substantially as a compensatory mechanism, which is not observed.

To gain some insight into the dynamics of β-cell mass changes during the development of diabetes, we utilized an animal model of nutrition-dependent type 2 diabetes, the gerbil Psammomys obesus. These animals have an inborn insulin resistance, but retain normal glucose tolerance under caloric restriction; when given a diet with circa 40% higher calories and low fiber content, they rapidly become hyperglycemic.³⁹ Figure 3 shows that as the animals develop hyperglycemia, they rapidly lose pancreatic insulin stores, since the cells are forced to secrete all their insulin granules in the face of the unrelenting hyperglycemic stimulation. Nevertheless, β-cell mass remains normal for a considerable period; it even increases slightly due to increased β-cell proliferation induced by the high glucose levels.³⁹ β-Cell mass collapses only after prolonged diabetes, with severe worsening of the hyperglycemia (so-called end-stage diabetes). Thus in this model, possibly in analogy with European type 2 diabetic patients, from a pathophysiological viewpoint significant β-cell mass reduction occurs only in long-standing and advanced T2DM. In earlier stages, the β-cell deficiency seems to be more of a functional nature. I therefore prefer to use the term “function- al β-cell mass” to denote a globally insufficient insulin delivery situation, until we gain access to in vivo imaging techniques to allow in situ β-cell mass determination in our patients.

Figure 3. The evolution of nutritional diabetes in Psammomys obesus.

Why do β cells die in a diabetic environment?

Extensive work over the past decade has shown that mimicking the diabetic environment in vitro, ie, exposure to high concentrations of glucose and fatty acids over extended periods, causes death of β cells by apoptosis (for a review, see reference 40). Both oxidative stress and endoplasmic reticulum (ER) stress in the β cell, induced by the high nutrient exposure, contribute to initiating programmed cell death. Our laboratory has been interested in &beat;-cell ER stress over the past few years. In β-cells exposed continuously, ie, in a noncyclic manner, to high glucose levels proinsulin biosynthesis is under continuous stimulation; this puts the ER system under high pressure, since proinsulin has to be correctly folded and exported to the Golgi apparatus for processing and further maturation in insulin granules. The ER responds to the increase in proinsulin mRNA translation and chaperone-guided proinsulin folding by what is named the unfolded protein response (UPR), which is an adaptive feedback response aimed at reducing the workload by partially blocking the translation of mRNAs and degrading them, and augmenting chaperones to prevent misfolding of newly formed proteins as well as removing misfolded proteins from the ER. If the load on the ER persists despite these measures, then the UPR activates several mechanisms that end in apoptosis, leading to the removal of the deficient cell (for a short-but-comprehensive overview, see reference 41). We have shown that exposure to chronic high glucose levels activates the inositol-requiring enzyme 1 (IRE-1 ) arm of the UPR both in β-cell lines and in Psammomys obesus islets.⁴² Furthermore, fatty acids (palmitate) and glucose exhibited a high degree of synergism in activating IRE-1 . This eventually leads to activation of c-jun N-terminal kinase (JNK) and increase in -cell apoptosis; by using specific JNK inhibitors we could demonstrate that JNK is indeed responsible for initiating the caspase cascade and β-cell death.⁴² Importantly, the effect of glucose on the IRE-1 cascade is mammalian target of rapamycin (mTOR)-dependent, since it could be inhibited by reducing the activity of mTOR complex 1 (mTORC-1) with rapamycin, thus rescuing cells from glucolipotoxicity-induced death.⁴² This unfortunately does not mean that rapamycin can be used as a therapeutic agent against type 2 diabetes. To our dismay, when we administered rapamycin to diabetic Psammomys obesus, the animals developed even higher hyperglycemia together with extreme lipemia and massive β-cell apoptosis.⁴³ Thus, the in vivo situation is more complex than that observed under well-controlled in vitro experiments. Intensive efforts are ongoing in numerous laboratories to design means for counteracting ER stress (as well as oxidative stress) in cells; these may eventually lead to the generation of new classes of antidiabetic drugs aimed at prolonging the life of the cell, thus preventing the seemingly ineluctable progression of type 2 diabetes.

Conclusions

Is T2DM a disease of insulin deficiency or insulin resistance? Obviously both. Nevertheless, I am comforted in my nearly 50-year-old belief in the primacy of insulin deficiency for the pathogenesis of T2DM by the consensus that has emerged in the last decade over the fact that hyperglycemia is not possible in the absence of β-cell deficiency. Compared to the near-total lack of insulin of the type 1 diabetic, the β-cell deficiency of the type 2 diabetic patient is modest, and therefore would not be sufficient to lead to the full diabetic state in such a high proportion of subjects without additional environmental factors. This is a classic gene-environment interaction. It is a fascinating idea that, had the whole genome association studies been performed immediately after World War II in the undernourished populations of Europe and Asia, none of the polymorphic genes being hotly investigated today would have been found to be associated with type 2 diabetes. Indeed, these polymorphic alleles seem to render the cell somewhat less efficient, ie, place it at the lower end of normal variation in terms of its functional adaptability and resistance to stress; nevertheless, these cells are normal until faced with unreasonable demands. I think too much emphasis is put on insulin resistance; I believe that the greatly augmented caloric intake, ie, the greatly increased nutrient flux in the cell, is the real problem, insulin resistance acting as a potent amplifier. The consequence of this thought is that the risk for an individual to develop T2DM would be inversely correlated with the magnitude of adaptability of his cells and directly correlated with the degree of caloric intake/ insulin resistance to which he would be exposed. Thus, the “stronger” the cell, the greater the degree of obesity that can be tolerated while maintaining normal glucose tolerance. There are cases of lean, insulin-sensitive T2DM, as there are cases of diabetes with severe insulin resistance and extreme hyperinsulinemia. However, these are rare. For the majority of type 2 diabetics, to prevent hyperglycemia and its consequences either food intake has to be reduced drastically, or the cell enforced to cope with the increased workload. Neither seems easy. Almost all research today on the cell in connection with T2DM deals with the cells’ reaction to various stresses, ie, the glucolipotoxicity situation. That this is most relevant to the fate of the cell in the diabetic environment, and therefore to diabetes progression, is clear. A legitimate question does arise, however: Are the various mechanisms of -cell stress discussed above (and in the literature) responsible also for the initiation of hyperglycemia? In other words, is -cell stress a secondary reaction to diabetes (glucolipotoxicity), almost a complication of the disease, or is it the etiopathogenic event that leads to the gradual impairment of glucose homeostasis until glucose intolerance and diabetes appear? This is an important question that awaits its solution through future research. _

References
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4. Saltiel AR. The molecular and physiological basis of insulin resistance: emerging implications for metabolic and cardiovascular disease. J Clin Invest. 2000; 106:163-164.
5. Cerasi E, Luft R. Plasma insulin response to sustained hyperglycaemia induced by glucose infusion in human subjects. Lancet. 1963;282:1359-1361.
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7. Pyke DA, Taylor KW. Glucose tolerance and serum insulin in unaffected identical twins of diabetics. BMJ. 1967;4:21-22.
8. Seltzer HS, Allen EW, Herron AL, Brennan MT. Insulin secretion in response to glycemic stimulus: relation of delayed initial release to carbohydrate intolerance in mild diabetes mellitus. J Clin Invest. 1967;46:323-335.
9. Soeldner JS, Gleason RE, Williams RF, Garcia MJ, Beardwood DM, Marble A. Diminished serum insulin response to glucose in genetic prediabetic males with normal glucose tolerance. Diabetes. 1968;17:17-26.
10. Cerasi E. Insulin deficiency and insulin resistance in the pathogenesis of type 2 diabetes: is a divorce possible? Diabetologia. 1995;38:992-997.
11. Kulkarni RN, Bruning JC, Winnay JN, Postic C, Magnuson MA, Kahn CR. Tissue- specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell. 1999;96:329-339.
12. Cavaghan MK, Ehrman DA, Polonsky KS. Interactions between insulin resistance and insulin secretion in the development of glucose intolerance. J Clin Invest. 2000;106:329-333.
13. Hollenbeck CB, Chen N, Chen Y-DI, Reaven GM. Relationship between the plasma insulin response to oral glucose and insulin-stimulated glucose utilization in normal subjects. Diabetes. 1984;33:460-463.
14. Lillioja S, Mott DM, Spraul M, et al. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians. N Engl J Med. 1993;329:1988-1992.
15. Kahn SE, Prigeon RL, McCulloch DK, et al. Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function. Diabetes. 1993;42:1663-1672.
16. Cerasi E, Luft R, Efendic S. Decreased sensitivity of the pancreatic beta-cells to glucose in prediabetic and diabetic subjects. A glucose dose-response study. Diabetes. 1972;21:224-234.
17. Della Casa L, Del Rio G, Glaser B, Cerasi E. Effect of 6-month gliclazide treatment on insulin release and sensitivity to endogenous insulin in NIDDM: Role of initial continuous subcutaneous insulin infusion-induced normoglycemia. Am J Med. 1991;90:37S-45S.
18. Cerasi E, Efendic S, Luft, R. Dose-response relationship of plasma insulin and blood glucose levels during oral glucose loads in prediabetic and diabetic subjects. Lancet. 1973;301:794-797.
19. Hales CN. The pathogenesis of NIDDM. Diabetologia. 1994;37(suppl 2):S162- S168.
20. Ferrannini E, Gastaldelli A, Miyazaki Y, Matsuda M, Mari A, DeFronzo R. Betacell function in subjects spanning the range from normal glucose tolerance to overt diabetes: A new analysis. J Clin Endocrinol Metab. 2005;90:493-500.
21. Ilkova H, Glaser B, Tunçkale A, Bagriaçik N, Cerasi E. Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients by transient intensive insulin treatment. Diabetes Care. 1997;20:1353-1356.
22. Weng J, Li Y, Wen X, et al. Effect of intensive insulin therapy on beta-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-group trial. Lancet. 2008;371:1753-1760.
23. Brunzell JD, Robertson RP, Lerner RL, et al. Relationships between fasting plasma glucose levels and insulin secretion during intravenous glucose tolerance tests. J Clin Endocrinol Metab. 1976;42:222-229.
24. Pørksen N, Holligdal M, Juhl C, Butler P, Veldhuis JD, Schmitz O. Pulsatile insulin secretion: detection, regulation, and role in diabetes. Diabetes. 2002;51 (suppl 1):S245-S254.
25. Alvarsson M, Wajngot A, Cerasi E, Efendic S. K-value and low insulin secretion in a non-obese white population predicted glucose tolerance after 25 years. Diabetologia. 2005;48:2262-2268.
26. Utzschneider KM, Prigeon RL, Faulenbach MV, et al. Oral disposition index predicts the development of future diabetes above and beyond fasting and 2-h glucose levels. Diabetes Care. 2009;32:335-341.
27. Cali AMG, Dalla Man C, Cobelli C, et al. Primary defects in beta-cell function further exacerbated by worsening of insulin resistance mark the development of impaired glucose tolerance in obese adolescents. Diabetes Care. 2009;32:456-461.
28. Cerasi E, Luft R. Insulin response to glucose infusion in diabetic and non-diabetic monozygotic twin pairs. Genetic control of insulin response? Acta Endocrinol. 1967;55:330-345.
29. Pyke DA, Cassar J, Todd J, Taylor KW. Glucose tolerance and serum insulin in identical twins of diabetics. BMJ. 1970;4:649-651.
30. Iselius L, Lindsten J, Morton NE, et al. Genetic regulation of the kinetics of glucose- induced insulin release in man – Studies in families with diabetic and nondiabetic probands. Clin Genet. 1985;28:8-15.
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32. Pascoe L, Frayling TM, Weedon MN, et al. Beta cell glucose sensitivity is decreased by 39% in non-diabetic subjects carrying multiple diabetes-risk alleles compared with those with no risk alleles. Diabetologia. 2008;51:1989-1992.
33. t’Hart LM, Simonis-Bik AM, Nijpels G, et al. Combined risk allele score of eight type 2 diabetes genes is associated with reduced first-phase glucose-stimulated insulin secretion during hyperglycaemic clamps. Diabetes. 2010;59:287-292.
34. Gloyn AL, Braun M, Rorsman P. Type 2 diabetes susceptibility gene TCF7L2 and its role in beta-cell function. Diabetes. 2009;58:800-802.
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Keywords: insulin secretion; first-phase response; low insulin response; insulin resistance; IGT; type 2 diabetes; &bata-cell function; β-cell mass; ER stress

