Implications of ADVANCE in the management of glucose lowering in diabetic patients

by D. R. Matthews,United Kingdom

DPhil, BM, BCh, FRCP
Oxford Centre for Diabetes,
Endocrinology and Metabolism
National Institute for Health
Research, Oxford Biomedical
Research Centre, Oxford

Major studies have addressed the problem of whether improved glycemic control would improve the outcome in type 2 diabetes. Two large studies from the 20th century caused controversy: the Universities Group Diabetes Program (UGDP) raised a suggestion that tolbutamide might not be efficacious, and the United Kingdom Prospective Diabetes Study (UKPDS) had an equivocal outcome for myocardial infarction. In recent years, a number of landmark studies, including PROspective pioglitAzone Clinical Trial In macroVascular Events (PROACTIVE), Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE), Action to Control CardiOvascular Risk in Diabetes (ACCORD), Veterans Affairs Diabetes Trial (VADT), Steno 2, and the United Kingdom Prospective Diabetes Study-PostTrial Monitoring (UKPDS-PTM) have all reported. Ongoing trials, such as Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycemia in Diabetes (RECORD) and Outcome Reduction with an Initial Glargine Intervention (ORIGIN), may add to our knowledge. The outcomes from these trials have given some answers. We are now convinced that early intervention and intensive control is worthwhile. However, there are still unanswered questions, including questions of interpretation and uncertainties about the choice of agents.

Medicographia. 2009;31:245-250 (see French abstract on page 250)


Type 2 diabetes is now pandemic. In the World Health Organization report of 1997 the world estimate for diabetes was 140 million people. The estimates from current epidemiology suggest that this number will increase to 200 million people by the year 2010, and to 300 million by 2025. The problem is not one confined to country, race, or geographical location. Type 2 diabetes pervades societies in countries as diverse as Mexico, China, Japan, and the Ukraine.

The challenge for health care in the 21st century is one of provision of appropriate health care and establishing therapeutic regimes which optimize the outcome of metabolic control in the short term and minimize tissue damage, including retinopathy, neuropathy, nephropathy, stroke, and heart disease, in the longer term. Epidemiological studies from a wide range of data sources suggest that relative risks for ischemic heart disease are probably 3 times those of nondiabetic individuals, and that overall all-cause morbidity from diabetes-associated pathology is twice that of the nondiabetic age-matched population.

What is appropriate treatment for type 2 diabetes? What should our goals and targets be? How aggressively should we be treating hyperglycemia? Are there targets and goals to which we should adhere or simply aspire?

Trials of glycemic control

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 quality of life and to longevity in type 2 diabetes. Clinical acumen and observation had demonstrated that allowing glycosuria and very high blood glucose levels led to poor quality of life, but some physicians, up until late into the 20th century, were still thinking that perhaps poor control had an advantage in terms of weight loss. It was certainly cheaper than intensive therapy.

The Universities Group Diabetes Program (UGDP)1 was the first to attempt to answer the question using a controlled trial approach: launched in 1960, this placebo-controlled, multi- center clinical trial aimed to determine which, if any, of the treatments for type 2 diabetes was efficacious. Although the differences seen in the 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 in that, at baseline, there were 30% more ECG abnormalities, 40% more angina, and 90% more hypercholesterolemia in the tolbutamide group.2 So, randomization had failed to deliver equipoise in the outcome.

The United Kingdom Prospective Diabetes Study (UKPDS) was established to give a definitive answer to the glycemic control controversy as well as an attempt to answer important questions about class of agents used to achieve control.3 The UKPDS had stringent aims for glycemia, but allowed for fasting glucose to rise to 15 mmol/L before adding new therapies. Because it aimed to address the questions about which therapy should be used, the glycemia rose progressively throughout the trial. At the closeout, the results showed that intensive glucose control was efficacious in reducing many complications, but the results for myocardial infarction were borderline with a statistical value for efficacy of P=0.052.4,5 The world divided into the statistical fundamentalists, who used this as evidence against the hypothesis that macrovascular disease could be prevented by good glycemic control, and into those who pointed out that the odds of glycemic control not being important were 1 in 19.2 as opposed to 1 in 20.

