HbA1c target goal: individualization vs recommended guidelines?



HbA1c target goal: individualization vs recommended guidelines?

1. A. H. Aamir, Pakistan
2. B. Akinci, Turkey
3. Y. M. Bee, Singapore
4. C. A. Jimeno, Philippines
5. S. Liatis, Greece
6. B. N. Mankovsky, Ukraine
7. B. M. Mihai, Romania
8. A. M. Mkrtumyan, Russia
9. E. Montanya, Spain
10. M. Rigato, Italy
11. D. A. Zozulinska-Ziolkiewicz, Poland

1. A. H. Aamir, Pakistan

Azizul H. AAMIR,
MRCP, FRCP, FACE
Professor and Head of the Diabetes and
Endocrinology Department
Postgraduate Medical Institute Hayatabad
Medical Complex
Peshawar, PAKISTAN
(email: drahaamir@gmail.com)

The cornerstone in the management of type 2 diabetes is setting up glycemic and HbA1c targets for individual patients. Across the world, most of the guidelines on the management of type 2 diabetes recommend tighter glycemic control by achieving an HbA1c target of 7%, which is based on data from numerous trials, particularly the landmark UKPDS trial (United Kingdom Prospective Diabetes Study). UKPDS showed that improved glycemic control reduces microvascular complications and all-cause mortality in patients with type 2 diabetes.1 Our understanding of glycemic control and cardiovascular outcomes was challenged when the ACCORD trial (Action to Control CardiOvascular Risk in Diabetes) showed an overall detrimental effect of tight glycemic control.2 During the same year, the results of the ADVANCE trial (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) showed that lowering HbA1c to lower levels is not detrimental, even when choosing an HbA1c target of 6.5%.3

The two key questions that were raised after these trials were: (i) is there a risk of hypoglycemia and, if so, what is its effect on cardiovascular safety?; and (ii) is it worth reducing or relaxing the targets in some patient groups who may not benefit from tighter control or in whom a tighter control may, in fact, be detrimental?

In the real world, or shall we say “operational” world, the meaning of all this would be to follow the guidelines, while keeping in mind the individualization of treatment. When choosing a specific target range for any given patient, several factors must be considered, including the patient’s risk for hypoglycemia related complications in the context of comorbidities (especially cardiovascular complications), capacity for self-care, social support, and economic considerations.

The UKPDS trial data on type 2 diabetes showed that there was a cumulative benefit of better glycemic control from the time of diagnosis and that it may be many years before cardiovascular benefits become evident. From the ACCORD trial, we learned that, if patients are older and have had suboptimal HbA1c control for a longer duration of time and have other comorbid conditions, including cardiovascular disease and end-organ damage, instituting tighter control may be detrimental compared with younger patients who have achieved HbA1c control from the outset, as was done in UKPDS. In older patients with long-standing diabetes, the ADVANCE trial did not show any significant benefit of intensive treatment on reducing macrovascular events.

The optimal HbA1c target remains at 7%, but further analysis is important for the reassessment of HbA1c targets. If the patient has an increased risk of developing hypoglycemia (ie, taking secretagogues or insulin), is older, with prior cardiovascular events, or has a risk of arrhythmia due to hypoglycemia, or an increased risk of falls and its sequelae, then the recommended HbA1c target of 7% may not be ideal. This reassessment of HbA1c targets also means that these patients may, in fact, experience more harm than benefit if tight control is targeted.

This situation can occur in any part of the health care delivery system, but it will be particularly relevant when dealing with patients in resource-limited countries, where the capacity for self-care and the economic situation play a key role in glycemic control in patients with diabetes.4 Therefore, treatment individualization becomes even more important than following stringent standard guidelines, maybe at the cost of higher HbA1c targets, which may mean that we have partly compromised on the strict control of diabetes, while making the treatment safer for our patients. As a medical practitioner, the famous Hippocratic Oath of “First, do no harm” stands so true when treating patients with type 2 diabetes after assessing and individualizing their HbA1c targets in the light of recommended guidelines. ■

References
1. 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). Lancet. 1998;352(9131):837-853.
2. Gerstein HC, Miller ME, Byington RP, et al; ACCORD Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24): 2545-2559.
3. 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(24):2560-2572.
4. Mahmood K, Aamir AH. Glycemic control status in patients with type-2 diabetes. J Coll Physicians Surg Pak. 2005;15(6):323-325.

