Controversial Question :HbA1c targets: does one size fit all or should they be tailored to individual patients?




HbA1c targets: does one size fit all or should they be tailored to individual patients?


1. B. Bauduceau, France
2. F. Carrilho, Portugal
3. L. Czupryniak, Poland
4. N. Ghannam, Saudi Arabia
5. L. Litwak, Argentina
6. B. Mankovsky, Ukraine
7. M. Mota, D. Protasiewicz, S. G. Popa, Romania
8. A. Orabi, Egypt
9. U. Phadke, India
10. M. V. Shestakova, Russia
11. L. Smircic-Duvnjak, Croatia
12. B. Tschiedel, Brazil
13. Z. Visockiene, Lithuania


1. B. Bauduceau, France

Bernard BAUDUCEAU, MD
Professor, Department of Endocrinology
Begin Hospital, Avenue de Paris
94160 Saint-Mandé, FRANCE
(e-mail: bernard.bauduceau@wanadoo.fr)



The discrepancies between different international recommendations clearly show that determining an optimal glycated hemoglobin (HbA1c ) target is not an easy task. However, the majority of these recommendations indicate that an HbA1c target of 7% is good enough for all diabetic patients.

In diabetology, the year 2008 was replete with learning experiences and suspense.1 Past studies, the UKPDS (United Kingdom Prospective Diabetes Study) in type 2 diabetic patients and the DCCT (the Diabetes Control and Complications Trial) in type 1 diabetic patients, have shown that intensive treatment over a short period reduces the incidence of microvascular events and, in the long term, the incidence of macrovascular events linked to diabetes.2 Nevertheless, conclusions from recent analyses of ACCORD (the Action to Control CardiOvascular Risk in Diabetes study) showed increased mortality in type 2 diabetic patients that used an intensive therapy.3 ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation), on the other hand, showed a 12% reduction in cardiovascular death and a 21% reduction in nephropathy in such patients.4 And the VADT (Veterans Affairs Diabetes Trial) showed no effect. Analysis of studies published since 2008 has contributed new knowledge, especially concerning glycemic memory, to clinical practice. Consequently, we now understand the importance of earlier detection and treatment of diabetic patients through lifestyle improvements and drugs, if necessary. Thus, early treatment of diabetes and prevention of hypoglycemia should be essential components of treatment strategies.

Moreover, results from the Steno-2 study showed that control of cardiovascular risk factors dramatically improves the prognosis of type 2 diabetes.5 The treatment of hypertension, for example, is always useful because of the absence of tensional memory. Though management of type 2 diabetic patients requires early treatment combined with strict control of cardiovascular risk factors, this should be done without intensive methods, so as to avoid hypoglycemia. HbA1c targets should be based on many criteria, including patient characteristics and potential adverse drug events, such as hypoglycemia. Thus, there is no single HbA1c level that can be considered the optimal target for all diabetic patients.

HbA1c targets must be individualized, as is the profile of each patient, including age, history of diabetes, presence of complications, and potential risk of hypoglycemia. To summarize and to simplify, a young diabetic patient with recently discovered diabetes and without cardiovascular complication should receive intensive treatment in order to reach the target HbA1c level of 6.5%. On the other hand, much caution should be exercised for elderly or frail patients. The risk of hypoglycemia is very high for this population with cardiovascular or cerebral complications. Cognitive decline, dementia, and depression in elderly patients increase the risk of hypoglycemia, leading to poor quality of life with considerable social and economic impacts. Accordingly, the target HbA1c level must be adjusted to lie between 7.5% and 8.5%.

In conclusion, we should focus on the patient. Definition of the HbA1c target must consider all the characteristics of the particular diabetes condition, comorbid diseases, and the social situation of each patient. _

References
1. Cugnet-Anceau C, Bauduceau B. Glycaemic control and cardiovascular morbimortality: the contribution of the 2008 studies. Ann Endocrinol (Paris). 2009; 70:48-54.
2. 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.
3. Bonds DE, Miller ME, Bergenstal RM, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ). 2010;340:b4909.
4. ADVANCE Collaborative Group; 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.
5. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med). 2008;358:580-591.

2. F. Carrilho, Portugal

Francisco CARRILHO, MD
Department of Endocrinology
University Hospital
Praça Mota Pinto, 3000
Coimbra, PORTUGAL
(e-mail: fmcarrilho@netcabo.pt)



Type 2 diabetes is a very complex disease, more so than we previously thought. Patients with type 2 diabetes treated with aggressive management of glycemic control and cardiovascular risk factors have greater benefits in regard to microvascular complications, but remain at elevated risk of cardiovascular morbidity and mortality. Type 2 diabetes is also associated with increased risk of cancer, cognitive decline, and chronic liver disease.1 Many clinicians are calling for a more realistic approach to treatment of patients with type 2 diabetes. They emphasize that diabetic patients are very different from one another with regard to age, duration of disease, motivation, associated comorbidities, and so on.2

Glycated hemoglobin (HbA1c) is the principal target of treatment as it reflects blood glucose level and is associated with the risk of microvascular and macrovascular complications. In the UKPDS (United Kingdom Prospective Diabetes Study), intensive therapy was associated with a reduction in the risk of microvascular complications; however, reduction in myocardial infarction rates did not reach statistical significance. Nevertheless, the 10-year follow-up demonstrated statistically significant benefits in terms of cardiovascular end points and total mortality in the intensive group. Thus, macrovascular benefits emerge over time and so take longer to evaluate.3

Three studies—ACCORD (Action to Control CardiOvascular Risk in Diabetes), ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation), and the VADT (Veterans Affairs Diabetes Trial)—published in 2008, with two protocols for more intensive or less intensive glycemic control, evaluated cardiovascular end points in middle- aged and older diabetic patients with high risk for cardiovascular events. ACCORD and the VADT used oral agents, insulin, and a target HbA1c of <6.0%. ADVANCE patients were treated with gliclazide targeting an HbA1c of <6.5%. None of the trials demonstrated a significant reduction in the combined cardiovascular end points. A 22% increase in total mortality, mainly attributable to cardiovascular mortality, with intensive treatment was found in ACCORD. Was hypoglycemia the cause for this high mortality rate or was it due to the higher complexity of the patients and therapies?4

Patient-centered care is “providing care that is respectful of and responsive to individual patient preferences, needs, and values.”5 Patient preferences are particularly important with regard to lifestyle choices as this defines how patients live their everyday lives. Pharmaceutical intervention can also be, to some degree, a shared-decision approach. Involvement of the patient in health care decisions enhances adherence to therapy.