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Stephen COLAGIURI, MBBS, FRACP
Boden Institute of Obesity, Nutrition & Exercise, University of Sydney, New South Wales
AUSTRALIA
Ruth COLAGIURI,BEd
Health and Sustainability Unit Menzies Centre for Health Policy, University of Sydney
New South Wales AUSTRALIA

Diabetes has reached epidemic proportions throughout the world. There is overwhelming evidence that the diabetes burden can be reduced through prevention and improving overall diabetes management. Despite the available evidence, strategies have not been widely incorporated into clinical practice, and the care received by many people with diabetes is less than optimal worldwide. Evidence-based diabetes guidelines are an essential tool for redressing this situation. The evidence-based guideline movement has evolved over many years in response to the explosion of medical knowledge, a perceived need to protect against the potential for biases in the consensus approach, and the ever-increasing need to optimize the cost-effectiveness of treatment interventions. Evidence-based medicine is designed to complement and integrate clinical experience. The International Diabetes Federation is leading a worldwide movement to make diabetes care more consistent, more systematic, and more accountable through engagement of the international diabetes community in the development and implementation of guidelines. There has been much progress over the past 25 years. Evidencebasedmedicine is now firmly entrenched as an essential component of healthcare services and delivery. Evolution and refinement of the guideline development process continues with moves towards simplifying and reducing the human and financial cost of preparing guidelines without compromising integrity. In addition, the focus has shifted from guideline development to addressing the, as yet, unresolved challenge of guideline implementation.

The May 13, 2010 resolution of the United Nations (UN) General Assembly to hold a UN summit on chronic diseases is testimony to the impact of the global tsunami of diseases such as diabetes. Diabetes has reached epidemic proportions throughout the world and is a major contributor to the growing burden of chronic disease, especially in developing countries.¹ It is associated with significant morbidity and decreased life expectancy due to its complications, which include heart disease, stroke, amputation, blindness, and kidney failure. Diabetes reduces quality of life and is associated with increased psychosocial problems, including depression and anxiety. Diabetes results in a heavy socioeconomic burden for people with the disease, the health-care system, and society.² Over and above the burgeoning health-system costs attributable to diabetes, in both developed and developing countries, diabetes incurs huge costs due to lost productivity as a result of its debilitating complications and early mortality in the productive years of life.^3,4

The World Health Organization (WHO) proposes that 80% of all diabetes is preventable,⁴ and there is overwhelming evidence that diabetes complications can be prevented or delayed by processes and practices of care aimed at: improving overall diabetesmanagement; correcting blood glucose, blood pressure, and lipid abnormalities; avoiding smoking and excessive food intake; increasing physical activity; and controlling body weight. The cost-effectiveness of interventions to improve diabetes care has been well established by many international studies. Despite the available evidence, prevention strategies have not been widely incorporated into clinical practice, and the care received by many people with diabetes is less than optimal worldwide.⁵

The reasons for this disappointing situation are unclear, but are likely to be multifactorial and may include lack of practitioner awareness of the evidence, deficiencies in undergraduate and continuing medical education, and/or a mismatch between provider education and workplace culture and constraints, eg, insufficient material and human resources to implement the evidence.Whatever the reason, given the extent of the evidence that the morbidity and premature mortality associated with diabetes are reduced when care is closely aligned with guidelines,⁶ the globally endemic wide variations in the clinical care of diabetes are unacceptable.

Evidence-based diabetes guidelines are an essential tool for redressing this situation. Their recommendations synthesize the evidence to identify which clinical practices and processes of diabetes care lead to better outcomes. They provide practitioners and consumers with objective information about which interventions are likely to work best for most people with diabetes in most situations, and provide a solid foundation for clinical policy and protocols. Similarly, guideline recommendations establish standards and benchmarks that can assist funders and policy makers to allocate resources judiciously and assess the need for services and workforce development to achieve desired standards of care and, ultimately, improved health outcomes.

Background

Early consensus guidelines and position statements based on expert knowledge and clinical wisdom were a vital step in setting standards and benchmarks for promulgating and evaluating “best practice” and raising the profile and quality of diabetes care worldwide. As the next logical step, the evidence- based guideline movement evolved over many years in response to: (i) the explosion of medical knowledge enabled by technological advances; (ii) the associated proliferation of medical evidence in the form of journal reports; (iii) a perceived need to protect against the potential for biases in the consensus approach; and (iv) the ever-increasing need to optimize the cost-effectiveness of treatment interventions.

The role of clinical management guidelines is to synthesize and summarize research evidence into easily accessible information on the effects and possible consequences of available treatment options for use by clinicians and consumers. Field and Lohr⁷ defined evidence-based guidelines as: “…systematically generated statements which are designed to assist health care clinicians and consumers to make informed decisions about appropriate treatment in specific circumstances.”

Since then, guideline development has evolved into a highly sophisticated, technical, and resource-intensive model of research.⁸ Today, guideline methodology has its own body of evidence with each of several national research authorities around the world publishing their own requirements and grading criteria. In tandem with the evolution of guideline development methodology, a variety of clinical management guidelines across almost all common disease areas has proliferated in a global attempt to promote evidence-based clinical practice, reduce unacceptable variations in treatments, and minimize potential treatment harm.⁸

Evidence-based medicine aims to apply the best available evidence to medical decision-making. Evidence-based guidelines, which formulate recommendations based on evidence, influence policy and regulations, and are an essential starting point for improving clinical care. However, their application in evidence-based individual decision-making by the healthcare provider for the benefit of an individual patient needs to take into account the many other factors that influence treatment choices, including relevance to the individual and the patient’s expectations and values, cost, and cost-effectiveness. Evidence-based medicine should complement and integrate clinical experience.

The methodology for preparing evidence-based guidelines is well established and includes identifying specific research questions around important clinical issues. These questions are the focus of the subsequent systematic reviews and synthesis of the medical literature that generate the evidence for formulating clinically relevant recommendations to guide patient care. Several national research authorities set out strict criteria for developing guidelines, and the development process is rigorous, objective, replicable, and transparent. Nonetheless, it should be recognized that guideline methodology has some inherent limitations. The heavy reliance on randomized placebo-controlled trials unfairly undervalues qualitative studies, which are often particularly relevant to decisionmaking in diabetes. Treatment effectiveness reported in clinical studies may be higher than that achieved in subsequent routine clinical practice. Other problems include the validity of extrapolating evidence to different populations or over longer timeframes than those covered by the study, and bias related to nonpublication of negative studies.

Despite their acknowledged limitations, guidelines can be a powerful tool in reducing unacceptable variations in clinical practice. They are increasingly shaping best practice, and the promulgation of evidence in diabetes care and, subsequently, evidence-based medicine is increasingly shaping the content and focus of diabetes guidelines.

The International Diabetes Federation (IDF)

The International Diabetes Federation (IDF) is an umbrella international non-governmental organization (NGO) of over 200 national diabetes associations in over 160 countries and has been leading the global diabetes community since 1950. IDF’s mission is to promote diabetes care, prevention, and a cure worldwide. The IDF led the “Unite for Diabetes” campaign, which secured a UN resolution on diabetes in December 2006. The resolution encourages UN member states to develop national policies for the prevention, treatment, and care of diabetes in line with the sustainable development of their health-care systems, taking into account internationally agreed development goals, including the Millennium Development Goals.

There is now extensive evidence on the optimal management of diabetes, offering the opportunity of improving the immediate and long-term quality of life of people with diabetes. Unfortunately, such optimal management is not reaching many, perhaps the majority, of the people who could benefit. Reasons include the size and complexity of the evidence base, and the complexity of diabetes care itself.