2. B. Akinci, Turkey

Bariş AKINCI,
MD
Associate Professor, Division of
Endocrinology and Metabolism
Department of Internal Medicine
Dokuz Eylul University Medical School
Izmir,TURKEY
(email: baris.akinci@deu.edu.tr)

Better glycemic control induces a favorable outcome in most patients with diabetes, but it does not work for everyone. The UKPDS study (United Kingdom Prospective Diabetes Study)1,2 was a landmark study showing that intensive glycemic control targeting a glycated hemoglobin (HbA1c) of 7% decreased the progression of microvascular disease. The ADVANCE study (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation)3 took this benefit one step further by showing that a greater reduction in HbA1c to a near normal level of 6.5% significantly reduced the risk of microvascular complications. On the other hand, the VADT study (Veterans Affairs Diabetes Trial)4 failed to show that intensive glucose control reduces cardiovascular events. To make things more complicated, the ACCORD study (Action to Control Cardiovascular Risk in Diabetes) showed an unexpected increase in cardiovascular mortality in the intensive treatment arm (HbA1c<6%).5 These controversial results are possibly affected by certain differences in the design of the studies, which mainly differed in their patient-selection strategies. In addition, the ACCORD study allowed the participating physicians to treat their patients with any antidiabetic medication; whereas, almost all patients took gliclazide in the ADVANCE study.

In particular, tight glycemic control is likely to provide the highest benefits for people who have had a shorter duration of diabetes and no complications. Special conditions, such as pregnancy, should also be considered when optimizing HbA1c targets. On the contrary, there are no indications for intensive glycemic control in some patients, such as those with recurrent severe hypoglycemia or hypoglycemia unawareness or those with major comorbidities that may limit life expectancy. Recent data indicate that the potential benefit of intensive glycemic control is out of the question for patients with a longer duration of diabetes or clinical cardiovascular disease. In addition to glycemic targets, the management of diabetes should focus on the control of other risk factors for micro- and macrovascular diabetes complications, including hypertension, hyperlipidemia, obesity, and smoking.

It is true that many patients fail to achieve long-term glycemic control despite the major advances in the management of type 2 diabetes and the availability of new therapies. It can be difficult to achieve HbA1c targets in patients with type 2 diabetes who have tight HbA1c goals (6% to 6.5%); however, patients with more relaxed glycemic targets (8% to 8.5%) may not follow the lifestyle modifications strictly and physicians may delay treatment intensification. Therefore, the individualization of HbA1c targets may have contributed to the reduction in glycemic control. To overcome this potential problem, physicians should discuss the importance of achieving individualized glycemic targets with their patients at every visit. ■

References
1. 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). Lancet. 1998;352(9131):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(15):1577- 1589.
3. 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(24):2560-2572.
4. Duckworth W, 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. Gerstein HC, Miller ME, Byington RP, et al; ACCORD Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24): 2545-2559.

3. Y. M. Bee, Singapore

Yong Mong BEE, MBBS, MRCP(UK)
FRCP(Edin)
Senior Consultant, Department of
Endocrinology
Singapore General Hospital
Adjunct Assistant Professor
Duke-NUS Medical School
SINGAPORE
(email: bee.yong.mong@singhealth.com.sg)

Maintaining good glycemic control reduces the risk of microvascular complications, and it may also reduce the risk of some macrovascular complications in both type 1 and type 2 diabetes. For years, most diabetes guidelines and organizations have recommended that the glycated hemoglobin (HbA1c) targets be between 6.5% and 7.0%. More recently, the results of several major studies have generated a discussion about the individualization of HbA1c targets based on the patient’s characteristics, which has changed the management paradigm from conformity in the HbA1c targets to one that incorporates individualization.

Individualization of the glycemic target can be appealing to clinicians because it is a way to maximize patient benefits while minimizing the risk. Clinicians are familiar with patients who cannot achieve conventional HbA1c targets, where reasons such as fear of hypoglycemia and weight gain are often cited as contributing factors. The individualization of HbA1c targets gained attention due to the concerns raised during the ACCORD study (Action to Control CardiOvascular Risk in Diabetes).1 In this study, the intensive treatment strategy aiming for an HbA1c target <6.0% resulted in a 22% higher mortality, and the risk for mortality appeared to be greater in patients with a prior history of cardiovascular events or a baseline HbA1c >8.0%. These results suggest that tight glycemic control in a subgroup of patients is associated with higher mortality. Further support for individualization of HbA1c targets comes from the VADT trial (Veterans Affairs Diabetes Trial),2 which showed that improvements in the intensively managed group were accompanied by more hypoglycemic episodes, more weight gain, and more patients having at least one serious adverse event. However, the ADVANCE trial (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation)3 showed a 10% relative reduction in the combined outcome of major macrovascular and microvascular events without any associated weight gain, and the rate of severe hypoglycemic events was low in both study arms (0.7 vs 0.4 events per 100 patients per year). Collectively, the results from these trials showed that some individuals derived more benefit from a selected strategy for tight glycemic control, while others derived more harm.