For clinical practice, the results of the aforementioned studies suggest that intensive glycemic treatment of diabetic patients is not good for all. The new perspective emphasizes individualized treatment objectives and targets. To decide on an HbA1c target, the clinician needs to evaluate: (i) patient attitude and cooperation; (ii) hypoglycemia and associated risks; (iii) disease duration; (iv) life expectancy; (v) associated comorbidities and established vascular complications; (vi) costs, and health care system support.5

Some health care organizations evaluate the percentage of diabetic patients who achieve an HbA1c of <7.0% as a quality indicator, but such practice is inconsistent with an emphasis on individualization of the treatment of type 2 diabetic patients.5 The American Diabetes Association recommends an HbA1c of <7.0% for the great majority of patients in order to reduce microvascular complications.6HbA1c targets of 6.0%- 6.5% may be appropriate in patients with short disease duration, no vascular comorbidities, no important hypoglycemic events, and a long life expectancy. However, HbA1c targets of 7.5%-8.0% or slightly higher may be appropriate for more complicated patients with important vascular comorbidities, severe hypoglycemia, and limited life expectancy. In conclusion, we must tailor the HbA1c target to the patient. _

References
1. Matthews DR, Tsapas A. Four decades of uncertainty: landmark trials in glycaemic control and cardiovascular outcome in type 2 diabetes. Diab Vasc Dis Res. 2008; 5:216-218.
2. Smith RJ, Nathan DM, Arslanian SA, Groop L, Rizza RA, Rotter JI. Individualizing therapies in type 2 diabetes mellitus based on patient characteristics: what we know and what we need to know. J Clin Endocrinol Metab. 2010;95:1566-1574.
3. 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.
4. Skyler JS, Bergenstal R, Bonow RO, et al; American Diabetes Association; American College of Cardiology Foundation; American Heart Association. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Diabetes Care. 2009; 32:187-192.
5. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2012;55:1577-1596.
6. American Diabetes Association. Standards of medical care in diabetes—2011. Diabetes Care. 2011;34(suppl 1):S11-S61.

3. L. Czupryniak, Poland

Leszek CZUPRYNIAK, MD, PhD
Department of Internal
Medicine and Diabetology
Barlicki University Hospital No. 1
Medical University of Lodz
Lodz, POLAND
(e-mail: leszek.czupryniak@umed.lodz.pl)



In 2012, the answer to this question is simple: we should absolutely tailor the therapy target to every patient we treat. However, only a few years ago, the answer would have been quite the opposite: treat all diabetic subjects to one glycated hemoglobin (HbA1c) target, eg, ≤7% according to the American Diabetes Association and the European Association for the Study of Diabetes (ADA/EASD) consensus1 or ≤6.5% as per the International Diabetes Federation (IDF) guideline.2 Our view on blood glucose targets and hyperglycemia management strategies in type 2 diabetes changed thoroughly in 2008.

In 2008, the results of ACCORD (Action to Control CardiOvascular Risk in Diabetes)3 and the VADT (Veterans Affairs Diabetes Trial)4 were published, showing that targeting an HbA1c of <6.5% or <7% is beneficial only for younger patients without a history of microvascular and macrovascular complications. These data sparked many analyses and commentaries,5 and eventually led to publication of the extensively revised ADA/EASD position statement in April 2012.6

That position statement is a milestone in the history of diabetes guidelines. It very convincingly documents why we should abandon the one-target-fits-all strategy and depicts the complexity of type 2 diabetes management. For the first time, such elements like patient motivation, hypoglycemia-associated risks, disease duration, life expectancy, presence of comorbidities and advanced vascular complications, and the availability of health care resources were strongly recommended to be taken into account while setting therapy targets. The importance of the individualization of dietary and exercise advice as well as drug regimens has also been fully justified, and various HbA1c targets have been proposed. An HbA1c of<7.0% is recommended in most patients so as to reduce the incidence of microvascular disease; more stringent targets of 6.0%-6.5% are for patients with short disease duration, long life expectancy, and no significant cardiovascular disease, providing this can be achieved without significant hypoglycemia or other adverse effects of treatment; and less stringent goals (7.5%-8.0% or even higher) are appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced complications, extensive comorbid conditions, and those in whom the target is difficult to attain despite intensive education and effective doses of multiple glucose-lowering agents. Most importantly, the position statement makes it clear that the desires and values of the patient should be considered, since the achievement of any degree of glucose control requires his or her active participation and commitment. In fact, any decided target should reflect an agreement between patient and clinician.6

Therefore, a 52-year-old woman with newly diagnosed type 2 diabetes should be treated so that her blood glucose remains within the (near) normal range. Why? Simply put, in the clinic, when we see a “healthy” (without other significant health problems) type 2 diabetic, we should do our best to maintain that patient’s health and protect the cardiovascular system from being damaged by hyperglycemia in the years to follow. However, for a 75-year-old man treated 20 years for type 2 diabetes, who has a history of myocardial infarction, repeated panretinal photocoagulation and right big toe amputation, the target should be somewhere between 7% and 8%. We know today that lowering his blood glucose to achieve an HbA1c of <6.5% will not repair his vasculature or reduce his cardiovascular risk. Tailoring HbA1c targets, leading to diversifying of glucose control regimens may be considered bad news for the medical community, as type 2 diabetes treatment will become more varied and thus complicated; however, it is great news for the patients, as we will be able to help each of them more— as different as they are—without doing (or at least doing less) harm. _

References
1. Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2006;49:1711- 1721.
2. Ceriello A, Colagiuri S, Gerich J, Tuomilehto J; Guideline Development Group. Guideline for management of postmeal glucose. Nutr Metab Cardiovasc Dis. 2008;18:S17-S33.
3. Action to Control Cardiovascular Risk in Diabetes Study Group; Gerstein HC, Miller ME, Byington RP. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545-2559.
4. Duckworth W, Abraira C, Moritz T, et al; for the VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129-139.
5. Czupryniak L, Szymanska-Garbacz E, Pawłowski M, Saryusz-Wolska M, Loba J. Intensified glucose lowering in type 2 diabetes: time for a bolder reappraisal. Diabetologia. 2011;54:701-702.
6. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2012;55:1577-1596.