Guidelines are one part of a process that seeks to address these problems. Many guidelines have appeared internationally, nationally, and more locally in recent years, but most of these have not used the rigorous new guideline methodologies for identification and analysis of the evidence. The IDF is leading a worldwide movement to make diabetes care more consistent, more systematic, and more accountable through engagement of the international diabetes community in the development and implementation of guidelines. The IDF Clinical Guidelines Taskforce focuses on developing evidencebased guidelines and clinical care recommendations which are globally and locally relevant.⁹

A global guideline presents a huge and unique challenge. Many national guidelines address one group of people with diabetes in the context of one health-care system, with one level of national and health-care resources. This is not true in the global context where, although every health-care system seems to be short of resources, the funding and expertise available for health care vary widely between countries and even between localities.
_ Levels of diabetes care
All people with diabetes should have access to cost-effective evidence-based care. It is recognized that in many parts of the world the implementation of particular standards of care is limited by lack of resources. The IDF has developed a practical approach to promote the implementation of costeffective evidence-based care in settings between which resources vary widely. The approach that has been adopted is based on acknowledging and making recommendations in relation to three levels of care:
_ Standard care
Standard care is evidence-based care which is cost-effective in most nations with a well-developed health-service base, and with health-care funding systems consuming a significant part of national wealth. Standard care should be available to all people with diabetes and the aim of any health-care system should be to achieve this level of care. However, in recognition of the considerable variations in resources throughout the world, other levels of care are described which acknowledge low and high resource situations.
_ Minimal care
Minimal care is the lowest level of care which anyone with diabetes should receive. It acknowledges that standard medical resources and fully trained health professionals are often unavailable in poorly funded health-care systems. Nevertheless, this level of care aims to achieve with limited resources (medications, personnel, technologies, and procedures) a high proportion of what can be achieved by standard care. Only low-cost or highly cost-effective interventions are included at this level.
_ Comprehensive care
Comprehensive care includes the most up-to-date and complete range of health technologies that can be offered to people with diabetes, with the aim of achieving the best possible outcomes. However, the evidence-base supporting the use of some of these expensive or new technologies is relatively weak.

Approaches to guideline development

Developing guidelines is a time-consuming and costly process that is beyond the resources of many health-care systems. As the science of evidence-based medicine continues to evolve, there is now increasing questioning of the need for and the relevance of the traditional full guideline development process. In 2003, the IDF addressed this in its Guide for Guidelines¹⁰ which proposed two basic approaches to developing an evidence-based guideline:
_ Full-process guideline
_ Derived guideline

The full-process guideline involves a full and systematic development of the clinical questions to be addressed, and develops recommendations supported by complete and formal evidence searching and review, using primary sources.

The derived guideline similarly develops clinical questions, but then seeks out and adapts previously developed full-process guidelines, updating the evidence base and seeking supporting evidence to develop recommendations for local circumstances. Preparing a derived guideline, a relatively simple process, can be done without a complex management structure or considerable resources and time, without compromising the end result.

While the move to review the need for full-process guidelines is welcome, this should not imply a return to consensus statements prepared by a small group with a limited and often uncritical review of the literature.

Complexity of decision-making in clinical management

Diabetes care is complex and involves a range of interventions – education, lifestyle modification (diet, physical activity), medications for diabetes complications prevention and treatment (eg, cardiovascular and renal disease), and ongoing monitoring and review (including self-monitoring blood glucose [SMBG], clinical [blood pressure and weight], and pathological [glycated hemoglobin, lipids, etc]). While multifactorial intervention has been shown to reduce morbidity and premature mortality,¹¹ demonstrating the efficacy of individual components of care has been more difficult (eg, education,¹² SMBG¹³). Clinical decision making requires more than just taking into account efficacy of a particular treatment, and this should be taken into account in formulating and interpreting guideline recommendations. Factors which influence the treatment used in a particular patient include not only the evidence of effect on glycemic control and diabetes outcomes, but also include contraindications, potential side effects, patient preference, local availability, prescribing restrictions, and the cost to the individual and health-care system. Ultimately, diabetes care decision-making is based on a balance between benefit and safety in the context of availability and cost. Fortunately, there is considerable high-quality evidence available to guide clinical diabetes care. However, there are limited data on clinical outcomes comparing different treatment schedules.

The United Kingdom Prospective Diabetes Study (UKPDS) reported similar improvements with sulfonylurea- and insulinbased treatment policies on microvascular complications and on any diabetes-related end point.¹⁴ Although metformin therapy was associated with improved cardiovascular outcomes in a subgroup of overweight individuals, it should be noted that this was against a backdrop of no improvement in microvascular outcomes and no significant reduction in glycated hemoglobin.¹⁵

Most of the data relating to pharmaceutical interventions are based on efficacy in improving blood glucose, which is generally similar between agents depending on whether it is used as first-, second-, or third-line therapy. Therefore, individual treatment choices are ultimately more often based on other considerations. These include unwanted consequences, such as the risk of hypoglycemia and weight gain, which are inevitable with insulin, but which differ between other agents and between studies. The cost to the individual, the healthcare system, and society is an important consideration, and cheaper, well-established, and efficacious treatments (eg, metformin and sulfonylureas) continue to be widely used and recommended in guidelines globally.

Guideline implementation

The translation of guidelines into everyday practice remains a vexed problem with little clear direction about what works best across all circumstances. According to Grimshaw et al,¹⁶ failure to translate guidelines into everyday practice features among the commonest findings of health-service research.

Nonetheless, there is some evidence, although variable, on the effectiveness of certain strategies for improving the uptake of guidelines by health professionals in clinical practice.¹⁷ Many approaches have been used with varying success, but the most effective have been multidimensional and locally specific. The main targets of guideline implementation strategies are health-care professionals, health-care funders, and people with diabetes. However, other stakeholders, such as government and industry, have an important role in promoting and facilitating guideline implementation.

Successful guideline implementation requires more than its formulation and publication. Together, with its wide distribution among organizations worldwide, the IDF has been holding regional workshops to present its guidelines, explain their aims and evidence-based methodology, and analyze faceto- face with health-care organizations and providers the difficulties of successful implementation and possible strategies to solve such problems.

During these workshops the guidelines are presented, and attendees explain their approach to improving diabetes care and the problems identified for successful implementation and acceptance of care strategies. Small groups consider the pros and cons of the guideline, barriers to successful implementation, and possible strategies to overcome such barriers.¹⁸

Greater attention and support is needed for guideline implementation. Indeed, guideline development is rarely indicated unless there are plans, developed at the same time, for implementation of the recommendations. This should be considered an integral part of the planning stage of guideline development. Guideline implementation requires participation of people with diabetes, official support from government andhealth-financing entities, adequate distribution of a simplified version for daily use at primary health-care level, and training of providers/users. These strategies imply the appropriate allocation of human and economic resources.

There has been much progress over the past 25 years. Evidence- based medicine is now firmly entrenched as an essential component of health-care services and delivery. Evolution and refinement of the guideline development process continues with moves towards simplifying and reducing the human and financial cost of preparing guidelines without compromising integrity. Finally, the focus has shifted from guideline development to addressing the, as yet, unresolved challenge of guideline implementation. _

References
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3. American Diabetes Association. Economic costs of diabetes in the U.S. In 2007. Diabetes Care. 2008;31:596-615.
4. WHO. Preventing Chronic Diseases: A vital investment. 2005. www.who.int/chp/ chronic_disease_report/contents/en/index.html. Accessed October 11, 2010.
5. Chan JC, Gagliardino JJ, Baik SH, et al; IDMPS Investigators. Multifaceted determinants for achieving glycemic control: the International Diabetes Management Practice Study (IDMPS). Diabetes Care. 2009;32:227-233.
6. Grimshaw J, Thomas R, MacLennan G, et al. Effectiveness and efficiency of guideline dissemination and implementation strategies. Health Technol Assess. 2004;8:1-72.
7. Field MJ, Lohr KN, eds. Clinical Practice Guidelines: Directions for a New Program. Washington, DC; National Academy Press: 1990.
8. Colagiuri R. Implementing evidence based guidelines: Unlocking the secrets. Diabetes Res Clin Pract. 2009;85:117-118.
9. International Diabetes Federation website. http://www.idf.org/. Accessed October 11, 2010.
10. International Diabetes Federation Guide for Guidelines. http://www.idf.org/ guide-guidelines. Accessed October 11, 2010.
11. Gæde P, Lund-Andersen H, Parving H-H, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:580- 591.
12. Duke S, Colagiuri S, Colagiuri R. Individual patient education for people with type 2 diabetes mellitus. Cochrane Database Syst Rev. 2009;21:CD005268.
13. Clar C, Barnard K, Cummins E, Royle P, Waugh N; Aberdeen Health Technology Assessment Group. Self-monitoring of blood glucose in type 2 diabetes: systematic review. Health Technol Assess. 2010;14:1-140.
14. UKPDS Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.
15. UKPDS Study Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-865.
16. Grimshaw J, Eccles M, Tetroe J. Implementing clinical guidelines: current evidence and future implications. J Contin Educ Health Prof. 2004;24(suppl 1): S31-S37.
17. de Belvis AG, Pelone F, Biasco A, Ricciardi W, Volpe M. Can primary care professionals’ adherence to evidence based medicine tools improve quality of care in type 2 diabetes mellitus? A systematic review. Diabetes Res Clin Pract. 2009; 85:119-131.
18. Gagliardino JJ, Colagiuri S. An approach to implementing international diabetes guidelines. Int J Ther Rehabil. 2009;16;470. Editorial.

Keywords: evidence-based medicine; diabetes; guidelines

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John CHALMERS, MD, PhD
Andre Pascal KENGNE, MD, PhD
The University of Sydney and the Royal Prince Alfred Hospital
Sydney, New South Wales AUSTRALIA

The reductions in cardiovascular events observed in the Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) trial through routine blood pressure lowering with perindopril/indapamide and intensive glucose control with a Diamicron MR– based regimen have provided added incentive to develop tools for more accurate assessment of cardiovascular risk in patients with type 2 diabetes.Models based on earlier studies, including the Framingham and United Kingdom Prospective Diabetes Study risk equations, were based on populations treated in a much earlier therapeutic environment, before the availability of many of today’s protective cardiovascular drugs. Accordingly, we have used the opportunity afforded by the ADVANCE population with type 2 diabetes, a population that is both contemporary and representative of the broad cross-section of people with type 2 diabetes worldwide, to develop a new, improved risk engine for predicting the risk of cardiovascular events. The predictive baseline characteristics used to estimate cardiovascular risk through the ADVANCE risk engine are age at diagnosis of diabetes, known duration of diabetes, sex, pulse pressure, treated hypertension, atrial fibrillation, retinopathy, HbA1c, urinary albumin/creatinine ratio, and non-high-density–lipoprotein cholesterol. This model provides a considerable improvement over the older risk equations in predicting the risk of cardiovascular events. The new ADVANCE risk engine will shortly be available, through a specific ADVANCE Web site, to assist physicians around the world in calibrating their patients’ risk profile and in optimizing their therapeutic management to alleviate the global burden of cardiovascular disease in patients with type 2 diabetes.