The UKPDS used an intensive versus conventional treatment for blood-glucose control and achieved HbA1c in the study population of 7% in the intensive groups compared with 7.9% HbA1c in the conventional group. The totality of diabetes related end points was reduced by 12% (relative risk [RR], 0.88; 95% confidence interval [CI], 0.79-0.99).5 The contribution to the risk reduction was both from microvascular complications (RR, 0.75; 95% CI, 0.60-0.93) and myocardial infarction (RR, 0.84; 95% CI, 0.71-1.0).6 So questions remained— especially the question of how low should one aim in glycemic control. We did not know the extent to which more aggressive glucose control would decrease macrovascular or microvascular disease in conventionally normotensive diabetic patients. Nor did we understand the extent to which there might be differences in the outcomes between different racial groups. So, the question remained open. With new agents and new enthusiasm to demonstrate how diabetes should best be treated, a series of trials were initiated.

In 2005, PROspective pioglitAzone Clinical Trial In macro- Vascular Events (PROACTIVE)7 reported its results: it 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” was the composite of all-cause mortality, nonfatal myocardial infarction, and stroke: this showed a significant favorable response to pioglitazone (P=0.027).

So, the trial was marred by the known problem of selecting a primary combined outcome which involved not only the onset of new pathology, but the surgical interventions relating to pathology. Combining outcomes may increase the event count, but can do so at the expense of specificity.

Then, in 2007, Nissen et al8 produced a meta-analysis which seemed to demonstrate that rosiglitazone might have an ad- verse effect on cardiovascular outcome. That meta-analysis has been criticized,9 especially on the basis that the metaanalysis was not a comprehensive search for all studies that might yield evidence about rosiglitazone’s cardiovascular effects and that studies were combined on the basis of a lack of statistical heterogeneity, despite variability in study design and outcome assessment. Diamond et al9 concluded that the risk for myocardial infarction and death from cardiovascular disease for diabetic patients taking rosiglitazone was uncertain, and stated that “neither increased nor decreased risk is established”. One should certainly not regard such combinatorial analysis as being evidentially as good as a randomized trial. At this point, Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycemia in Diabetes (RECORD), an intervention trial using rosiglitazone, was under pressure to produce an early interim analysis,10 and this reported that, in a total of 217 patients in the rosiglitazone group and 202 patients in the control group, the hazard ratio for hospitalization or death from cardiovascular cause was 1.11 (95% CI, 0.93- 1.32) and there were more patients with heart failure in the rosiglitazone group than in the control group (hazard ratio [HR], 2.15; 95% CI, 1.30-3.57). So, it remains to be demonstrated that the use of rosiglitazone is not associated with cardiovascular risk. Then, in the summer of 2008,3 cardiovascular disease (CVD) trials reported at the American Diabetes Association. These were the Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE),11 the Action to Control CardiOvascular Risk in Diabetes (ACCORD),12 and the Veterans Affairs Diabetes Trial (VADT)13 trials. ACCORD produced a startling headline result that mortality was worse in the group that was intensively treated to lower HbA1c toward 6%. At 1 year, stable median glycated hemoglobin 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 occurred in 352 patients in the intensive-therapy group, compared with 371 in the standard- therapy group (HR, 0.90; 95% CI, 0.78-1.04; 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, 1.01-1.46; P=0.04).12 This then raised the question again about the main result from UKPDS. Is intensive glucose lowering actually harmful? Nevertheless, one cannot compare the patients in ACCORD directly with those recruited into UKPDS (Figure 1). UKPDS recruited “healthy” newonset type 2 diabetes patients (serious disease of any kind was a contraindication). In ACCORD, patients were 10 years into established diabetes and were selected for preexisting cardiovascular disease or specific risk factors. Making sudden changes in glycemia in such patients may not be a smart therapeutic idea. In fact, in this trial, the reports show that the majority of the glucose-lowering effect was already achieved within the first 4 months, by which time the median HbA1c was 6.6%. Although there was no explicit evidence that hypoglycemia was the precipitating cause of death, it remains the highest suspect for the increased death rate. Hypoglycemia rates were 3 times higher in the intensively treated group, and death precludes a contemporaneous measurement of blood glucose. Many of the patients were receiving rosiglitazone (91% in the intensive and 57% in the standard therapy arm, respectively). The excess mortality was not simply cardiovascular, but hypoglycemia can cause falls or aspiration at night, leading to pneumonia. In the elderly, any significant medical event may be seriously life-threatening.