4. N. Ghannam, Saudi Arabia

Nadia GHANNAM, MB, ChB, FRCPC, FACP
Consultant Endocrinologist
Section Head of Endocrinology
Director of Diabetes & Endocrinology
Center of Excellence
Clinical Nutrition Department
P. O. Box 2172, Jeddah 21451
SAUDI ARABIA
(e-mail: nghannam@imc.med.sa)



Glycated hemoglobin (HbA1c) measurement is integral to the management of individuals with diabetes.1 Studies such as UKPDS (United Kingdom Prospective Diabetes Study) and ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroNMR Controlled Evaluation) have confirmed that lowering HbA1c is of great importance to achieve risk reduction for complications in patients with diabetes. The recommended target of HbA1c <7% basically comes from studies such as ADVANCE, ACCORD (Action to Control CardiOvascular Risk in Diabetes), and the VADT (Veterans Affairs Diabetes Trial). ACCORD and the VADT both showed increases in cardiovascular disease morbidity and mortality risks, therefore the International Diabetes Federation (IDF), the American Diabetes Association (ADA), and most diabetes societies generally recommended the target of HbA1c <7.0% which is less strict, but recommended to aim for a lower HbA1c in patients who are younger, who have had diabetes for a short time, and who have no cardiovascular complications. Therefore, there is a general target and there is an individualized target. This is very important, especially when addressed as early as possible, as it has been suggested that with earlier and more aggressive intervention, we are more successful in reaching the target than with conventional therapy, and the resulting benefit is known as the legacy effect.2

Why should we address HbA1c levels? One reason is that the UKPDS showed a relationship between the risk of fatal myocardial infarction (MI), nonfatal MI, and risk reduction for complications with lowering of HbA1c. Other published data shows that HbA1c level is a predictor of mortality, and this increase in risk appears between the levels of 5%-6% and is obvious at an HbA1c >7.0%.3

To sum up, there are three major points each clinician should keep in mind when measuring baseline HbA1c in patients with diabetes and when trying to reach an HbA1c target: (i) Is the patient already at the general target for HbA1c, ie, <7%? If yes, is it possible and is it safe to target a lower HbA1c, ie, <6.5%? If baseline HbA1c is not <7%, the aim should be to reach this target and then reevaluate the need for a lower HbA1c. (ii) Is it possible to target an HbA1c of <6.5% for a particular patient? (iii) Apart from HbA1c and hyperglycemia, are there other associated comorbidities that need to be addressed in order to reduce the risk of cardiovascular complications? These comorbidities may include blood pressure, triglycerides, low density lipoprotein cholesterol, and high-density lipoprotein cholesterol.4

Finally, the argument should not be about trying to find a particular HbA1c target that fits all patients. Even an acceptable target might be “too loose” or “too tight” for some patients. Thus, the target should be individualized, for example, we definitely need an aggressive approach targeting an HbA1c <6.5% for newly diagnosed and younger patients with no diabetes complications. _

References
1. Little RR, Sacks DB. HbA1c: how do we measure it and what does it mean? Curr Opin Endocrinol Diabetes Obes. 2009;16(2):113-118.
2. Del Prato S, Felton AM, Munro N, Nesto R, Zimmet P, Zinman B; Global Partnership for Effective Diabetes Management. Improving glucose management: ten steps to get more patients with type 2 diabetes to glycaemic goal. Int J Clin Pract. 2005;59:1345-1355.
3. Khaw KT,Wareham N, Luben R, et al. Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European Prospective Investigation of Cancer and nutrition (EPIC-Norfolk). BMJ. 2001;322(7277):15-18.
4. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348(5):383-393.

5. L. Litwak, Argentina

León E. LITWAK, MD
President of the Argentinian Diabetes Society
Head of the Diabetes and Metabolism Section
of the Endocrinology and Nuclear Medicine
Unit, Hospital Italiano de Buenos Aires
Vice-Director of the Fellowship of
Endocrinology, School of Medicine of
the University of Buenos Aires
1192 Buenos Aires, ARGENTINA
(e-mail: leon.litwak@hospitalitaliano.org.ar)



Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in type 2 diabetic patients, and glycated hemoglobin (HbA1c) levels are strongly correlated with risk of microvascular and macrovascular complications, even in nondiabetic subjects.1

Convincing evidence shows that the lower HbA1c threshold for macrovascular events should be 7%, and for microvascular disease it should be 6.5%. Every 1% above this boundary is associated with a 38%, 40%, and 38% higher risk for macrovascular and microvascular events, and death, respectively.2 On the other hand, the UKPDS (United Kingdom Prospective Diabetes Study) showed that every 1% decrease in HbA1c levels was associated with a 14% lower risk of myocardial infarction, 37% less microvascular disease, and a 14% lower risk of death.3 Based on this, HbA1c targets reflecting adequate metabolic (glycemic) control should be accepted—for all the patients—at <6.5% to avoid these complications. Three major studies were designed to evaluate the impact of attaining “euglycemia” (ACCORD [Action to Control CardiOvascular Risk in Diabetes]) or near-“euglycemia” (ADVANCE [Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation ] and the VADT [Veterans Affairs Diabetes Trial]) on macrovascular outcomes and mortality in type 2 diabetic patients.4-6 Collectively, the results of these trials showed some benefits from intensive glucose control, such as reductions in nonfatal myocardial infarction, blood pressure, and progression of microalbuminuria, but none demonstrated a significant reduction in cardiovascular mortality. Conversely, in these trials, patients assigned to the intensive treatment arm showed (at least) a trend toward more episodes of hypoglycemia, hospitalizations, weight gain, and— only in ACCORD—an increase in mortality. ADVANCE showed better combined results vs ACCORD, with a nonsignificant 12% reduction in cardiovascular death, probably due to an improvement in microvascular disease (31% less nephropathy). ACCORD alerted us to the risks of intensive treatments in type 2 diabetic patients with a higher baseline HbA1c, with baseline comorbidities, and an elevated risk for CVD.

As shown previously in the Steno-2 trial, and partially in ADVANCE, most benefits are mainly related to the simultaneous impact on multiple risk factors than to the intensive glucose control. For the majority of type 2 diabetic patients, tighter blood glucose targets are desirable, with an HbA1c <6.5% or, at least, <7%. However, the assumption that there is only one universal threshold for HbA1c remains controversial. Treatment must be individualized over time to maintain an appropriate balance between benefits and risks of tight glycemic control. Fortunately, guidelines for type 2 diabetes treatment have changed (quickly) since 2006, introducing a patient-centered approach. Most-intensive approaches (HbA1c <6%-6.5%) should be considered in pregnancy and in highly motivated, compliant young patients with adequate resources, low risk of hypoglycemia, short duration of the disease, long life expectancy, and absence of microvascular disease, CVD, and comorbidities. On the other hand, less-intensive treatments (HbA1c >7.5%-8%) should be offered to older type 2 diabetic patients that are less motivated, noncompliant, who have inadequate resources, high risk of hypoglycemia, long duration of the disease, shorter life expectancy, advanced microvascular complications, presence of CVD, and multiple or severe coexisting conditions. Indeed, for patients over 70 years, the proposed range for HbA1c is between 7.5% and 8.5%.7