Adopting individualized glycemic targets may potentially contribute to fewer patients achieving optimal glycemic targets in a real-world setting, which is supported by ongoing evidence of a treatment gap in many clinical practices. Clinical inertia is evident from both physicians and patients. Despite poor and worsening HbA1c, many patients are kept on the same medications, with treatment intensification being delayed persistently. The departure from conformity in HbA1c targets may reinforce this inertia and give physicians and patients the excuse of “individualized” therapy. For the majority of individuals with diabetes, tighter glycemic targets are desirable. Meta-analyses that include the aforementioned trials showed that intensive therapy is not associated with an increased risk of mortality, but there was a significant 9% reduction in the risk of major cardiovascular events.4 Newer oral agents that are associated with a minimal risk of hypoglycemia can also contribute to better glycemic control without undue fear of hypoglycemia.

Therefore, there must be a balance between the benefit and risk of good glycemic control to help more patients safely and effectively achieve their HbA1c targets. Evidence suggests that algorithm-driven protocols that incorporate individualized HbA1c targets may be the preferred clinical approach. Several studies showed that the consistent use of treatment algorithms by both physicians and nurses resulted in more patients achieving their glycemic target.5

In summary, an aggressive pharmacological management to reach HbA1c targets around 6.5% to 7.0% may be inadvisable or impractical for some patients. Treatment must be individualized over time and specific patient characteristics must be taken into consideration. To avoid increasing the treatment gap, both the physicians and health care teams should adopt a well-structured algorithm-driven protocol coupled with tangible HbA1c targets to help more patients achieve their HbA1c targets. ■

References
1. Gerstein HC, Miller ME, Byington RP, et al; ACCORD Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24): 2545-2559.
2. Duckworth W, 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.
3. 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(24):2560-2572.
4. Turnbull FM, Abraira C, Anderson RJ, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia. 2009;52:2288-2298.
5. Fanning EL, Selwyn BJ, Larme AC, Defronzo RA. Improving efficacy of diabetes management using treatment algorithms in a mainly Hispanic population. Diabetes Care. 2004;27:1638-1646.

4. C. A. Jimeno, Philippines

Cecilia A. JIMENO, MD
Professor, Department of Pharmacology
and Toxicology, University of the Philippines
College of Medicine
Clinical Associate Professor, Section
of Endocrinology, Diabetes and Metabolism
Philippine General Hospital
Manila, PHILIPPINES
(email: cajimeno@up.edu.ph)

Has the recent individualization of glycated hemoglobin (HbA1c) targets contributed to a reduction in the proportion of patients with diabetes who achieve glycemic control? The answer is NO! Previously, the guidelines have given a one-size-fits-all approach to setting HbA1c targets by advocating a general target of <7.0% for most patients. Prior to this, even lower near-normal goals were advocated despite the absence of any strong evidence supporting this practice. Recently, a more enlightened patient-centered approach has been recommended that emphasizes individualized goals for each patient with diabetes, which considers their age, duration of diabetes, comorbid conditions, presence of established vascular complications, life expectancy, risk or history of (severe) hypoglycemia, psychological status and attitude, capacity for self-care, economic considerations, and social support in a psychosocial economic context.1-4

Briefly, the guidelines recommend a general HbA1c target <7.0% for most individuals with type 2 diabetes, tighter targets (6% to 6.5%) for younger (<45 years old) and healthier individuals, and less intensive targets (7.5% to 8.0%) for those who are older (>65 years old), have comorbidities or complications, or are prone to hypoglycemia. The rationale for these targets comes from recent trials showing that lower targets in the elderly or those with established complications do not have an impact on mortality, but that they could potentially be harmful due to the risks associated with (severe) hypoglycemia. However, the benefits of tight glycemic control are greatest for those who are newly diagnosed, with the major benefit being a consistent prevention of microvascular complications.

Has this individualization of HbA1c targets resulted in a failure to reach glycemic targets because the doctors and patients have become overly cautious? The answer is no. Hospital or insurance registries, or even the results of national surveys, show a continued failure to reach glycemic targets; however, this is only because these surveys have continued to use a single HbA1c target instead of an analysis using individualized targets. This type of analysis is, of course, more difficult and tedious as it requires that the patients be stratified according to age, duration of diabetes, and the presence of vascular complications, and then specifying targets according to these strata. Such an analysis was done in 2013 for patients with diabetes (n=757) based on data from the 2007- 2008 US National Health and Nutrition Examination Survey. The results showed that, if a single universal HbA1c target <7.0% was used, then 47% (41% to 54%) of adults with diabetes would not achieve adequate glycemic control. On the other hand, if a stratified, individualized approach following the American Diabetes Association/European Association for the Study of Diabetes guidelines were used, then this proportion declined to 30% (range, 26% to 36%).5 This is only one example of how we may have misinterpreted the impact of individualization of glycemic targets. Rather than impeding the achievement of glycemic goals, this individualized, patient-centered approach should give health care practitioners and people with diabetes greater confidence in reaching their HbA1c targets. ■

References
1. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Diabetes Care. 2012;35:1364-1379.
2. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Diabetologia. 2012;55:1577-1596.
3. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes 2015: a patient-centered approach. Diabetes Care. 2015;38: 140-149.
4. 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.
5. Laiterapppong N, John PM, Nathan AG, Huang ES. Public health implications of recommendations to individualize glycemic targets in adults with diabetes. Diabetes Care. 2013;36:84-89.