As documented elsewhere in this issue, the epidemic of diabetes is evolving at alarming speed in both developed and developing regions of the world, with dramatic growth in the burden of cardiovascular disease (CVD). The most common cause of death among individuals with diabetes is coronary disease, but stroke, renal failure, and heart failure are also important contributors. The elevated risks of major vascular events have been well documented in a range of populations,1 and the risks are apparent in the young and the old, in the East and the West.¹ As a result, there is an urgent need, not only for effective preventive and treatment programs that minimize the complications of diabetes, but also for tools to help physicians in assessing the risks of cardiovascular complications in individuals with type 2 diabetes.

Figure 1. 4-year predicted rates of major cardiovascular events in ADVANCE by the Framingham and UKPDS equations.

Indeed, many patients with diabetes live long lives with quite good health, while others are cut down prematurely! It is clearly of vital interest to these patients, their families, and their physicians to have an accurate assessment of the risk of serious complications of diabetes so that appropriate plans for prevention may be formulated. Since cardiovascular disease constitutes the major burden of ill health in type 2 diabetes, there is an urgent need for tools that help the physician to advise the patient about the risks of serious cardiovascular events, such as heart attacks and strokes, so that together they can plan and implement the lifestyle and therapeutic measures needed to reduce this risk and prevent these complications.

The need for accurate prediction of cardiovascular risk is much greater now that the Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) has clearly demonstrated the benefits of both routine blood pressure lowering with the fixed combination of perindopril and indapamide and more intensive glucose control with a Diamicron MR–based regimen, irrespective of baseline blood pressure or baseline glycated hemoglobin (HbA1c).^2,3 In each case, the regimens used in ADVANCE reduced the composite primary outcome of major macrovascular and microvascular events by around 10% and renal events by around 20%, with additional significant reductions in mortality and coronary events in the perindopril/indapamide arm of the trial.

Many studies have highlighted the importance of key individual risk factors, such as the level of HbA1c and presence or absence of albuminuria, in determining the level of risk in the individual patient. However, modern guidelines increasingly emphasize the importance of estimating the individual’s global cardiovascular risk as a more appropriate basis for risk factor management. Global cardiovascular risk is a quantitative estimate of an individual’s chances of experiencing a cardiovascular event within a given time period. This estimate depends on the combination and intensity of all risk factors rather than on the presence of any single risk factor. In this paper, we examine the performance of a variety of existing “clinical prediction models,” also referred to as “absolute risk equations,” in estimating cardiovascular risk, and we present preliminary information describing the new “ADVANCE risk engine,” based on a contemporary and representative population of individuals with type 2 diabetes around the world.

Performance of older cardiovascular risk equations in the contemporary ADVANCE population

Currently, the most widely used models in people with diabetes are the Framingham cardiovascular risk equations and the United Kingdom Prospective Diabetes Study (UKPDS) risk engines. The utility of both the Framingham and UKPDS equations in people with diabetes has been documented in historic cohorts,⁴ but not established in contemporary populations. The Framingham equations are less than ideal for predicting risk in people with diabetes, since they are not only based on populations from a previous era with a very differ- ent therapeutic environment, but are also based on a general population having only a small minority of individuals with diabetes.^5,6 The UKPDS equations are also based in people with diabetes in the previous century, and they provide separate estimates or the risks of coronary heart disease or of stroke, but no estimate for the risk of combined major cardiovascular events.^7,8

In order to assess the performance of a risk equation in a contemporary population, it is necessary to test and quantify how well a particular model, derived from a distinct and specific population, predicts risk in another quite different and independent modern population. The main criteria used to describe the performance of the model being tested are termed “calibration” and “discrimination.”We illustrate this below, in assessing the performance of the older Framingham and UKPDS equations in the contemporary ADVANCE cohort.^5-8

“Calibration” quantifies how close the predictions are to the actual outcome. For instance, a 5-year estimated probability of cardiovascular disease of 20% for a patient means that, in a given group of patients with similar characteristics, 20% will experience a cardiovascular event within a 5-year period. Figure 1 shows that, in the cohort of ADVANCE patients who had no known history of cardiovascular disease at enrolment in the trial, the 4-year risk of cardiovascular events was largely overestimated by the Framingham-Anderson,⁵ Framingham- D’Agostino,⁶ and UKPDS equations.^7,8 This overestimation was observed in men and women, whites and non-whites, and in the double-placebo cohort of ADVANCE (ie, those assigned to the placebo group in the blood pressure–lowering arm and the standard care group of the blood pressure– control arm).⁹

“Discrimination” describes the performance of a model in distinguishing between patients who go on to develop a cardiovascular event and those who remain event free. Discrimination using the Framingham and UKPDS equations in predicting CVD events in the ADVANCE patients was modest to acceptable for coronary heart disease and for total CVD, but poor for stroke.⁹

Recalibration is a method for improving an equation’s predictive capacity. It usually consists of adjusting the equation by replacing the average value of the risk factors and event rates in the equation (derived from the original population) by those in the test population. When applied to the Framingham and UKPDS equations, this approach substantially attenuated the overestimation of risk for the ADVANCE patients. However, discrimination was not improved, indicating the need for a new equation with improved discriminatory capability for people with diabetes, particularly those receiving many contemporary cardiovascular risk-reducing therapies.⁹

Table I. Baseline characteristics for the ADVANCE participants and other cross-sectional studies.

Development of the new ADVANCE risk engine for predicting risk and improving cardiovascular event prevention in type 2 diabetes

In developing a new model for risk prediction, it is important to address the limitations of the existing models. The inclusion in ADVANCE of participants from many countries has provided the opportunity to account for the substantial variation in the care of diabetes and cardiovascular disease around the world, whereas existing models have been derived from homogenous populations from the UK and the USA. The generalizability of the ADVANCE cohort to current contemporary populations of patients with type 2 diabetes around the world is shown in Table I, which compares the characteristics of patients participating in ADVANCE with those of individuals with type 2 diabetes at community level in a number of countries.^10-13 The ADVANCE model also aims to predict total cardiovascular risk and therefore to capture the interrelation between components of cardiovascular disease, such as coronary heart disease and stroke, unlike other models, such as the UKPDS equations, that focus specifically and separately on these components. Moreover, the complexity of the relationship between chronic hyperglycemia and cardiovascular risk has not been as well addressed in existing models. In the ADVANCE model, further improvements have been achieved through the integration of risk factors to capture exposure to chronic hyperglycemia both before and after the clinical diagnosis of diabetes.

Several risk factors were considered for inclusion in the ADVANCE model, including the traditional risk factors for CVD, HbA1c, and some novel risk factors. The final ten predictors that emerged as independent predictors and were chosen for inclusion in the ADVANCE risk engine are shown in Table II.¹⁴ Age at diagnosis of diabetes and known duration of diabetes were preferred to age at baseline, in order to improve the applicability of the ADVANCE equation to other populations. Although cognitive function has been confirmed as an independent predictor of CVD in ADVANCE,¹⁵ this characteristic was not considered for inclusion in the model, given the difficulties in assessing cognitive function in a standardized way around the world. Surprisingly, smoking status was not a significant predictor when tested alone or together with other risk factors in the ADVANCE population, possibly reflecting the small proportion of current smokers in that cohort.

The capacity to predict the risk of events was tested against the actual recording of events that occurred during the postrandomization period of follow-up within the ADVANCE population. The calibration of the ADVANCE model was excellent and the discrimination acceptable with an area under the curve (AUC) of 0.7. Validation of the ADVANCE model in an external, independent population of people with type 2 diabetes is currently proceeding. To facilitate the uptake of the ADVANCE model in clinical practice, a risk scoring table is being developed. This will assign scores for various levels of each of the ten final risk factors selected, in each individual patient. Other tools from this model are also planned, including an online calculator.

Conclusions

The ADVANCE trial has provided a major impetus for development of accurate tools to predict the risk of cardiovascular events in individuals with type 2 diabetes. The routine administration of the fixed combination of perindopril and indapamide reduced all-cause mortality by 14%, cardiovascular mortality by 18%, major vascular events by 9%, and coronary and renal events by 14% and 21 %, respectively.¹ Additionally, more intensive glucose control using a gliclazide MR–based regimen reduced the risk of major macro- or microvascular events by 10%, of major microvascular events by 14%, and of new or worsening nephropathy by 20%. Given these potential benefits, it is incumbent on physicians responsible for the care of patients with type 2 diabetes to ensure that they prescribe such treatments for all patients at high risk of experiencing cardiovascular events. In turn, this places a premium on developing the capacity to predict the risk of cardiovascular events much more accurately than was previously possible.

Table II. Predictors selected for the ADVANCE risk engine.

It is in this context that the new ADVANCE risk engine presents a new and valuable tool. In an effort to overcome some of the limitations of the existing models for estimating cardiovascular risk in people with diabetes, the new model is founded on some of the unique features of the ADVANCE cohort. The ADVANCE model is based on parameters that are easily assessable and widely available in routine clinical care. When tested, the performance of this new model was highly acceptable. Inclusion of participants from developing countries in the ADVANCE cohort highlights the potential of the ADVANCE risk engine for assisting cardiovascular risk stratification efforts in many settings around the world.

We are currently actively working to develop a specific ADVANCE risk engine Web site that will assist physicians all around the world to determine the risk of cardiovascular disease in their own individual patients with type 2 diabetes, and we invite all physicians to use this tool as soon as it becomes available. _

References
1. Asia Pacific Cohort Studies Collaboration. The effects of diabetes on the risks of major cardiovascular diseases and death in the Asia-Pacific region. Diabetes Care. 2003;26:360-366.
2. ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE Trial): a randomised controlled trial. Lancet. 2007;370:829-840.
3. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl JMed. 2008;358:2560-2572.
4. Chamnan P, Simmons RK, Sharp SJ, et al. Cardiovascular risk assessment scores for people with diabetes: a systematic review. Diabetologia. 2009;52: 2001-2014.
5. Anderson KM, Odell PM, Wilson PW, Kannel WB. Cardiovascular disease risk profiles. Am Heart J. 1991;121:293-298.
6. D’Agostino RB Sr, Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation. 2008; 117:743-753.
7. Stevens RJ, Kothari V, Adler AI, Stratton IM. The UKPDS risk engine: a model for the risk of coronary heart disease in type II diabetes (UKPDS 56). Clin Sci (Lond). 2001;101:671-679.
8. Kothari V, Stevens RJ, Adler AI, et al. UKPDS 60: risk of stroke in type 2 diabetes estimated by the UK Prospective Diabetes Study risk engine. Stroke. 2002;33:1776-1781.
9. Kengne AP, Patel A, Colagiuri S, et al; ADVANCE Collaborative Group. The Framingham and UKPDS risk equations do not reliably estimate the probability of cardiovascular events in a large ethnically diverse sample of patients with diabetes: the Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) Study. Diabetologia. 2010;53:821-831.
10. Marant C, Romon I, Fosse S, et al. French medical practice in type 2 diabetes: the need for better control of cardiovascular risk factors. Diabetes Metab. 2008;34:38-45.
11. Berthold HK, Gouni-Berthold I, Bestehorn KP, et al. Physician gender is associated with the quality of type 2 diabetes care. J Intern Med. 2008;264:340-350.
12. Barr EL, Zimmet PZ, Welborn TA, et al. Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance: the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). Circulation. 2007;116:151-157.
13. Andel M, Grzeszczak W, Michalek J, et al; DEPAC Group. A multinational, multicentre, observational, cross-sectional survey assessing diabetes secondary care in Central and Eastern Europe (DEPAC Survey). Diabet Med. 2008;25: 1195-1203.
14. Kengne AP, Patel A, Colagiuri S, et al. Derivation of the ADVANCE models for predicting the risk of major cardiovascular disease in people with diabetes. International Diabetes Federation 2009, Montreal. Abstract 0199 (p.71).
15. De Galan BE, Zoungas S, Chalmers J, et al; ADVANCE Collaborative Group. Cognitive function and risks of cardiovascular disease and hypoglycaemia in people with type 2 diabetes: the ADVANCE trial. Diabetelogia. 2009;52:2027- 2036.