For the remaining type 2 diabetic patients, we should consider the universally accepted target of a mean HbA1c of 7%.We must tailor therapeutic goals for each patient thusly: first, determine the HbA1c target together with the other therapeutic targets (hypertension, lipids, weight, etc); second, build a personalized treatment with combined goals (glycemic, blood pressure, lipids, weight); and third, avoid side effects and elevated costs. _

References
1. Narayan KM, Boyle JP, Thompson TJ, Sorensen SW, Williamson DF. Lifetime risk for diabetes mellitus in the United States. JAMA. 2003;290:1884-1890.
2. Borg R, Kuenen JC, Carstensen B, et al; ADAG Study Group. HbA1c and mean blood glucose show stronger associations with cardiovascular disease risk factors than do postprandial glycaemia or glucose variability in persons with diabetes: the A1C-Derived Average Glucose (ADAG) study. Diabetologia. 2011;54:69-72.
3. Zoungas S, Chalmers J, Ninomiya T, et al; ADVANCE Collaborative Group. Association of HbA1c levels with vascular complications and death in patients with type 2 diabetes: evidence of glycaemic thresholds. Diabetologia. 2012;55:636- 643.
4. 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.
5. ADVANCE Collaborative Group, 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.
6. Action to Control Cardiovascular Risk in Diabetes Study Group, 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.
7. Ismail-Beigi F, Moghissi E, Tiktin M, Hirsch IB, Inzucchi SE, Genuth S. Individualizing glycemic targets in type 2 diabetes mellitus: implications of recent clinical trials. Ann Intern Med. 2011;154:554-559.

6. B. Mankovsky, Ukraine

Boris N. MANKOVSKY, MD
Professor, Department of Diabetology
National Medical Academy for
Postgraduate Education
Kiev, UKRAINE
(e-mail: mankovsky1964@yahoo.com)



The level of glycated hemoglobin (HbA1c) is the most important parameter characterizing metabolic control in patients with type 1 and type 2 diabetes mellitus and is emphasized by all guidelines on the management of these patients. However, there is an ongoing discussion about what level of HbA1c should be achieved and whether this goal is the same for all patients with diabetes.

Most respected authorities (eg, American Diabetes Association [ADA], 2012; International Diabetes Federation [IDF], 2011) advocate an HbA1c target below 7%.1,2 This target is based on strong epidemiological data which showed a linear increase in microvascular and macrovascular risk if HbA1c levels exceed 7%, and a much more gradual increase in risk at HbA1c levels below 7%. In ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation), a 1% increase in HbA1c was associated with increased risks of microvascular complications (26%), macrovascular complications (22%), total mortality (22%), and cardiovascular mortality (25%).3

From a clinical standpoint, it is very important to know whether we should aim for lower HbA1c levels. Findings from ADVANCE and ACCORD (Action to Control CardiOvascular Risk in Diabetes) make choosing a lower target controversial. While ACCORD showed a 22% increase in total mortality and a 35% increase in cardiovascular death in intensively treated diabetic patients,4 ADVANCE showed a 10% reduction in combined microvascular and macrovascular end points and a 21% reduction in nephropathy in intensively treated patients. The HbA1c levels achieved were similar in the intensive arms of these 2 trials: 6.4% and 6.5%, respectively. However, even in ACCORD, not all results were negative. The intensive control of blood glucose was beneficial for the reduction of primary end points in diabetic patients with basal HbA1c levels below 8% and no history of cardiovascular disease. Therefore, these landmark clinical trials justify the individualized approach to the treatment of patients with type 2 diabetes. Moreover, the recent position statement (April 2012) of the ADA and the European Association for the Study of Diabetes (EASD) highlights the importance of patient-oriented treatment. For example, in type 2 diabetic patients with a long life expectancy and no history of cardiovascular disease, who are newly diagnosed or at least have had diabetes only for a short duration (less than 5 years), we should aim for HbA1c levels below 6.5% toward normoglycemia, so as to prevent development of microvascular complications and significantly reduce the risk of macrovascular complications. However, we must consider whether this HbA1c level can be achieved without significantly increasing the risk of hypoglycemia. Even in such a relatively healthy group of subjects, if treatment to achieve normoglycemia leads to frequent and severe hypoglycemia, the HbA1c goal should be loosened to 7.0%. Social issues, eg, patient’s occupation and marital status, should also be considered. If, due to the social situation, the risk of hypoglycemia is unacceptable, the target should be loosened.

On the other hand, in type 2 diabetic patients with a short life expectancy, history of cardiovascular disease, significant risk of hypoglycemia, and high medical and social risk of hypoglycemic episodes, the HbA1c target should be higher, with an upper threshold of 7.5% or in some cases even higher, below 8%. However, one should realize that increasing the target level of HbA1c is associated with higher risk of diabetic complications, especially retinopathy and nephropathy, and such loosening of glycemic control is a compromise due to difficult circumstances in a specific patient profile. We believe that the results of ongoing trials such as ADVANCE-ON (ADVANCE posttrial ObservatioNal study) will shed further light on the benefits and long-term safety of strict metabolic control. _

References
1. American Diabetes Association. Standards of medical care in diabetes—2012. Diabetes Care. 2012;35(suppl 1):S11-S63.
2. International Diabetes Federation. Treatment algorithm for people with type 2 diabetes. www.idf.org/treatment-algorithm-people-type-2-diabetes.
3. ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560-2572.
4. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 358(24):2545-2559.

7. M. Mota, D. Protasiewicz, S. G. Popa, Romania

Maria MOTA, Prof, MD, PhD
Diana PROTASIEWICZ, MD
Simona G. POPA, Asst Prof, MD, PhD
Maria Mota, MD, PhD
Professor, Clinical County Emergency
Hospital Craiova
No. 1, Tabaci Str. Diabetes Clinic
Zip code 200642
ROMANIA
(e-mail: mmota53@yahoo.com)



Glycated hemoglobin (HbA1c) was introduced into clinical use in the 1980s and nowadays has become a cornerstone of clinical practice. Many organizations— AACE (American Association of Clinical Endocrinologists), ADA (American Diabetes Association), EASD (European Association for the Study of Diabetes), IDF (International Diabetes Federation), and UK NICE (National Institute for Health and Clinical Excellence)—currently advocate a target level for HbA1c of 6.5%-7%. They also agree that the therapeutic targets should be individualized.