5. S. Liatis, Greece

Stavros LIATIS, MD, PhD,
Consultant in Internal Medicine and Diabetology
First Department of Propaedeutic Internal
Medicine, Diabetes Center
National & Kapodistrian University of Athens
Laiko General Hospital
Athens, GREECE
(email: sliatis@med.uoa.gr)

Glycemic control is a cornerstone of type 2 diabetes management, and failure to achieve it is associated with the development of chronic microvascular and macrovascular complications. Several clinical trials have shown that an improvement in hyperglycemia is directly related to a reduction in microvascular complications; however, its impact on macroangiopathy is far more complex. Three landmark clinical trials that were performed in patients with advanced stages of type 2 diabetes—ACCORD (Action to Control CardiOvascular Risk in Diabetes), ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation), and VADT (Veterans Affairs Diabetes Trial)—failed to show any cardiovascular benefit from strict glycemic control, with the ACCORD trial showing possible harm from strict glycemic control. However, an extension of the earlier UKPDS trial (United Kingdom Prospective Diabetes Study), which was performed in newly diagnosed patients with type 2 diabetes, showed a clear reduction in cardiovascular morbidity and mortality in the intensive treatment arm.1

For a long time, a glycated hemoglobin (HbA1c) level <7% (the median HbA1c value achieved in the intensive treatment arm of the UKPDS study) was considered the “holy grail” of glucose- lowering management and was, therefore, recommended by the clinical guidelines. The most frequently emphasized benefit of the guidelines is that they offer specific recommendations for clinicians and increase the probability that patients with the same conditions will be treated similarly. However, this comes at the expense of leaving insufficient space for clinicians to accommodate remedies and for patients to receive individualized treatment.2

There is an increasing recognition that establishing specific glycemic targets should be a highly individualized decision,3 and it should be based on multiple demographic, socioeconomic, and clinical parameters, which usually interact with each other. The clinician should always bear in mind that elevated blood glucose takes a long time (usually several years) to induce its detrimental vascular effects. Therefore, in younger and healthier patients, who are expected to live longer, one should aim for normoglycemic levels, while in older and frail individuals, a less tight control (indicated by an HbA1c target between 7.0% and 8.0%) may be more appropriate. If the glucose-lowering treatment increases the risk of hypoglycemia, further consideration for loosening glycemic targets is necessary, since serious harm may be induced by achieving glycemic levels that are too low. In a recent survey among 244 leading diabetologists worldwide, life expectancy and the risk of hypoglycemia were considered as the two most important parameters for determining an appropriate glycemic target.4

Glycemic control appears to be rather poor among patients with type 2 diabetes worldwide,5 but the relevant surveys are based on uniform HbA1c values of 6.5% or 7.0%. Alternatively, to capture the true quality of glucose-lowering care, a shift from a single HbA1c target to individualized goals is needed. Individualization of care is best implemented within an integrated health care system, which includes, among other items, coordination between members of the health care team, education of patients and health care providers, prevention and health care promotion, social support, and community engagement. Moreover, providers should acknowledge that patient preferences are an essential component of personalized care.

The recent American Diabetes Association/European Association for the Study of Diabetes guidelines made a “courageous” step toward promoting the individualization of diabetes care using a patient-centered approach.5 There is high-quality evidence showing that decision aids (tools that facilitate a shared decision-making approach) improve people’s knowledge regarding options and reduce their decisional conflict.6 Unfortunately, there is limited high-quality evidence testing the impact of structured and personalized management on quality of care and, most importantly, on diabetes complications. Future studies on this topic are urgently needed, and the increasingly available “real-world” data from large electronic databases may provide a valuable tool to address this question. ■

References
1. Riddle MC, Karl DM. Individualizing targets and tactics for high-risk patients with type 2 diabetes: practical lessons from ACCORD and other cardiovascular trials. Diabetes Care. 2012;35:2100-2107.
2. Woolf SH, Grol R, Hutchinson A, Eccles M, Grimshaw J. Clinical guidelines: potential benefits, limitations, and harms of clinical guidelines. BMJ. 1999;318: 527-530.
3. 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.
4. Cahn A, Raz I, Kleinman Y, et al. Clinical assessment of individualized glycemic goals in patients with type 2 diabetes: formulation of an algorithm based on a survey among leading worldwide diabetologists. Diabetes Care. 2015;38:2293- 2300.
5. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach. Diabetes Care. 2015;38: 140-149.
6. Stacey D, Légaré F, Col NF, et al. Decision aids for people facing health treatment or screening decisions. Cochrane Database Syst Rev. 2014;1:CD001431.