Keywords: perindopril/indapamide; Preterax; Diamicron MR; type 2 diabetes; blood pressure lowering; intensive glucose control; cardiovascular risk; risk prediction; calibration; discrimination

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Leszek CZUPRYNIAK, MD, PhD
Department of Internal Medicine
and Diabetology
Barlicki University Hospital No. 1
Medical University of Lodz
Kopcinskiego 22
90-153 Lodz, POLAND

Screening for type 2 diabetes has become accepted policy in the modern world, in which, more often than not, preventive medicine is practised. Using plasma or capillary blood glucose measurements for diabetes screening is an acknowledged procedure. However, the debate about whether fasting or postprandial/postchallenge values should be used for this purpose has never been unanimously resolved. Fasting plasma glucose (FPG) is easier to categorize, while (ab)normal postprandial values will probably never be defined. Yet, fasting measurements only allow you to diagnose diabetes in a third of afflicted individuals.¹ The need for a more effective screening tool is therefore apparent.

Nevertheless, even with the limitations, I would use HbA_1c for diabetes screening, with two caveats. First, positive screening results do not necessarily equate to making a final diagnosis. In many cases, a diagnosis of diabetes with elevated HbA_1c will have to be confirmed by either repeating the test or using plasma glucose parameters. The ADA recommends confirming positive diagnostic results of HbA_1c, fasting glucose, or oral glucose tolerance tests (OGTT) with repeat testing if equivocal hyperglycemia is found.³ Second, the HbA_1c threshold value for positive screening is debatable. In cases with high HbA_1c levels (>7%), the diagnosis will probably be obvious, but within the range slightly exceeding normal values (6.0%-6.5%), doubts will remain until another test has been performed as HbA_1c <6.5% (or even <6.0%) does not exclude the possibility of diabetes, particularly at an early stage. _

References
1. Drzewoski J, Czupryniak L. Concordance between fasting and 2-h post-glucose challenge criteria for the diagnosis of diabetes mellitus and glucose intolerance in high risk individuals. Diabet Med. 2001;18:29-31.
2. Svendsen PA, Jørgensen J, Nerup J. HbA1c and the diagnosis of diabetes mellitus. Acta Med Scand. 1981;210:313-316.
3. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33(suppl 1):S62-S69.
4. Selvin E, Steffes MW, Zhu H, et al. Glycated hemoglobin, diabetes and cardiovascular risk in nondiabetic adults. N Engl J Med. 2010;362:800-811.
5. NGSP Factors that Interfere with HbA1c Test Results. Updated 4/2010. http://www.ngsp.org/factors.asp. Accessed November 26, 2010.
6. Herman WH, Fajans SS. Hemoglobin A1c for the diagnosis of diabetes. Practical considerations. Pol Arch Med Wewn. 2010;120:37-41.

Santiago DURAN-GARCIA, MD, PhD
Hospital Universitario De Valme
Carretera De Sevilla-Cadiz S/N
Sevilla 41014, SPAIN

It has recently been published that “it is reasonable to consider an HbA_1c range of 5.7% to 6.4% as identifying individuals with high risk for future diabetes and to whom the term prediabetes may be applied if desired.” Glycated hemoglobin (HbA_1c) is a widely used marker of chronic glycemia and plays a critical role in the management of patients with diabetes. Prior expert committees have not recommended the use of the HbA_1c test for the diagnosis of diabetes, due to a lack of standardization of the assay. More recently an international committee, after an extensive review of both established and emerging epidemiological evidence, recommended the use of the HbA1c test to diagnose type 2 diabetes, with a threshold of ≥6.5%. The diagnostic test should be performed using a method certified by the NGSP (National Glycohemoglobin Standardization Program). Point-ofcare HbA_1c assays are not sufficiently accurate at this time to use for diagnostic purposes. There is an inherent logic to using a chronic marker of dysglycemia rather than an acute one, particularly since HbA_1c has several advantages to fasting plasma glucose (FPG), including greater convenience (since fasting is not required), evidence to suggest greater preanalytical stability, and less day-to-day perturbations during periods of stress and illness.

The application of this test in the diagnosis of type 2 diabetes, as well as in situations of type 2 prediabetes, may have major repercussions in habitual clinical practice on the pass-on costs in the health system and on the early prevention of the development of vascular complications. It must not be forgotten that, in any case, the goal is to diagnose this condition as early on as possible, which may be easier with the availability of this diagnostic tool. _

References
1. International Expert Committee. The international expert committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care. 2009;32: 1327-1334.
2. American Diabetes Association. Standards of Medical Care in Diabetes—2010. Diabetes Care. 2010;33(suppl 1):S11-S61.
3. Aguilar Diosdado M. Hemoglobin A1c for the diagnosis of diabetes mellitus? Pros and cons. Avances en Diabetologia. 2010;26:4-5.
4. Fernandez I, Hernandez C, Gonzalez MC, Roldan E, Duran S. Determinación de los niveles de hemoglobinas glucosiladas: estudios en pacientes con intolerancia hidrocarbonada y correlaciones clínico-biológicas en pacientes diabéticos. Medicina Clínica. 1983;81:839-843.
5. Duran S, Fernandez I, Guillen R, Costa C. Gestational diabetes: heterogeneity and glycemic control. Duran S, ed. Diabetes & Pregnancy. Seville, Spain: Publications of the University of Seville; 1987:51-64.

Hanan GAWISH,MD
Professor of Internal Medicine
Diabetes and Endocrinology Unit
Mansoura University, EGYPT

Glycated hemoglobin (HbA1c) value and its cutoff level have always been the subject of debates. A target goal of HbA_1c ≤7% was recommended by the American Diabetes Association (ADA), while both the American College of Endocrinology (ACE) and the American Association of Clinical Endocrinology (AACE) adopted a lower target of HbA ≤6.5% in 2001. Although HbA_1c had been proved to be significantly linked to the risk of diabetes complications, until recently it was not accepted for use in the diagnosis of diabetes. In June 2009, the ADA raised the prospect of making HbA_1c essential for the diagnosis of diabetes. A threshold HbA_1c of 6.5% or above being diagnostic of diabetes, and levels between 5.7% and 6.4% identifying patients at high risk of developing diabetes and its complications. The ADA’s last report succeeded in starting a debate among professionals internationally.

In conclusion, the utility of HbA_1c as a marker for metabolic control cannot easily be extended to validate its use for the diagnosis of diabetes. A consensus with clear answers to all questions raised should be reached before HbA_1c becomes widely accepted as a reliable diagnostic tool. _

Linong JI,MD
Department of Endocrinology
The People’s Hospital of Peking University
11 Xizhimen South Street, Xicheng District
Beijing, CHINA

The increasing prevalence of diabetes across the world has become a major public health issue of global concern. Early diagnosis and treatment of diabetes is key for reducing the risk of diabetic complications. For a long time, researchers have been looking for easier and more accurate ways of diagnosing diabetes.

To address these issues, studies are now being undertaken to look for the HbA_1c cutoff for diagnosing diabetes and to examine the relationship between HbA_1c level and risk of retinopathy in the general Chinese population. A grant program, the China HbA_1c Education Program, was launched to educate health-care providers and patients on how to use HbA_1c in the daily management of diabetes. Another important part of this program is to educate laboratory technicians to use standard assays of HbA_1c in order to provide a high-quality service in diabetes care. _

Shashank R. JOSHI,MD, DM,
FACP (USA), FACE (USA), FRCP(Glsg)
Professor, Consultant Endocrinologist
Lilavati & Bhatia Hospital, Mumbai, INDIA

Historically, the measurement of glucose has been the means of diagnosing type 2 diabetes. Glycated hemoglobin (HbA_1c) has the following technical advantages when compared with glucose testing for this purpose:
_ Standardization and alignment to the Diabetes Control and Complications Trial (DCCT)/United Kingdom Prospective Diabetes Study (UKPDS); measurement of glucose is less well standardized
_ Better index of overall glycemic exposure and risk for longterm complications
_ Substantially less biologic variability
_ Substantially less preanalytic instability
_ No need for fasting or timed samples
_ Relatively unaffected by acute (eg, stress- or illness-related) perturbations in glucose levels
_ Currently used to guide management and adjust therapy

Based on a detailed review, an international Expert Committee¹ has concluded that the best current evidence supports the following recommendations:
_ Individuals with an HbA_1c level <6% but >6.5% are likely to be at the highest risk for progression to diabetes, but this range should not be considered an absolute threshold at which preventative measures are initiated.
_ The classification of subdiabetic hyperglycemia, such as prediabetes, is problematic because it suggests that all individuals so classified will develop diabetes and that individuals who do not meet these glycemia-driven criteria (regardless of other risk factor values) are unlikely to develop diabetes— neither of which is the case. Moreover, the categorical classification of individuals as high risk (eg, impaired fasting glycemia [IFG] or impaired glucose tolerance [IGT]) or low risk, based on any measure of glycemia, is less than ideal because the risk for progression to diabetes appears to be a continuum. Glucose-related terms describing subdiabetic hyperglycemia will be phased out of use as clinical diagnostic states, as HbA_1c measurements replace glucose measurements for the diagnosis of diabetes.
_ When assessing risk, implementing prevention strategies, or initiating a population-based prevention program, other diabetes risk factors should be taken into account. In addition, the HbA_1c level at which to begin preventive measures should reflect the resources available, the size of the population affected, and the anticipated degree of success of the intervention. Further analyses of cost-benefit should guide the selection of high-risk groups targeted for intervention within specific populations.
_ In developed economies where methodologies are well standardized, HbA_1c may be used as a diagnostic add-on tool. But in developing countries where both liberal use as well as standardization of methodology is poor, it is a premature step. Also, there is still a role for glucose tolerance curves in modern metabolic medicine in several areas of epidemiology as well as clinical practice. _

Reference
1. International Expert Committee. International expert committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care. 2009;32:1327-1334.