As a consequence of the failure of the intensive treatment arm of the ACCORD study (Action to Control CardiOvascular Risk in Diabetes), the ACC (American College of Cardiology), ADA, and AHA (American Heart Association) issued a joint position statement recommending that the general target for HbA1c should be <7%, but for some patients they recommended individualized glycemic targets.1 Lowering HbA1c levels to below or around 7% has been shown to reduce microvascular complications of diabetes and, if implemented soon after the diagnosis of diabetes mellitus, is associated with long-term reduction in macrovascular disease.2,3 Patients with limited life expectancy, extensive comorbid conditions, long-standing diabetes, advanced microvascular and macrovascular complications, a history of severe hypoglycemia, or inappropriate glucose monitoring possibilities, should have less stringent HbA1c goals.

The DCCT (Diabetes Control and Complications Trial), the Kumamoto study (Kumamoto Study on Optimal Diabetes Control in Type 2 Diabetic Patients), the UKPDS (United Kingdom Prospective Diabetes Study), the VADT (Veterans Affairs Diabetes Trial), ACCORD, and ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) proved that glycemic control is fundamental in the management of diabetes. Recently, the need for individualization has gained interest because of the results of the glycemic intervention in the ACCORD study.

In the group treated intensively, with an HbA1c target of <6%, mortality increased by 22%, requiring premature discontinuation of the study.1 There are fears that increased mortality could be the result of an HbA1c level that is lowered too much and/or decreasing too rapidly. Although the number of hypoglycemia events was higher in the intensively managed group, an association with higher risk of mortality was not proven.

The ADVANCE study analyzed the intensive treatment group (target HbA1c ≤6.5%) versus the standard treatment group in patients with more than 55 years of age, a mean HbA1c of 7.5%, having type 2 diabetes, and a history of major microvascular and macrovascular complications or at least another cardiovascular (CV) risk factor. Although patients in the intensive control group suffered more severe hypoglycemia episodes (2.7% vs 1.5% of those in the standard control group) and more weight gain (+0.1 kg vs –0.8 kg for those in the standard control group), there seemed to be a 22% reduction in all-cause mortality, and a 25% reduced CV mortality for every 1% reduction in HbA1c.

The VADT analyzed CV events in an intensive glycemic control group (HbA1c goal ≤6.0%) vs a standard glycemic control group (HbA1c goal =8.0%-9.0%). No difference in mortality was registered,1 but one should note that the hypoglycemic events were three to four times higher in the intensive control group than in the standard control group.

The UKPDS—a prospective, randomized, controlled trial of intensive vs standard glycemic control in patients with recent type 2 diabetes—showed that improved glycemic control is associated with significantly decreased rates of microvascular complications. The DCCT and the Kumamoto study reported the same benefits from improved glycemic control.

In conclusion, we the clinicians should keep in mind the key words for this approach: “maximizing benefit while minimizing risks.” _

References
1. Teoh H, Home P, Leiter LA. Should A1C targets be individualized for all people with diabetes? Arguments for and against. Diabetes Care. 2011;34(suppl 2):S191- S194.
2. World Health Organization. Use of Glycated Haemoglobin (HbA1c) in the Diagnosis of Diabetes Mellitus. Abbreviated Report of a WHO Consultation. Geneva, Switzerland: World Health Organization; 2011.
3. American Diabetes Association. Standards of medical care in diabetes—2011. Diabetes Care. 2011;34(suppl 1):S11-S61.

8. A. Orabi, Egypt

Abbas ORABI, MD
Professor of Diabetology & Endocrinology
Zagazig University
EGYPT
(e-mail: abbasorabi@yahoo.com)



In the normal 120-day life span of the red blood cell, glucose reacts with hemoglobin, forming glycated hemoglobin (HbA1c). Once glycated, it remains that way. A buildup of HbA1c, therefore, reflects the average level of glucose to which the red cell has been exposed. In general, the reference range (that found in healthy subjects) is about 4%-5.9%.1

As HbA1c is the laboratory measure that captures long-term blood glucose exposure. It should provide a better marker for the presence and severity of the disease than single measures of glucose concentration. The correlation between HbA1c levels and complications has been proven by many controlled trials in type 1 and type 2 diabetes, most importantly the DCCT (Diabetes Control and Complications Trial) for type 1 diabetes and the UKPDS (United Kingdom Prospective Diabetes Study) for type 2 diabetes.

The large volume of data from diverse populations has established strong justification for assigning an HbA1c cut point of ≥6.5% for the diagnosis of diabetes.2 In 2010, the American Diabetes Association (ADA) considered the HbA1c (≥6.5%) as another criterion for the diagnosis of diabetes.3

In spite of the widely accepted recent concept to use the HbA1c assay for both chronic management and diagnosis of diabetes, there are some conditions that may require a specific HbA1c method or may preclude its testing. These conditions include some hemoglobin traits, changes in red cell turnover, age factor, and racial disparities; however, it is premature to establish race-specific diagnostic values.2

In 2008, only the ADVANCE trial (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) demonstrated reduction in cardiovascular (CV) death by 12%, and 65% reduction in end-stage renal disease (ESRD). Neither ACCORD (Action to Control CardiOvascular Risk in Diabetes) nor the VADT (Veterans Affairs Diabetes Trial) demonstrated a statistically significant reduction in the primary combined CV end point. An unexpected 22% increase in total mortality was observed in the intensive arm (HbA1c<6%) of the ACCORD study, mainly due to increased CV mortality (CVM). In spite of more hypoglycemia in the intensive arm (threefold higher), the explanation behind this increasing CVM remains unclear. These trials suggested that patients with a shorter duration of disease and lower base HbA1c, without overt CV disease (CVD), benefitted more from intensive strategies. A meta-analysis of CV outcomes in these trials suggested that every HbA1c reduction of 1% may be associated with a 15% relative risk reduction in nonfatal myocardial infarction.4

The accumulated results from the aforementioned type 2 diabetes CV trials suggest that the benefits of tight glycemic control varies, depending both on type of patients and the strategy by which this tight glycemic control is achieved. It follows that it is important to individualize targets and treatment strategies.5 According to the latest ADA and European Association for the Study of Diabetes (EASD) position statement, more stringent HbA1c targets (6.0%-6.5%) might be considered in patients with short disease duration, long life expectancy, and no significant CVD. Conversely, a less stringent HbA1c goal (7.5%-8% or even slightly higher) may be more suitable for patients with a history of severe hypoglycemia, limited life expectancy, advanced complications, extensive comorbidities, or established vascular complications, and even for those in whom the target is difficult to achieve due to less motivation and nonadherence or limited resources and support systems.6