6. B. N. Mankovsky, Ukraine

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

It is well accepted that controlling hyperglycemia is the cornerstone for the successful treatment of patients with either type 1 or type 2 diabetes mellitus. There is also a general consensus that achieving and maintaining good metabolic control leads to a significant reduction in the risk of microvascular complications. Moreover, this beneficial effect on the delay of progression of diabetic kidney disease was present for at least 5 years (so-called metabolic memory) after the conclusion of the landmark ADVANCE trial (Action in Diabetes and Vascular disease: PreterAx and DiamicroN Modified Release Controlled Evaluation ),1 which was clearly shown by the results of the follow-up ADVANCE-ON trial (ADVANCE ObservatioNal study).2 The long-term follow-up (up to 30 years) of the UKPDS trial (United Kingdom Prospective Diabetes Study)3 showed that the protective effect of intensive antihyperglycemic treatment on the risk of myocardial infarction and the reduction in cardiovascular mortality became more pronounced and statistically significant many years after the conclusion of the trial. Therefore, we believe that patients with type 2 diabetes should have good metabolic control.

However, the current guidelines addressing the treatment of hyperglycemia in patients with type 2 diabetes (eg, the 2015 American Diabetes Association/European Association for the Study of Diabetes [ADA/EASD] Consensus Statement and the 2016 ADA Standards of Care) advocate individualized glycemic goals or a so-called patient-centered approach. For the majority of patients with diabetes, the HbA1c target should be <7%; however, for some patients, this goal should be more (<6.5%) or less stringent (<7.5% or even <8.0%). Such individualization of treatment depends on the assessment of many important factors, ie, duration of diabetes, age and life expectancy, comorbid conditions, known cardiovascular disease and its severity, the presence of advanced microvascular complications, the risk of hypoglycemia and an assessment of its consequences, the presence of hypoglycemia unawareness, and other individual patient considerations. Of course, this approach seems to be justified based on the results of the ACCORD trial (Action to Control CardiOvascular Risk in Diabetes),4 which unexpectedly showed an increase in mortality in intensively treated patients with type 2 diabetes, and the growing body of evidence regarding the risk of hypoglycemia in patients with type 2 diabetes who are not taking insulin.

The individualized approach to treating hyperglycemia highlights the issue of patient safety. Indeed, the risk and seriousness of the consequences of hypoglycemia (cardiovascular accidents, arrhythmia, and even sudden death) are frequently overlooked. Moreover, even less dangerous signs of hypoglycemia could lead to a significant impairment in quality of life.

However, some patients may not actually realize that there is a link between hypoglycemia and their impaired well-being. In contrast, other patients make this association empirically and, as a result, decide to stop their medications. Their adherence to the prescribed antihyperglycemic treatment is thus impaired and this results in poor metabolic control. Of course, some social factors must be considered when choosing the appropriate HbA1c target, eg, the type of employment, especially jobs for which hypoglycemia is absolutely contraindicated (such as drivers), the presence (or lack) of support within the immediate family and/or community, the willingness of the patient to check blood glucose levels and address the issue of hypoglycemia. We may conclude that the issue of hypoglycemia is not just a matter of safety for the patients and, in some cases, other people (in the job, on the road, etc), but also a matter of good treatment adherence.

However, I am afraid that, in some cases, individualizing the treatment for hyperglycemia can lead to an unnecessary loosening of glycemic control and can be used as an “excuse” by the physician or the patient. The factors that should be considered when choosing the appropriate treatment target are quite subjective and difficult to predict (such as life expectancy, patient attitude, etc). In some cases, patients tend to choose a less demanding approach that ignores the risk of complications that seem to be too far in the future. Another important point is that, in some cases, the stricter guidelines are necessary to help those physicians who are not very experienced in treating patients with diabetes. I believe that the treatment for hyperglycemia must be individualized, but that this individualization should not be used as an excuse for poor metabolic control. ■

References
1. Patel A, MacMahon S, Chalmers J, et al; 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(9590):829-840.
2. Zoungas S, Chalmers J, Neal B, et al; ADVANCE-ON Collaborative Group. Follow- up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med. 2014;371:1392-1406.
3. 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). Lancet. 1998;352(9131):837-853.
4. Gerstein HC, Miller ME, Byington RP, et al; ACCORD Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24): 2545-2559.

7. B. M. Mihai, Romania

Bogdan M. MIHAI, MD, PhD
Associate Professor, Department of Diabetology
Nutrition and Metabolic Diseases
‟Grigore T. Popa” University of Medicine
and Pharmacy
Iași, ROMANIA
(email: bogdanmihai2003@yahoo.com)

Glycated hemoglobin (HbA1c ) estimates the extent of glucose binding to hemoglobin within erythrocytes and reflects long-term glycemic control by identifying sustained hyperglycemia in the last 2 to 3 months, which corresponds to the half-life of an erythrocyte. Major randomized trials in patients with type 1 diabetes (DCCT [Diabetes Control and Complications Trial]) or type 2 diabetes (UKPDS [United Kingdom Prospective Diabetes Study]) showed that a reduction in HbA1c decreases the risk for chronic diabetes complications.