Edoardo MANNUCCI,MD
Agenzia Diabetologia
Padiglione Ponte Nuovo
Via delle Oblate, 4
50141 Firenze, ITALY

An International Expert Committee, which included members designated by American, European, and International Diabetes Associations, proposed to include glycated hemoglobin (HbA_1c) among the diagnostic criteria for diabetes, with a threshold of 6.5%.1 HbA_1c is a more stable parameter than blood glucose,^1,2 allowing a reliable assessment of carbohydrate metabolism without the need for repeated measurements that are required for the diagnosis of diabetes based on glycemic levels. The greater stability of this parameter may explain the results of epidemiological studies showing that HbA_1c is a better predictor of the microvascular complications of diabetes and cardiovascular disease than either fasting glucose or postload/postprandial glucose.^1-3 Furthermore, both fasting and postload glucose contribute to HbA_1c .

Any clinical decision should be based on a careful evaluation of advantages and disadvantages. Although the standardization of laboratory procedures and costs are relevant issues, the benefits of using HbA_1c in the screening of diabetes largely outweigh the disadvantages. In particular, the possibility of identifying cases of diabetes characterized by postload hyperglycemia with normal (or near-to-normal) fasting glucose, without the need to perform an oral glucose tolerance test is a major advantage, together with the possibility of diagnosing diabetes without the need to repeat the test, and of using blood samples drawn under nonfasting conditions for screening. At the same time, clinicians should be aware that values of HbA_1c should not be used for diagnosis without critical consideration of the clinical conditions that could interfere with results. _

References
1. International Expert Committee. International expert committee report on the role of A1C assay in the diagnosis of diabetes. Diabetes Care. 2009;32:1327-1334.
2. Vistisen D, Colagiuri S, Borch-Johnsen K; DETECT-2 Collaboration. Bimodal distribution of glucose is not universally useful for diagnosing diabetes. Diabetes Care. 2009;32:397-403.
3. Khaw KT,Wareham N, Bingham S, Luben R,Welch A, Day N. Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk. Ann Intern Med. 2004;141:413- 420.
4. Consensus Committee. Consensus Statement on the worldwide standardization of the haemoglobin A1c measurement: American Diabetes Association, European Association for the Study of Diabetes, International Federation of Clinical Chemistry and Laboratory Medicine, and the International Diabetes Federation. Diabetes Care. 2007;30:2399-2400.

João F. RAPOSO,MD, PhD
Rua do Salitre, 118-120, 1250
203 Lisbon, PORTUGAL

Not yet. In contrast to type 1 diabetes, type 2 diabetes mellitus (T2DM) has been a difficult disease to diagnose throughout time. In fact, apart from their common definition as hyperglycemic conditions, their etiologies are significantly different.

In my opinion, and having discussed all these arguments, I consider the ADA’s current recommendation of continuing to use previous criteria and of using the new HbA_1c one for the diagnosis of diabetes to be at least prudent and will give us time to answer all these questions. After decades of apparent stagnation, diabetes has been in a state of constant turmoil in the last few years, in different fields. A period of judicious reflection should follow. _

Olga M. SMIRNOVA,MD, PhD, DMedSc
Federal State Institution: Endocrinology
Research Center under the Federal Agency
for High-Tech Medical Care
11 Dmitriya Ulyanova str
Moscow 117036, RUSSIA

Over the past few decades, the diagnosis of diabetes mellitus (DM) has been based on plasma glucose levels, either fasting or 2 hours after a 75-gram oral glucose load. While developing the new diagnostic criteria in 1997, the first Expert Committee on the Diagnosis and Classification of Diabetes Mellitus considered the results of studies that examined the association between fasting plasma glucose (FPG) levels and retinopathy development. Three epidemiologic studies identified the glycemic level below which there was minimal prevalence of retinopathy and above which the prevalence of retinopathy increased in a linear progression. The values of FPG, 2-hour plasma glucose after a 75- gram oral glucose load, and glycated hemoglobin (HbA_1c) were the same for each population. Their study findings allowed the establishment of the diagnostic criteria that are currently recommended by the World Health Organization (WHO).

The significant arguments against the routine use of this assay for these purposes in our country today are the higher cost of the analysis and the absence of the corresponding standardized methods and equipment. I suppose that another obstacle is doctors’ inertia of thinking, especially general practitioners and physicians. On the other hand, in large medical centers, it is not only possible, but entirely feasible to use this assay for screening the limited number of subjects at high risk of DM with obesity and vascular diseases._

Bernardo L. WAJCHENBERG,MD, PhD
University of São Paulo Medical School
São Paulo, SP, BRAZIL

According to what has been suggested by experts in the area of diabetes and now by the American Diabetes Association (ADA), which considers glycated hemoglobin (HbA_1c) an appropriate diagnostic test, the main factors in support of using HbA_1c as a screening and diagnostic test are: HbA_1c does not require patients to fast; it is a marker of chronic glycemia, reflecting average plasma glucose levels over 2 to 3 months; less day-to-day perturbations during periods of stress and illness; methods for its measurement are standardized and reliable; and errors caused by nonglycemic factors, such as hemoglobinopathies, are infrequent. The cutoff point suggested was 6.5%, as at this level the prevalence of diabetic retinopathy begins to rise above that of nondiabetic patients.

Using two cutoff values, rather than one, for HbA1c gives high sensitivity for screening plus optimal specificity for diabetes diagnosis: HbA_1c ≤5.5% and ≥7.0% predicts the absence and presence of type 2 diabetes, while with an HbA_1c of 6.5%- 6.9%, diabetes is highly probable.⁴ _

References
1. Bloomgarden ZT, Einhorn D. Hemoglobin A1c in diabetes diagnosis: Time for caution. Endocr Pract. 2010;16:5-6.
2. van’t Riet E, Alssema M, Rijkelijkhuizen JM, Kostense PJ, Nijpels G, Dekker JM. Relationship between A1c and glucose levels in the general Dutch population: The new Hoorn Study. Diabetes Care. 2010;33:61-66.
3. International Expert Committee: International expert committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care. 2009;32:1-8.
4. Lu ZX, Walker KZ, O’Dea K, Sikaris KA, Shaw JE. A1c for screening and diagnosis of type 2 diabetes in routine clinical practice. Diabetes Care. 2010;33: 817-819.

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Sylvie LAROCHE, MD
Servier International
Suresnes, FRANCE

The results of the Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) in June 2008 highlighted the role of Diamicron MR (gliclazide modified release) as a cornerstone treatment in the clinical management of type 2 diabetes. This agent has been available since 2000 in a 30-mg strength, allowing 24-h coverage with a once-daily dosage. In ADVANCE, Diamicron MR was used in the intensified glucose-lowering strategy and showed distinctive therapeutic benefits in terms of glycemic control, HbA1c reduction (down to 6.5%), and clinical end points, with a 21% reduction in diabetic nephropathy, a 7% reduction in totalmortality, and a 12%reduction in cardiovascularmortality. Last but not least, these benefits were associated with an excellent safety profile with respect to risk of hypoglycemia and absence of weight gain. Importantly, these results were achieved using a specific, simple, and pragmatic algorithm, which led to the optimization of Diamicron MR dosage before the addition of other therapy. At the end of the study, most patients were on the maximum dosage of 120 mg (ie, 4 tablets) per day. Today, a new scored-tablet formulation of Diamicron MR is available, Diamicron MR 60 mg, ensuring improved efficacy through greater ease of use and better patient compliance. Moreover, Diamicron MR 60 mg compares favorably with other oral antidiabetic drugs, thanks to its specific antioxidant properties, giving Diamicron MR 60 mg a unique profile.

With the ever-growing pandemic of type 2 diabetes throughout the world, the burden of vascular complications is expected to rise inexorably. It is thus of the utmost importance to find therapeutic strategies that are able to stabilize, if not prevent, these types of debilitating complications. The last century was witness to staggering discoveries that completely revolutionized the clinical management of type 2 diabetes, beginning with the discovery of insulin in 1921, up to 2000, with the latest discoveries of new pharmacological targets. In parallel, the improvement in pathophysiological knowledge highlighting the role of inflammation and oxidative stress in the pathogenesis of type 2 diabetes, together with epidemiological studies, paved the way for and validated new therapeutic strategies that stress the need to treat patients as early as possible. The United Kingdom Prospective Diabetes Study (UKPDS) in newly diagnosed patients with type 2 diabetes was the first landmark trial to demonstrate the benefit of tight glycemic control inmicrovascular complications and, to a lesser extent, in a subgroup of 342 over-weight patients, in macrovascular complications.^1,2 At the time, “proof of concept” was based on oral therapies, such as sulfonylureas (chlorpropamide and tolbutamide) and metformin, but also on the early use of insulin.

It was not until 2000 that a glycated hemoglobin (HbA_1c) target was carefully evaluated in a series of large morbidity-mortality trials, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE)³ and Action to Control CardiOvascular Risk in Diabetes (ACCORD),⁴ whose results were released at the same time at the American Diabetes Association (ADA) congress in San Francisco in June 2008. The discrepancy in results regarding total and cardiovascular (CV) mortality led to numerous debates, which ended with the publication of the COllaborators oN TRials Of Lowering glucose (CONTROL) meta-analysis,⁵ a meta-analysis of the five megatrials on clinical outcomes advocating a “gentle” strategy like ADVANCE’s, with an individualized approach according to patient profile.

It is nowadays clear that apart from aiming to reach target HbA_1c, the achievement of glycemic control is a far from simple matter. Care and consideration must be taken in choosing a therapeutic strategy with the best benefit-to-risk ratio, the greatest convenience for patients, and the best evidence for clinicians of both short- and long-term clinical benefits.