Figure 1
Figure 1. Schematic of HbA1c in the study populations of UKPDS, ACCORD, and ADVANCE. The schematic shows how these studies are not directly comparable in terms of their populations, especially with regard to duration of diabetes at recruitment. Grey lines are the control groups. Left group of four lines all relate to UKPDS: grey = conventional treatment; green = glibenclamide; blue = chlorpropamide; and red = insulin. Right group of lines relate to: ACCORD, solid lines (——); and ADVANCE, dashed lines (—-) [red = intensive group for both studies].
Abbreviations: ACCORD, Action to Control CardiOvascular Risk in Diabetes; ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation; UKPDS, United Kingdom Prospective Diabetes Study.

ADVANCE11 was 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 (MR) plus other drugs, as required, to achieve an HbA1c value of 6.5% or less. After a median of 5 years of follow-up, the mean HbA1c in the intensive-control group had achieved 6.5% compared with 7.3% in the control group. In the intensive group, there was a reduced incidence in the combined end point of major macrovascular and microvascular events (HR, 0.90; 95% CI, 0.82-0.98; P=0.01) as well as that of major microvascular events (9.4% vs 10.9%; HR, 0.86; 95% CI, 0.77-0.97; P=0.01), primarily because of a reduction in the incidence of nephropathy (HR, 0.79; 95% CI, 0.66-0.93; P=0.006). However, there were no significant effects of the type of glucose control on major macrovascular events (HR with intensive con- trol, 0.94; 95% CI, 0.84-1.06; P=0.32), death from cardiovascular causes (HR with intensive control, 0.88; 95% CI, 0.74- 1.04; P=0.12), or death from any cause (HR with intensive control, 0.93; 95% CI, 0.83-1.06; P=0.28).

Comparisons between the trials

The effects shown in the ADVANCE trial were mainly attributable to a 21% relative reduction in nephropathy, but unlike in the ACCORD trial, there was no signal that achieving the target of 6.5% gradually over 4 years had any detrimental cardiovascular effects nor any increased mortality. How can one explain the differences between these outcomes?

Figure 2
Figure 2. Summary of the evidence for glycemia trials in type 2 diabetes. The lines show the stylized glycemia over time, and the boxes summarize the evidence from the trials.
Abbreviations: ACCORD, Action to Control CardiOvascular Risk in Diabetes; ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation; PROACTIVE, PROspective pioglitAzone Clinical Trial In macroVascular Events; RECORD, Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycemia in Diabetes; UKPDS, United Kingdom Prospective Diabetes Study. UKPDS-PTM, United Kingdom Prospective Diabetes Study-PostTrial Monitoring.

ADVANCE used gliclazide (mainly gliclazide modified release) to achieve a lower glycemia in the intensive control group, and this contrasts with ACCORD where there was a high usage of rosiglitazone (in both arms) and insulin and sulphonylurea, in combination. In ACCORD, the glycemic targets were aggressively pursued, and the control of glycemia over time did not deteriorate (Figure 2). By contrast in ADVANCE, the target of HbA1c below 6.5% was achieved only 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. On the other hand, the duration of diabetes was similar (8 years). So, the differences between the 2 trials was a marked difference in rate of achievement of target glycemia, a very high hypoglycemia rate in ACCORD (a nearly 4 times greater rate than in ADVANCE), and a clear difference in the choice of agents for the 2 trials. ACCORD suggests that intensive glycemic control achieved fast and late in diabetes using multiple agents might not be wise. ADVANCE suggests that achieving such targets over several years is not contraindicated, and there may be gains to be achieved in the prevention of renal disease.

The VADT trial also presented its results at the American Diabetes Association meeting, though they were not then available in print. The trial ran for about 6 years, but the numbers of patients were few, and it was not surprising that there was no differential in the cardiovascular outcome. Essentially, the trial was under powered—1792 subjects14 followed for “5 to 7” years.13 This was a strange error to make in view of the known longevity of UKPDS in terms of patient years required to produce a meaningful answer. A subgroup analysis of calcification in VADT<15 suggested that this was a clear marker of CVD risk—though these data do not help us decide on the generality of CVD risk reduction.

UKPDS long-term follow-up

In 2008, the glycemic control debate was galvanized not only by the presentation of the outcomes of seminal trials, but also by the publication and simultaneous presentation of the United Kingdom Prospective Diabetes Study-PostTrial Monitoring (UKPDS-PTM).16 This examined the outcome of the patients in UKPDS 10 years after the trial had finished. It examined the question of 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 follow patients who were unable to attend the clinics, and all patients in years 6 to 10 were assessed through questionnaires. For 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 10 years, the effects of lower incidence of pathology were 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 (Figure 3). 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 an early loss of glycemic differences, a continued reduction in microvascular risk and emergent risk reductions for myocardial infarction and death from any cause were observed during 10 years of posttrial follow-up.