Therefore, the American Diabetes Association recommended HbA1c values <7% as a target for glycemic control, whereas the American Association of Clinical Endocrinologists (AACE) recommended HbA1c targets <6.5%. However, recent trials on type 2 diabetes demonstrated that HbA1c targets that are too strict might harm patients with diabetes who have certain characteristics. Therefore, since 2012, the American Diabetes Association/European Association for the Study of Diabetes guidelines recommend that glycemic targets should be individualized; HbA1c<7% is recommended for most patients with type 2 diabetes, but more relaxed targets (HbA1c 7.5% to 8%) are accepted in patients with a reduced life expectancy, an increased risk for hypoglycemia, extended diabetes complications, or major comorbidities; however, more stringent glycemic targets (HbA1c<6.5%) would offer benefits to young patients, with a short duration of the disease, no comorbidities or diabetes complications, and a reduced risk of hypoglycemia.1 The AACE also recommends individualization of glycemic targets based on concurrent serious illness and hypoglycemic risk.2 These individualized glycemic targets aim to maximize the benefits of good glycemic control without increasing the risk of adverse events. In recent years, due to the better medical care received by people with diabetes and the emergence of new and efficient therapies, the life expectancy of people with diabetes has increased; however, the number of patients with complications and comorbidities has also increased, which means that an increasing number of patients need higher glycemic targets. In addition to individualized glycemic targets, specific patient groups need particular therapeutic measures, with a minimal risk of causing harm, to reach these targets safely.

Information on the number of patients with type 2 diabetes who achieve glycemic control after the individualization of glycemic targets is scarce. The new recommendations made it possible for a larger proportion of patients with diabetes to be considered as having good glycemic control. Data from the National Health and Nutrition Examination Survey (NHANES) indicate that approximately 50% of patients with diabetes in the US do not exhibit a good glycemic control when the universal HbA1c target (<7%) is considered, but only 30% are inadequately controlled when the individualized targets set by the American Diabetes Association are applied.3

Nevertheless, the individualization of HbA1c targets must not be used as an excuse for suboptimal metabolic control; the negative impact of untreated or undertreated hyperglycemia (hydroelectrolyte disorders, dizziness, dehydration, urinary incontinence, etc) may manifest even in old patients with a long duration of the disease and with comorbidities and complications, wherein the American Diabetes Association recommends relaxing the HbA1c targets.4 Long-term studies are needed to assess whether these individualized targets will reduce chronic diabetes complications and the risk of hypoglycemia in patients with diabetes. Last, but not least, the final decision in selecting glycemic targets for each patient with diabetes is driven by the experience and clinical judgment of the physician caring for all the medical problems in that specific patient.5

References
1. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Diabetes Care. 2012;35(6):1364- 1379.
2. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm — 2016 executive summary. Endocr Pract. 2016;22(1):84-113.
3. Laiteerapong N, John PM, Nathan AG, Huang ES. Public health implications of recommendations to individualize glycemic targets in adults with diabetes. Diabetes Care. 2013;36(1):84-89.
4. Dardano A, Penno G, Del Prato S, Miccoli R. Optimal therapy of type 2 diabetes: a controversial challenge. Aging. 2014;6(3):187-206. 5. Esposito K, Maiorino MI, Bellastella G, Giugliano D. New guidelines for metabolic targets in diabetes: clinician’s opinion does matter. Endocrine. 2014;46(3): 431-434.

8. A. M. Mkrtumyan, Russia

Ashot M. MKRTUMYAN, MD
Professor and Head of the Endocrinology
and Diabetology Department,
“A.I. Evdokimov” University of Medicine
and Dentistry
Head of the Research Department of
Endocrine and Metabolic Disorders
Moscow Clinical Research and Practical Center
Moscow, RUSSIA
(email: vagrashot@mail.ru)

Type 2 diabetes remains a widespread disease with serious implications for both the health of patients and health care systems in general. It is no secret that diabetes, which in Michel Berger’s words is not a disease, but a “lifestyle,” is actually the cause of much drama. Throughout the entire history of the United Nations there were only four resolutions made concerning the need for all countries to unite in the fight against a particular disease that threatens mankind, and the recent Resolution 4, adopted on December 20, 2006, was devoted to diabetes.

One of the major issues that modern diabetology faces is the failure to achieve target values of glycated hemoglobin (HbA1c) in a substantial proportion of patients. Russia ranks second in the world for cardiovascular mortality. Two-thirds of the patients with type 2 diabetes in the Russian Federation do not achieve the HbA1c target of 7%. However, this raises the question of whether all patients need such an aggressive reduction in HbA1c, which is recommended in the American Diabetes Association (ADA) guidelines. There is actually a requirement in the American Diabetes Association/European Association for the Study of Diabetes guidelines to consider the patient’s clinical and socioeconomic characteristics when deciding between more or less intensive treatment regimens. However, it should be noted that these guidelines do not specify individual targets for HbA1c.