Finally, the desires and values of the patient should be considered, since the achievement of any degree of glucose control requires active participation and commitment.5 _

References
1. Mathur R. Hemoglobin A1c Test. MedicineNet.comWeb site. http://www.medicine net.com/hemoglobin_a1c_test/article.htm. Accessed December 12, 2007.
2. International Expert Committee. International Expert Committee report on the role of the A1c assay in the diagnosis of diabetes. Diabetes Care. 2009;32(7): 1327-1334.
3. American Diabetes Association. Executive summary: standards of medical care in diabetes—2010. Diabetes Care. 2010;33(suppl 1):S4-S10.
4. Turnbull FM, Abraira C, Anderson RJ, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia. 2009;52:2288-2298. Erratum 52:2470.
5. Inzucchi SE, Bergenstal RM, Buse SB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1-16.
6. Ismail-Beigi F, Moghissi E, Tiktin M, Hirsch IB, Inzucchi SE, Genuth S. Individualizing glycemic targets in type 2 diabetes mellitus: implications of recent clinical trials. Ann Intern Med. 2011;154:554-559.

9. U. Phadke, India

Uday PHADKE, MD, DNB,
DM (Endocrinology)
INSTRIDE 6
Poonam Arcade, Revenue Colony
1170/11, Shivaji Nagar, JM Road
Pune – 411005, INDIA
(e-mail: uday.instride@gmail.com)



Glycated hemoglobin (HbA1c) is not a one-size-fits-all target in type 2 diabetic patients, and it should be adjusted to the clinical condition of the patient. The UKPDS (the United Kingdom Prospective Diabetes Study) showed that interventions for glycemic control targeting an HbA1c of 7%significantly decreased risk of microvascular complications.1 Furthermore, these benefits persisted over the longer term despite glycemic control similar to patients who were not treated to target.2 Subsequently, the ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) study demonstrated that a greater reduction in HbA1c to a near normal level of 6.5% with a gliclazide MR– and metformin-based treatment regimen further reduced vascular risk to a significant degree.3 Achieving, as far as possible, near normal glycemic control is therefore central to the prevention of complications in type 2 diabetes. However, pursuing this with a non–gliclazide-based treatment strategy requires much greater effort, with substantially increased risk of hypoglycemia and mortality. This was observed in the ACCORD (Action to Control CardiOvascular Risk in Diabetes) trial,4 which also attempted near normal glycemic control based on a treatment regimen of mostly glimepiride, metformin, glitazones, and insulin.

It is against this background that the mortality risk in attempting a uniform, one-size-fits-all HbA1c control target for all patients may outweigh the vascular benefits of glycemic control. While epidemiological studies support lowering of HbA1c from 7% to 6% because of a further reduction in microvascular risk, they also point to a curvilinear relationship between HbA1c and microvascular complications. Therefore, at the population level, the greatest number of complications will be averted by moving patients from very poor to fair or good, rather than “best possible” near normal glycemic control.5

Thus, for maximum risk benefit, the treatment target should be adjusted to the clinical condition of the patient. For individual patients with little comorbidity and long life expectancy, who stand to gain the most from a further lowering of HbA1c to below 7%, glycemic targets that are as close to normal as possible may be adopted, provided hypoglycemia is not a problem. On the other hand, less stringent HbA1c goals of around 7% are recommended for patients with one or more of the following characteristics: susceptibility to severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, and extensive comorbid conditions. A loosened HbA1c target would also be appropriate for those with long-standing diabetes in whom the general goal is difficult to attain despite effective doses of multiple glucose-lowering agents including insulin.6 _

References
1. UK Prospective Diabetes Study (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.
2. 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.
3. ADVANCE Collaborative Group; 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.
4. ACCORD Study Group; ACCORD Eye Study Group; Chew EY, Ambrosius, WT Davis MD, et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med. 2010;363:233-244.
5. 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.
6. American Diabetes Association. Standards of medical care in diabetes—2011. Diabetes Care. 34(suppl 1):S11-S61.

10. M. V. Shestakova, Russia

Marina Vladimirovna SHESTAKOVA
MD, PhD, DSc
Director of the Institute of Diabetes
Endocrinology Research Center
Dm. Ulyanov str. 11
117036 Moscow, RUSSIA
(e-mail: nephro@endocrincentr.ru)



In December 2011, a document entitled “The consensus of the Russian Association of Endocrinologists (RAE) on the initiation and intensification of glucose-lowering therapy in type 2 diabetes mellitus” was adopted in Russia.1 This document describes the decision made on individualization of glycated hemoglobin (HbA1c) targets for each patient with type 2 diabetes mellitus, depending on the patient’s age or life expectancy, disease duration, presence of vascular complications, and risk of hypoglycemia. It is also noted that other factors may influence individual HbA1c targets, such as motivation, compliance with therapy, patient education, and use of other treatments (Table). A decision was also made about individualization of the rate of achievement of target HbA1c values.


Table
Table. Individual targets of HbA1c in type 2 diabetes mellitus.

Abbreviations: HbA1c, glycated hemoglobin.
Based on reference 1: Dedov et al. Diabetes mellitus. 2011;4:6-17. © 2011,
Diabetes Mellitus.



The consensus was based on the results of recently completed studies: ACCORD (Action to Control CardiOvascular Risk in Diabetes), ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation), and the VADT (Veterans Affairs Diabetes Trial).2,3,4 ACCORD showed that excessively rapid and aggressive adjustment of therapy is associated with increased risk of hypoglycemia and cardiovascular mortality.2 ADVANCE3 showed that a gradual and smooth achievement of glycemic targets helps avoid frequent hypoglycemic episodes, and thus reduces microvascular and macrovascular complications.

Commentaries on individualized HbA1c targets:

_ Patient age is not a clear-cut variable on which to base goals for glycemic control, as the age-related functional deterioration of organs and systems in each person is strictly individual. Therefore, in parallel with the relative concepts of “young”, “medium” and “old” age, there is a concept of “life expectancy” (LE), which better determines the estimated overall condition of the patient and likelihood of vascular complications. In patients of young and middle age with high LE, stricter goals for glycemic control are proposed in order to prevent the development of microvascular and macrovascular complications in type 2 diabetes mellitus. In patients with an LE of <5 years, the target for glycemic control may be less strict regardless of age, because LE in such patients is usually determined by other disorders (eg, cancer). _ The presence of severe diabetic complications (especially cardiovascular in nature) imposes certain restrictions on the setting of individual targets for glycemic control. The above mentioned studies, ACCORD2 and the VADT,4 have shown that in the presence of cardiovascular complications, treatment targeting normoglycemia is dangerous due to potential development of hypoglycemic states, which lead to cardiovascular and cerebrovascular events.