From discovery to clinical research

The story of the discoveries of oral antidiabetic drugs in the past is absolutely amazing, as many of them were not the result of a systematic, step-by-step approach, but rather more often a matter of chance. This was indeed the case for the biguanides and sulfonamides, which were first developed as anti-infectious agents in the 1940s. In the 1950s, the first generation of another important class of antidiabetic agents, the sulfonylureas, which includes tolbutamide and chlorpropamide, was brought to market. Thanks to the promise shown by the first generation, the next generation of sulfonylureas, which includes glipizide, glibenclamide, glimepiride, and gliclazide (Diamicron), was developed.

The modified-release formulation of Diamicron (DiamicronMR) was first launchedas a 30mg tablet inthe year 2000. It had clear advantages in terms of pharmacokinetic and pharmacodynamic properties, improving bioavailability, enabling once-daily dosage (up to 120 mg per day), and providing less variability and better tolerability, especially with regard to hypoglycemia. Several advantages of this new formulation were subsequently demonstrated, notably regarding the safety profile by direct comparison with other second-generation sulfonylureas like glimepiride (GUIDE [GlUcose control In type 2 diabetes: Diamicronmodified release versus glimEpiride] study),⁶ in which there were twice as few hypoglycemic episodes with Diamicron MR. In recent years, focus has shifted toward ever better performance with the search for a formulation that combines optimal efficacy and compliance.

Nevertheless, the best demonstration of efficacy still remains the gold standard “clinical outcomes” criteria, namely vascular complications, and this was the reason for the design of the ADVANCE study, the largest study ever performed in type 2 diabetes. ADVANCE started in 2000 and its results were disclosed in Diabetologia at the prestigious ADA congress in 2008.

ADVANCE: the integration of evidence-based medicine into clinical management

_ Study design
The ADVANCE study was an investigator-initiated international trial whose design can be found in previous publications.⁷ In summary, ADVANCE was a combined 2×2 factorial study comparing active BP lowering with Preterax (a fixed combination of perindopril/indapamide) versus placebo, and comparing intensive glucose control with Diamicron MR (gliclazide modified release) versus conventional treatment, on major vascular outcomes in diabetes. The trial was conducted in 215 centers and 20 countries. Patients eligible for recruitment were at least 55 years of age, and had a history of microvascular and macrovascular disease or at least one CV risk factor. Patients were randomly assigned to either standard blood pressure control or reinforced blood pressure control with Preterax and to either intensive glucose-lowering therapy with an HbA_1c target of 6.5% or lower, or standard glucose control. The principal treatment in the intensive glucose- lowering regimen was Diamicron MR (30 to 120 mg daily, ie, 1 to 4 tablets daily). Patients in each study group were followed up for a median of 5 years. The primary end points of ADVANCE were a composite of major macrovascular events (nonfatal stroke, nonfatal myocardial infarction, or CV death) and a composite of major microvascular events (new or worsening nephropathy or diabetic eye disease), considered together or separately. Moreover, the two treatment strategies were assessed separately as well as together (in those patients receiving both intensive regimens), so as to determine their joint effect.

Figure 1. Glucose control at baseline and after follow-up in
ADVANCE (Action in Diabetes and Vascular disease: PreterAx
and DiamicroN MR Controlled Evaluation).
Modified from reference 3: ADVANCE Collaborative Group. N Engl J Med.
2008;358:2560-2572. © 2008, Massachusetts Medical Society.

_ Results
_ Main results of the glucose-lowering arm
Of the 12 877 patients from Europe, Canada, Asia, and Australia registered for the study, 11 140 were randomized. Hence, the ADVANCE population was highly representative of the population of patients with diabetes worldwide, and also highly representative of daily clinical practice, patients having a mean age of 66 years and having had diabetes for about 8 years. The two treatment groups had similar blood glucose parameters at baseline, includingmean HbA_1c (7.5%), and fasting plasma glucose (FPG) (8.5 mmol/L). In both groups, 32% of patients had a history of macrovascular disease and 10% had microvascular disease. CV risk factors, including mean blood pressure, serum cholesterol and triglycerides, body mass index, and cigarette smoking, were comparable in the two groups.³ At the end of follow-up, the mean HbA_1c achieved was 6.5% in the intensive group and 7.3% in the conventional group. In the intensive blood glucose–lowering strategy based on Diamicron MR, the target of 6.5% was reached after 36months and wasmaintained until the end of the study. At the end of the study, over 80%of the patients had achieved an HbA_1c≤7%, while 65% had reached an HbA_1c target below 6.5%.⁸ In contrast, standard glucose lowering reduced mean HbA_1c to 7.3% after 6 months and HbA_1c remained stable thereafter (Figure 1).³

A new analysis presented at the International Diabetes Federation (IDF) 2009 in Montreal showed that the efficacy of Diamicron MR on HbA_1c was remarkably consistent across a wide variety of subgroups, defined according to their characteristics at baseline, and in particular regardless of baseline HbA_1c, body mass index (BMI), duration of disease or age, and also previous treatments and treatment regimen (P<0.0001) (Figure 2, Figures 3 and 4 page 66).⁸ The strongest predictor of reduction in HbA_1c during follow-up was baseline HbA_1c. It is also interesting to note that an increase in diabetes duration also independently correlated with a fall in HbA_1c (patients with the longest diabetes duration having the most sustained efficacy on HbA_1c) (Figure 3).⁸

Figure 2. Mean HbA_1c change from baseline to final glucose visit by baseline HbA_1c in ADVANCE.

The intensive glucose-lowering strategy based on Diamicron MR achieved its primary end point, a significant 10% relative risk reduction (RRR) in the composite of macro- and microvascular complications, compared with standard control (18% versus 20%, respectively; P=0.01), and this effect appeared to be driven by a 14% decrease in microvascular events (9.4% versus 10.9%; P=0.01), and particularly by a 21% significant reduction in renal events (new or worsening nephropathy) (P=0.006), together with a 30% decrease in macroalbuminuria (P0.001).³

Figure 3. Mean HbA_1c change from baseline to final glucose visit
by diabetes duration in ADVANCE.

Figure 4. Change in weight by baseline BMI in ADVANCE.

New results presented at the European Association for the Study of Diabetes (EASD) 2010 congress showed that not only was Diamicron MR able to prevent progression to diabetic nephropathy, but that it was also able to regress macroalbuminuria and microalbuminuria to normoalbuminuria—the albuminuria of 62% of patients with baseline albuminuria in the intensively treated group regressed by at least one stage, with the majority achieving normoalbuminuria.⁹

Importantly, in contrast to the ACCORD results, where a significant 22% increase in total mortality was seen,⁴ there was not only no increase in total mortality in ADVANCE, but a 7% reduction (although this was not significant). The reduction in CV mortality (12% decrease, P=0.12) was even more pronounced. Lastly, it should be noted that the effects of study treatment on vascular outcomes were consistent across subgroups of age, sex, baseline blood pressure, baseline HbA_1c, previous vascular disease, or concomitant CV medications.

_ Results from the interaction analysis
The factorial design of ADVANCE also allowed the assessment of the interaction of the two active treatment strategies (Preterax and Diamicron MR) at the end of the follow-up period of the blood pressure–lowering arm of the study (4.3 years). The effects of the two treatments were independent and fully additive, amplifying the benefits of each treatment taken separately, with a significant 24% reduction in CV mortality, a 33% reduction in renal disease, and an 18% reduction in all-cause mortality.¹⁰ It is important to stress that the benefits in terms of diabetic nephropathy are relevant in light of the strong relationship between CV events and indices of renal impairment.¹¹

_ Safety analysis
In the intensive glucose control group, there was no weight gain, even in the obese. Severe hypoglycemia was quite uncommon, although more frequent than in the standard control group (Table I). Compared with ACCORD, there was 6 times less severe hypoglycemia even though median HbA_1c was identical (6.4%) and, furthermore, the 3.5 kg gain in ACCORD puts the weight neutrality observed in ADVANCE into perspective.⁸

Table I. Severe hypoglycemia and weight change in the ADVANCE
and ACCORD studies.

_ What did ADVANCE tell us?
The intensive glucose control strategies used in ADVANCE and ACCORD differed substantially both regarding HbA1c target and how this target was achieved.^3,4 In ADVANCE, opti- mized titration of Diamicron MR up to the maximum dose was implemented before the addition of any other oral antidiabetic, which resulted in progressive rather than aggressive glucose control as seen in ACCORD. Even though the publication of several post hoc analyses of ACCORD tried to analyze the association between increased mortality, especially CV mortality, and multiple parameters, such as severe hypoglycemia and HbA_1c at baseline and during follow-up,^12-14 it is clear today that the treatment strategy in ADVANCE appears to be safe, whereas we still don’t understand the exact underlying cause of excess mortality in ACCORD.

Shortly after the publications of the ADVANCE and ACCORD results, a series of meta-analyses were undertaken to assess and to give a broader perspective of the effect of intensive glucose lowering on macrovascular outcomes by combining the data of several large morbidity-mortality trials (UKPDS, ADVANCE, ACCORD, the Veterans Affairs Diabetes Trial [VADT], and the PROspective pioglitAzone Clinical Trial In macroVascular Events [PROACTIVE] study).^5,15,16 By far, the most interesting of these meta-analyses is the CONTROL meta-analysis,⁵ as it was performed in collaboration with the investigators of each megatrial and analyzed with source data. CONTROL found very consistent results in terms of CV event risk reduction (10% decrease), in particular a decrease in nonfatal myocardial infarction (17% reduction) with no significant effect on stroke or total mortality, although there was heterogeneity between the different trials both in terms of populations studied and therapeutic strategies. A favorable decreasing trend in terms of CV event mortality and morbidity and the best efficacy- to-benefit ratio was found in ADVANCE.¹⁷

In addition to randomized clinical trials (RCTs) like ADVANCE and ACCORD, observational studies are of interest as they provide physicians with a picture of daily practice and are also an important source of additional information when their results are viewed in the context of large RCTs. Several national studies have been published showing a reduction in the risk of vascular complications and death in different subsets of patients, with a trend toward a superior beneficial effect with Diamicron MR.^18-21