The sorrowful example of the ACCORD study (Action to Control CardiOvascular Risk in Diabetes) should not be consigned to oblivion. When treating type 2 diabetes, appropriate individual goals for reducing hyperglycemia should be set based on the patient’s needs. The guidelines from the Russian Association of Endocrinologists define the type of patients in whom individual HbA1c values can be <6.5% and up to 8%, taking into account age, presence of complications, risk of hypoglycemia, and projected life expectancy. An individual approach should be used when determining the HbA1c targets and initiating treatment. A question then arises as to whether the start of treatment with metformin is substantiated in all cases or whether it is possible to use an alternative approach in some patients. Up to the 1920s, diabetes was still treated as in the days of the Roman Empire or Ancient Egypt. Pharmacotherapy for diabetes has only been available for less than 100 years. Nevertheless, over the past decades, it has been enriched with many antidiabetic drugs, both oral and injectable. Despite these advances, according to some data, the situation of glycemic control did not improve, and even deteriorated, which led to Abrahamson’s 2015 publication in Diabetes Care.1

The 2014 International Diabetes Federation (IDF) guidelines emphasize that “intensive therapy with sulfonylurea-based treatment improved long-term outcomes,” and the ADVANCE study (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) showed an improvement in outcomes without weight gain and with low rates of hypoglycemia. Concurring with IDF experts, the authors of the Dutch guidelines3 stated that, in patients >70 years, the HbA1c target should be adjusted according to the patient’s characteristics, ie, the duration of diabetes, intensity of treatment, and concomitant diseases. In this group of patients, the HbA1c target should be less strict. Medical therapy should be stepwise, with metformin as the first-line treatment. If the HbA1c target is not achieved, a sulfonylurea should be added, with gliclazide being the first-choice sulfonylurea. Thus, with a patient-oriented approach to effective glycemic control, it is possible to achieve a reduction in both cardiovascular risk and the rate of other complications in patients with type 2 diabetes. ■

References
1. Abrahamson MJ. Should sulfonylureas remain an acceptable first-line add-on to metformin therapy in patients with type 2 diabetes? Yes, they continue to serve us well! Diabetes Care. 2015;38(1):166-169.
2. Patel A, MacMahon S, Chalmers J, et al; 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(9590):829-840.
3. Rutten GE, De Grauw WJ, Nijpels G, et al. Diabetes guideline of the Dutch College of General Practitioners (NHG-Standard Diabetes mellitus type 2 (derde herziening). Huisarts Wet. 2013;56(10):512-525.

9. E. Montanya, Spain

Eduard MONTANYA,MD, PhD
Professor, Department of Clinical Sciences
University of Barcelona
Barcelona, SPAIN
(email: montanya@ub.edu)

The DCCT (Diabetes Control and Complications Trial) and UKPDS (United Kingdom Prospective Diabetes Study) trials provided solid evidence that intensive glycemic control reduces the risk of microvascular diabetes complications.1,2 Their results supported the recommendation to lower blood glucose to levels as close to normal as possible, and achieving HbA1c targets <7% or ≤6.5% was encouraged for most patients. However, the benefits of intensive glycemic control on macrovascular disease, cardiovascular mortality, and all-cause mortality have been more difficult to prove. Early intensive glucose control did not significantly reduce macrovascular complications in the DCCT and UKPDS studies, although reductions were later identified with a longer-term follow- up.3,4 The ACCORD (Action to Control CardiOvascular Risk in Diabetes), ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation), and VADT (Veterans Affairs Diabetes Trial) trials did not reduce cardiovascular events in intensively treated patients, and mortality was increased in ACCORD, suggesting that not all patients benefit from aggressive glucose management, and that, in some patients, the risk of rigorous glycemic control may outweigh the benefit.5

Individualization of diabetes treatment emerged as an important strategy to address this concern, and, in recent years, a strong emphasis has been placed on individualizing glycemic targets.6 Although an HbA1c target <7% is considered a reasonable goal, less stringent HbA1c targets (7.5% to 8.0% or even slightly higher) are suggested as more appropriate in frail patients, those with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, longstanding diabetes, or when the target is difficult to attain. On the other hand, individualization should identify the patients that would benefit from more stringent HbA1c targets (≤6.5%), if achieved without significant hypoglycemia or other adverse effects.6

In the US, the number of patients with diabetes who achieved an HbA1c target <7.0% increased over the past two decades (1988-2010).7 This improvement in metabolic control, along with the enhanced management of other risk factors and the implementation of integrated care for patients with diabetes, may have contributed to the concomitant reduction in the development of chronic diabetes complications.8 However, a closer look at the data indicates that, in recent years (2007- 2010), the prevalence of patients achieving HbA1c targets <7.0% was not increased, and if anything, it was reduced. Since individualized targets are generally less intensive, a reasonable concern is that they may result in a general relaxation of glycemic control that would have negative consequences for the development of chronic diabetes complications. In addition, the identification of adequate HbA1c targets for each patient increases the complexity of diabetes management, placing an increased demand on health care providers, and its acceptance requires a higher level of patient education. Clinical inertia is a major limitation in the efforts to improve metabolic control, and it could be reinforced by an inadequate implementation of the individualization concept. Longitudinal data are needed to assess these concerns properly. The absence of a single HbA1c target that is valid for the vast majority of patients also affects the complexity of the methods used to evaluate the quality of care provided by individual physicians or institutions.