_ The risk of severe hypoglycemia sharply limits the ability to achieve strict glycemic control, as it poses the risk of cardiovascular events. According to the VADT, prevalent severe hypoglycemia increases the risk of cardiovascular mortality almost fourfold and exceeds other risk factors by importance, such as age, presence of dyslipidemia, and cardiovascular disease.4

The decision of the RAEs is fully congruent with the opinion of Ismail-Beigi and collaborators,5 who are also considering the possibility of a differentiated approach to the setting of targets for glycemic control according to a patient’s risk for hyperglycemia-related complications, comorbid conditions, psychological status, capacity for self-care, economic considerations, and family and social support systems. _

References
1. Dedov II, Shestakova MV, Ametov AS, et al. Russian Association of Endocrinologists expert consensus document on initiation and intensification of antihyperglycemic therapy in type 2 diabetes mellitus [in Russian]. Diabetes mellitus. 2011; 4:6-17.
2. Action to Control Cardiovascular Risk in Diabetes Study Group; 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.
3. ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572.
4. DuckworthW, Abraira C, Moritz T, et al; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360: 129-139.
5. Ismail-Beigi F, Moghissi E, Tiktin M, Hirsch IB, Inzucchi SE, Genuth S. Individualizing glycemic targets in type 2 diabetes mellitus: implications of recent clinical trials. Ann Intern Med. 2011;154:554-559.

11. L. Smircic-Duvnjak, Croatia

Lea DUVNJAK,Prof, MD, PhD
Vuk Vrhovac Clinic for Diabetes
Endocrinology and Metabolic Diseases
Merkur University Hospital
School of Medicine, University of Zagreb
Zajčeva 19, Zagreb
CROATIA
(e-mail: lduvnjak@idb.hr)



For many years, we have treated diabetic patients to achieve target HbA1c values recommended by international guidelines and thus decrease the risk of microvascular and macrovascular complications. According to the American Diabetes Association (ADA), the goal for type 2 diabetic patients has been to lower HbA1c below 7%. However, for many people, tight control led to many episodes of hypoglycemia, which are potentially dangerous, especially in older patients, those with a history of heart disease, and those with diabetes for a long duration. Consequently, the goal to reach an HbA1c level below 7% did not necessarily prolong or improve quality of life in such people.

The importance of tight glycemic control in decreasing microvascular complications was well illustrated in the UKPDS (United Kingdom Prospective Diabetes Study), which showed that lowering HbA1c levels to 7% or less was related to a decrease in neuropathy, nephropathy, and retinopathy. For every 1% drop in HbA1c, a 33%-37% reduction in each of these microvascular complications occurred.

The relationship between blood glucose and macrovascular complications, however, appears to be more complex. The UKPDS 10-year follow-up showed the importance of lowering glucose immediately following diagnosis. In patients that were initially assigned to intensive treatment and who reached an HbA1c of 7%, compared with those assigned to conventional therapy and who reached an HbA1c of 7.9%, reduced rates of myocardial infarction and total mortality were maintained over 10 years, in spite of the fact that the difference in mean HbA1c between the two groups was lost after the first year of posttrial monitoring.

Based on these results, clinicians expected that reducing HbA1c would lower cardiovascular (CV) risk. However, concerns regarding the benefits of intensive glycemic control on macrovascular outcomes in type 2 diabetic patients, driven by the results from ACCORD (Action to Control Cardiovascular Risk in Diabetes), ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation), and the VADT (Veterans Affairs Diabetes Trial), have contributed to uncertainties in clinical practice decision making. None of these trials demonstrated that an intensive glycemic approach statistically significantly decreased CV end points.

These trials included patients that were older (by 8 to 10 years) than those in the UKPDS, and who had diabetes for a duration of 8 to 11.5 years. From 32% to 40% of the patients had a history of CV disease; in comparison, the UKPDS included newly diagnosed type 2 diabetes patients, of whom only 7.5% had a history of CV disease.

In ACCORD and the VADT, patients were randomized to intensive management using multiple combinations of oral agents, whereas the intensive approach in ADVANCE was based on gliclazide. ACCORD and the VADT aimed at an HbA1c of <6.0%, and ADVANCE at ≤6.5%. ACCORD patients on intensive treatment showed a 22% increase in total mortality, mainly driven by CV mortality. However, the rates of hypoglycemia and reduction in HbA1c level were not recognized as factors responsible for adverse outcomes. ADVANCE showed a 12% reduction in CV death and a 21% reduction in nephropathy, with a 30% reduction in the development of macroalbuminuria, a well-established marker of increased CV risk.

A meta-analysis of all these studies has proved that tight glycemic control significantly reduces coronary events without increasing the risk of death, emphasizing that in everyday clinical practice, the HbA1c goal should be tailored to each patient. While a tight HbA1c target of 6.0% to 6.4% can be considered in newly diagnosed type 2 diabetic patients, in older patients with longer disease duration and comorbidities requiring multiple medications, a higher target of 7.5% to 8.0% seems to be more appropriate. _

12. B. Tschiedel, Brazil

Balduino TSCHIEDEL,MD, MSc
Institute for Children with Diabetes
Conceição Hospital Group
Ministry of Health
Porto Alegre, RS
BRAZIL
(e-mail: badutsch@gmail.com)



Until recently, most diabetologists believed in the glucocentric approach to diabetes management. Common belief was that glycemic control was most important, and the lower the glycated hemoglobin (HbA1c), the fewer complications the patient would have. However, the classic UKPDS (United Kingdom Prospective Diabetes Study) has already raised some questions about this line of thinking, showing that patients with type 2 diabetes that received intensive treatment did not exhibit significant differences in cardiovascular events and mortality rates from those treated conventionally. Nevertheless, the lower rate of microvascular events observed in patients receiving intensive treatment supports the intensive strategy and lower HbA1c targets.