Recent retrospective studies with very large cohorts found very consistent findings with ADVANCE, when comparing Diamicron MR with other sulfonylureas (glibenclamide and glimepiride).^22,23 In particular, one nationwide study in more than 70 000 patients with type 2 diabetes that compared different glucose-lowering therapeutic strategies on the risk of overall and CV mortality. The results are particularly interesting as they show that in patients treated solely with Diamicron MR, there was a significant 67% risk reduction in total mortality and a 71% risk reduction in CV mortality, in comparison with glibenclamide.²³ Another national registry, from Denmark, was presented during the last European Society of Cardiology (ESC) congress in Barcelona in 2009. It included more than 8000 Danish type 2 diabetics with a past history of myocardial infarction. All the patients included were treated with oral antidiabetic drugs in monotherapy. Of the oral antidiabetic drugs, Diamicron MR was the only sulfonylurea with a positive trend toward reduction in total mortality, whereas glimepiride and glibenclamide were associated with a significant increase in mortality.²²

_ What next with ADVANCE?
_ ADVANCE-ON
Even though no significant difference in reduction in macrovascular events and mortality could be observed between the intensive and standard blood glucose–lowering treatment groups, a reduction in microvascular events in the intensive blood glucose–lowering group taking Diamicron MR became obvious from the 5th year of treatment onward. The patients in ADVANCE may require much longer follow-up to demonstrate clear benefits in CV outcomes, given that the UKPDS long-termfollow-up took16 to 20 years to demonstrate a clearcut significant difference in death and myocardial infarction.²⁴

Moreover, it is important to consider the lower-than-anticipated rate of events in ADVANCE (less than 3% per year) resulting from the improvement in the multifactorial management of patients with diabetes. This was associated with the lower than anticipated difference in HbA_1c between the intensive and conventional glucose-lowering arms, which may have further limited the possibility of demonstrating a significant effect on macrovascular events. The long-term follow-up of ADVANCE (ADVANCE-ON) has been designed to observe the posttrial effect of intensive glucose lowering with Diamicron MR over a 5-year period, in ADVANCE patients worldwide.²⁵ The two primary outcomes are death from any cause and major CV events. The expected results should confirm the beneficial effects of an intensive glucose-lowering strategy in the long term.

_ ADVANCE risk engine
Providing tools to help clinicians achieve optimal management of their patients with diabetes is fundamental. In the past, the development of risk engines for CV risk estimation were based on two important trials: Framingham (CV risk in patients with an impaired lipid profile) and UKPDS (newly diagnosed diabetic patients). However, clinical management of type 2 diabetes has profoundly changed over the last few decades, owing to results of landmark studies (UKPDS, Steno 2) that shed light on the importance of multifactorial treatment that targets all CV risk factors. As a result, the UKPDS and Framingham risk engines are no longer adequate for the modern management of type 2 diabetes.

Accordingly, a new risk engine has been developed, the ADVANCE risk engine, based on the large and contemporary ADVANCE cohort of patients with type 2 diabetes receiving appropriate therapeutic strategies for optimal clinical man agement.²⁶ When the ADVANCE mathematical model is applied to the Framingham and UKPDS cohorts, the predictive risk of CV events was found to be overestimated, showing the real need for a new tool to adequately predict risk in the modern clinical management of patients with type 2 diabetes.²⁷ It is anticipated that this new model will provide a reliable and valuable tool for alleviating the ever growing burden of CV complications in diabetes.

What makes Diamicron MR 60 mg different from other drugs?

_ Unique structure and formulation
Patient compliance is of the utmost importance in the clinical management of diabetes. The once-daily formulation of Diamicron MR was one of the reasons justifying its choice in ADVANCE. Diamicron MR is the first oral hypoglycemic agent with an innovative formulation based on a hypromellose-based polymer that expands in the gastrointestinal tract to form a gel that progressively releases gliclazide over 24 hours, enabling once-daily administration before breakfast (a factor in improved patient compliance). The release of Diamicron MR 60 mg matches a circadian profile.

At the end of follow-up in ADVANCE, 70% of patients in the intensive glucose-lowering group were receiving the maximal, optimized dose of Diamicron MR of 120 mg/ day, ie, 4 tablets daily, thanks to the progressive and constant titration used in the study (Figure 5).⁸

In accordance with the ADVANCE results, a new formulation was developed: Diamicron MR 60 mg. Diamicron MR 60 mg is the first ever scored modified-release tablet in diabetology.The formulation boasts a unique hydrophilic modified-release matrix. This innovative matrix stores gliclazide inside millions of microunits, allowing the tablet to be scored. This in turn enables the number of tablets to be taken daily to be halved, for both better compliance and better flexibility. This new formulation has been available internationally since 2009.

_ Unique insulin secretion profile
Several studies using a variety of methods have convincingly demonstrated that the loss of the first phase of insulin secretion is one of the earliest demonstrable abnormalities in type 2 diabetes. Restoring this early peak results in improved postprandial glucose control and lower second-phase postprandial insulin levels. Diamicron MR’s pharmacokinetic profile favors this restoration and improves -cell function, restoring glucose-stimulatedinsulin secretion to a near-normal profile, ie, enhancing the first peak of insulin secretion and normalizing the late secretion phase. This has been confirmed by clamp experiments in type 2 diabetic patients as well as in isolated perfused pancreas.^28,29

The molecular mechanism of action of sulfonylureas has been progressively uncovered over the last two decades. Studies with cloned pancreatic-type sulfonylurea receptors have enabled the precise characterization of the receptor interaction profiles of the different sulfonylureas and binding affinity for the different isoforms of the sulfonylurea receptors (SUR-1 in the pancreatic βcell, SUR-2A in myocardial cells, and SUR- 2B in smooth muscle cells). Diamicron binds with high affinity and high selectivity to the SUR-1 receptor and demonstrates rapidly reversible binding, in contrast to the virtually irreversible binding of glibenclamide and glimepiride under the same conditions.^28-32

Figure 5. Mean daily dose of Diamicron MR in patients in the intensive glucose-lowering arm during follow-up in ADVANCE (Action in Diabetes and Vascular disease:
PreterAx and DiamicroN MR Controlled Evaluation).

Thus, the characteristics of the insulin secretion profile induced by Diamicron MR, which are close to those of the physiological profile, provide certain explanations for the lower hypoglycemia risk and weight neutrality reported in ADVANCE.³

_ β-Cell specificity and antioxidant properties
There is growing evidence that β-cell dysfunction is crucial for the development and the progression of type 2 diabetes. Both quantitative and qualitative defects have been reported in the progression of the disease, raising new demands on therapeutic approaches focused on the long-term maintenance of β-cell mass and function.³³

Not only is Diamicron MR selective for pancreatic SUR-1 receptors, but gliclazide also exerts specific antioxidant prop-erties, thanks to the aminoazabicyclo-octyl ring grafted onto the sulfonylurea group, which characterizes its chemical structure. With regard to the β-cell, in vitro experiments on human pancreatic cell lines clearly demonstrate specific protection of β-cell mass and function compared with glibenclamide and glimepiride, under hyperglycemic conditions.^34-36 In the last publication by Del Guerra et al,³⁵ isolated human islet cells exposed to intermittent high glucose concentrations demonstrated decreased responsiveness to acute glucose challenge as well as deleterious effects on β-cell mass. In this experiment, gliclazide, but not glibenclamide, increased Pdx-1 (pancreatic and duodenal homeobox 1) and Ki-67 expression, markers of βcell differentiation and regeneration both at a gene and protein level, in addition to significantly increasing insulin release. This finding confirms and extends previous results on the prevention of β-cell apoptosis under the same experimental conditions.³⁴

Sustained glycemic control is a very important goal in the management of type 2 diabetes. In ADVANCE, the target of HbA_1c ≤6.5% was achieved with intensive Diamicron MR– based therapy, and this effect was obtained progressively over 36 months and remained stable thereafter, delaying the use of insulin by up to 44 months after randomization.³⁷ This has also been documented in previous studies comparing Diamicron with other sulfonylureas, including one with glibenclamide.³⁸ This study investigated the time interval before the initiation of insulin therapy, and found a significantly longer interval before the initiation of insulin with Diamicron (mean 14.5 years) than with glibenclamide (mean 8 years), along with better blood glucose control, as shown by HbA_1c values (6.8% vs 7.4%, respectively; P<0.0001). These benefits might be explained by the direct protective effect of Diamicron MR on pancreatic β-cell function.

Last but not least, the beneficial effect of Diamicron MR shown in ADVANCE regarding micro- and macrovascular end points may be partially explained by the free radical–scavenging properties of DiamicronMR. In a previous study, DiamicronMR was shown to have beneficial effects on the progression of atherosclerosis, which was assessed by the measurement of the average carotid intima-media thickness. The outcome with Diamicron MR was better than that with glibenclamide inpatients with type 2 diabetes.³⁹ The antiatherogenic effect of DiamicronMR could be due to its antioxidant properties, which restore endothelial function, reduce platelet reactivity, and exert an anti-inflammatory effect.^40-45

From international guidelines to daily practice

The past two years have seen an incredible amount of data come from megatrials such as ADVANCE and ACCORD, and it has taken time to take on board the new lessons arising from these apparently discrepant results. Now the “hot debate” phase is over, it is the time for implementation, and the new guidelines from the ADA, EASD, and IDF will undoubtedly help clinicians to realize these lessons in their daily clinical practice.

The ADVANCE intensive glucose-lowering strategy based on Diamicron MR proved to be the most pragmatic and most practical, as well as being the strategy with the best benefitto- risk ratio, for ensuring efficient and long-term sustained lowering of HbA_1c down to 6.5% in a representative population of patients with type 2 diabetes. Not only was glycemic control achieved, but Diamicron MR–based therapy was also proven to protect patients from vascular complications, especially nephropathy (with a 21%decrease), and even to regress albuminuria to normoalbuminuria (in 62% of patients with albuminuria at baseline).

New guidelines are now focusing on the need to tailor clinical management to the different phenotypes in the wide and heterogeneous population of patients with type 2 diabetes. Subgroup analysis in the ADVANCE population showed very consistent results with Diamicron MR, whatever the patient profile at baseline, together with an excellent safety profile.

Conclusion

Only a stepwise approach with a safe, proven, and effective strategy will enable the medical community to curb the growing diabetes pandemic worldwide. Diamicron MR 60 mg offers a unique solution with the best combination of efficacy, safety, and weight neutrality, while offering patients an innovative formulation to help compliance. This therapeutic strategy constitutes a key step in a multifactorial approach ensuring maximum benefit and safety for all type 2 diabetic patients. _

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Keywords: diabetes; intensive glucose lowering; diabetic complications; vascular complications; nephropathy; treatment; clinical management; clinical trial; ADVANCE; gliclazide MR