Figure 3
Figure 3. Hazard ratios (intensive vs conventional treatment) for poststudy monitoring in UKPDS. During this period, the glycemic control of the two groups converged, so that there was no significant difference in glycemic exposure. Upper panel shows data for any diabetes-related end point and lower panel for myocardial infarction.
Abbreviations: UKPDS, United Kingdom Prospective Diabetes Study.

Clinical implementation

How do these data help in making decisions about what we should do in clinical practice? It is paradoxical that it has taken the UKPDS-PTM 20-year duration trial and a 10-year posttrial follow-up to establish that early intervention in glycemic control is worthwhile. Is it worth intervening after 8 or 10 years of indifferent control? The answer seems to be “yes,” but we need to add particular caveats. 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, then one can at least get gains from less renal pathology.

What agents should one use? The peroxisome proliferatoractivated receptor ã (PPARã) agonist pioglitazone has emerged as efficacious in the light of the PROACTIVE trial, but rosiglitazone still has to be proved to be effective in cardiovascular outcomes. The evidence tends to point in the other direction.

What about sulphonylureas? Despite the debates dating back to the UGDP, and the fear that â-cell failure might be affected, the sulfonylureas have continued to stand the test of time. There was no detrimental signal from UKPDS or from UKPDSPTM,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 the new analogue insulins? The Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial17 will report soon on CV outcome in a trial of people aged over 50 years with evidence of cardiovascular disease and with impaired fasting glucose, impaired glucose tolerance, or newly detected or established diabetes randomized to glargine or standard care to achieve fasting glucose of 5.3 mmol/L or less in the intensive group.

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 risk to life as well as to quality of life. Hypoglycemia in the elderly may lead to internal pathology (the myocardium is unlikely to function well) and will certainly cause threatening events related to falls, aspiration pneumonia, accidents, forgetfulness, and other significant risks.


All the trial data suggest that hyperglycemia is a risk for cardiovascular disease and should be lowered if possible. The targets for glycemia are for HbA1c lower than 7.5%, and may be nearer 6.5%, if achieved slowly and without dangerous hypoglycemia.

Finally, one should remember that diabetes cannot be treated simply as a disease of abnormal glucose. The trial data are strongly indicative that lipids and blood pressure18 should be treated in parallel, and the Steno 219,20 trial—a trial of multiple intervention care-packages—suggests real benefits from this approach.


1. 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.
2. Leibel B. An analysis of the University Group Diabetes Study Program: data results and conclusions. Can Med Assoc J. 1971;105:292-294.
3. UKPDS Group. UK Prospective Diabetes Study VIII: Study design, progress and performance. Diabetologia. 1991;34:877-890.
4. 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.
5. 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.
6. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405-412.
7. 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.
8. 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.
9. 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.
10. Yamasaki Y, Kawamori R, Wasada T, et al; AD-4833 Glucose Clamp Study Group. Pioglitazone (AD-4833) ameliorates insulin resistance in patients with NIDDM. Tohoku J Exp Med. 1997;183:173-183.
11. 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.
12. 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.
13. Abraira C, Duckworth W, McCarren M, et al. Design of the cooperative study on glycemic control and complications in diabetes mellitus type 2: Veterans Affairs Diabetes Trial. J Diabetes Complications. 2003;17:314-322.
14. Duckworth WC, McCarren M, Abraira C. Control of cardiovascular risk factors in the Veterans Affairs Diabetes Trial in advanced type 2 diabetes. Endocr Pract. 2006;12(suppl 1):85-88.
15. Reaven PD, Emanuele N, Moritz T, et al. Proliferative diabetic retinopathy in type 2 diabetes is related to coronary artery calcium in the Veterans Affairs Diabetes Trial (VADT). Diabetes Care. 2008;31:952-957.
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. Gerstein H, Yusuf S, Riddle MC, Ryden L, Bosch J; Origin Trial Investigators. Rationale, design, and baseline characteristics for a large international trial of cardiovascular disease prevention in people with dysglycemia: the ORIGIN Trial (Outcome Reduction with an Initial Glargine Intervention). Am Heart J. 2008;155: 26-32.
18. 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.
19. 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.
20. 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.