In addition to a continuous reduction in microvascular risk, the 10-year UKPDS follow-up has shown a reduction in the emerging risk of myocardial infarction and death from any cause in patients treated intensively, suggesting that the length of treatment is important in the evaluation of macrovascular complications and that lower glycemic targets are important from the very beginning.1 However, these patients from the UKPDS had recently been diagnosed with type 2 diabetes. On the other hand, the VADT (Veterans Affairs Diabetes Trial) showed that in patients with type 2 diabetes lasting 11.5 years and poor metabolic control, of whom 40% had had a previous cardiovascular event, the intensive treatment (HbA1c reaching 6.9%) vs conventional treatment (HbA1c of 8.4%) did not have a significant effect on major cardiovascular event rates, death, or microvascular complications, except for the progression of albuminuria.2

The Steno-2 study perhaps had the greatest influence on the drop in popularity of the glucocentric approach in diabetes management, showing that intensive intervention with multiple drugs, aimed at several different cardiovascular risk factors, in addition to behavioral modifications had beneficial effects with regard to vascular complications, cardiovascular death rates, and death fromany cause.3 In that same year, ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) and ACCORD (Action to Control CardiOvascular Risk in Diabetes) investigated whether the intensive glucose control strategy targeting strict glycemic goals (HbA1c ≤6.5% in ADVANCE and <6% in ACCORD) could reduce cardiovascular events in patients with type 2 diabetes for 8 to 10 years, respectively, and for which a large percentage already exhibited established macrovascular disease. In spite of a few differences in the results of the two studies, they showed that rigid glycemic control for this patient profile, over a period of 3.5 to 5 years, does not reduce cardiovascular events and can even be harmful.4,5

Thus, the new American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) joint statement seems very sensible, targeting a treatment focused on the patient.6 I share the opinion that a patient’s health must be evaluated as a whole, considering all risk factors to their health, whether cardiovascular or not: for instance, a fall, caused by a hypoglycemic event, could be extremely deleterious to an elderly patient. That is why, on the one hand, faced with a relatively young patient who has just recently been diagnosed with type 2 diabetes and who has no other major risk factors, our treatment strategy must aim for normoglycemia. On the other hand, faced with an elderly patient with established vascular complications, we must be much more complacent about the glycemic level, aiming for targets that do not increase risk of hypoglycemia, considering the obvious health problems it could lead to. Of course, all other risk factors must be treated simultaneously, using the same criteria to evaluate the patient. I am thus firmly convinced that we must tailor HbA1c targets to individual patients. _

References
1. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil AW. 10-Year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577-1589.
2. 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.
3. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Eng J Med. 2008;358:580-591.
4. ADVANCE Collaborative Group; 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.
5. Action to Control Cardiovascular Risk in Diabetes Study Group; Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes (The Action to Control Cardiovascular Risk in Diabetes Study Group). N Engl J Med. 2008;358:2545-2559.
6. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364-1379.

13. Z. Visockiene, Lithuania

Zydrune VISOCKIENE,MD, PhD
Center of Endocrinology
Vilnius University Hospital Santariskiu Klinikos
Santariskiu str. 2, 08661, Vilnius
LITHUANIA
(e-mail: zydrune.visockiene@santa.lt)



Professional organizations recommend a glycated hemoglobin (HbA1c) target between 7% and 6.5% for diabetes control, while stressing the importance of early diagnosis, treatment individualization, and prevention of microvascular and macrovascular complications. Arguments for an individualized approach are based on data from clinical trials and epidemiological studies consistently showing early and intensive glycemic control reduces the risk of microvascular complications, but showing lack of a benefit for macrovascular outcomes. Ten-year follow-up data from the UKPDS (the United Kingdom Prospective Diabetes Study) reported a 24% decrease in risk of microvascular complications in the intensive sulfonylurea/insulin treatment group.1 These data were only partially supported by three major prospective randomized trials with the primary end point of major cardiovascular (CV) events conducted in elderly patients with longstanding type 2 diabetes and known cardiovascular disease (CVD). ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) showed significant reduction in nephropathy (achieved HbA1c of 6.3%), and ACCORD (Action to Control CardiOvascular Risk in Diabetes) showed delay in the onset of albuminuria in intensive (achieved HbA1c of 6.3%) vs standard glycemic control; however, there was no benefit from the intensive strategy (achieved HbA1c of 6.9%) in the VADT (Veterans Affairs Diabetes Trial).2-4

The potential for intensive glycemic control to reduce CVD events in these studies is even more controversial. While ACCORD (HbA1c goal <6.0% vs 7.0%-7.9%) was stopped prematurely after a median duration of 3.5 years due to a 22% higher CV mortality with intensive therapy, especially in patients with a prior history of CVD or baseline HbA1c >8.0%, ADVANCE and the VADT saw no increase in overall or CV mortality in the intensive control arm (ADVANCE: HbA1c goal ≤6.5% vs that based on local guidelines; VADT: HbA1c goal <6.0% vs planned separation of 1.5%).5 Meta-analysis of these data showed that overall intensive therapy was associated with a significant 9% reduction in risk of major CV events, primarily because of a 15% reduction in risk of myocardial infarction (MI), and no effect on all-cause mortality during 4.4 years.6 Notably, in all these trials, allocation to more intensive control was associated with a significant increase in the risk of severe hypoglycemia, which occurred in <3% of intensively treated patients in ADVANCE,16% in ACCORD, and 21% in the VADT.6 Subgroup analysis suggested that participants who had a shorter duration of diabetes, lower HbA1c, and absence of known CVD prior to randomization appeared to benefit from more-intensive glycemic control, whereas those with a history of macrovascular disease and long-term diabetes did not. Another important point to remember is that other CVD risk factors were corrected in all trials, using statins, blood pressure treatment, and aspirin therapy, which all are proven to reduce CVD risk. Thus, although on the population level the UKPDS 10-year results show significant reduction in MI (up to 33%) and in all-cause mortality (up to 27%)—supporting the hypothesis of an early glucose control benefit—individual factors should be considered for each patient when choosing the treatment goals and strategy.

In summary, there is evidence that good glycemic control with a target HbA1c <7.0% reduces risk of microvascular complications. For newly diagnosed and very motivated younger patients without known CVD and comorbidities, a lower target may be appropriate, while an HbA1c goal of >7.0% may be advised for elderly patients with advanced microvascular or macrovascular complications, long-standing diabetes, history of severe hypoglycemia, and short life expectancy. A holistic approach should be used, focusing on treating the patient as an individual and finding appropriate balance between the benefits and risks. _

References
1. 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.
2. ADVANCE Collaborative Group; 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.
3. Ismail-Beigi F, Craven T, Banerji MA, et al; ACCORD Trial Group. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet. 2010;376:419-430.
4. DuckworthW, Abraira C, Moritz T, et al; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009; 360:129-139.
5. Bonds DE, Miller ME, Bergenstal RM, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ. 2010;340:b4909.
6. Control Group; Turnbull FM, Abraira C, Anderson RJ, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia. 2009;52: 2288-2298.