Thus, the individualization of HbA1c targets is a welcomed refinement to diabetes management that should help patients achieve better glycemic control by assigning stricter HbA1c targets for those that will benefit from a tight control, or more relaxed HbA1c targets for those who will most likely not benefit. However, the implementation of individualized treatment is associated with significant challenges. ■

References
1. Nathan DM, Genuth S, Lachin J, et al; DCCT Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329 (14):977-986.
2. 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). Lancet. 1998;352(9131):837-853.
3. Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353(25): 2643-2653.
4. 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(15):1577- 1589.
5. Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials. Diabetes Care. 2009;32(1):187-192.
6. American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care. 2016;37(suppl 1):S14-S80.
7. Stark Casagrande SS, Fradkin JE, Saydah SH, Rust KF, Cowie CC. The prevalence of meeting A1c, blood pressure, and LDL goals among people with diabetes, 1988-2010. Diabetes Care. 2013;36(8):2271-2279.
8. Gregg EW, Li Y, Wang J, et al. Changes in diabetes-related complications in the United States, 1990-2010. N Engl J Med. 2014;370(16):1514-1523.

10. M. Rigato, Italy

Mauro RIGATO,MD
Department of Medicine
Division of Metabolic Disease
University of Padova,
Padova, ITALY
(email: mauro.rigato@unipd.it)

In the past decade, the guidelines from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) advocated an HbA1c target <7.0% to reduce the risk of chronic complications.1 However, more recently, the same organizations have recognized that this target is not valid for all patients, and that it must be tailored to the clinical characteristics of each patient. In particular, the importance of individualization has been highlighted after the publication of three landmark trials: ACCORD (Action to Control CardiOvascular Risk in Diabetes),2 ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation),3 and VADT (Veterans Affairs Diabetes Trial).4

The aforementioned trials studied the effect of tight vs conventional glycemic control on cardiovascular outcomes in patients with type 2 diabetes, a long duration of the disease, and an elevated cardiovascular risk. The results of such trials did not seem to support a protective effect of strict glycemic control against cardiovascular events in patients with established diabetes and a history of cardiovascular disease. The ACCORD trial was even interrupted early due to excess cardiovascular mortality in the intensive treatment group, in which a 3-fold higher rate of hypoglycemia was observed. Conversely, the 10-year follow-up of the UKPDS study (United Kingdom Prospective Diabetes Study) showed a long-term protective effect of early good glycemic control in newly diagnosed patients with type 2 diabetes.5 Based on this evidence, individualization of glycemic targets seems to be a rational choice as it minimizes the potential harm associated with severe glycemic control, according to the clinical characteristics of each patient, such as age, disease duration, cardiovascular morbidity, risk of hypoglycemia, and life expectancy. However, the evidence that this approach will help more patients achieve their target is limited.

Laiteerapong et al6 evaluated the implications of individualized glycemic targets on the quality of diabetes care in a cohort of 672 adult patients with diabetes from the National Health and Nutrition Examination Survey. The population of adults with diabetes was characterized by the clinical variables suggested by the ADA guidelines as criteria to individualize HbA1c targets. The results from this observational study demonstrated that, by using an individualized approach, HbA1c targets >7.0% would be recommended for about half of the patients with diabetes, but one-third would still have poor glycemic control. Therefore, these results showed that individualizing glycemic targets does not conflict with the need to improve the management of diabetes.

In summary, good glycemic control is crucial to reduce the risk of chronic complications. An appropriate balance between the benefits and risk of good glycemic control could be achieved by individualizing the glycemic targets, taking into account the clinical characteristics of each patient and the safety profiles of the different classes of antidiabetic agents. ■

References
1. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Diabetes Care. 2012;35:1364- 1379.
2. Gerstein HC, Miller ME, Byington RP, et al; ACCORD Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24): 2545-2559.
3. 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(24):2560-2572.
4. Duckworth W, 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. 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(15):1577- 1589.
6. Laiteerapong N, John PM, Nathan AG, Huang ES. Public health implications of recommendations to individualize glycemic targets in adults with diabetes. Diabetes Care. 2013;36(1):84-89.

11. D. A. Zozulinska-Ziolkiewicz, Poland

Dorota A. ZOZULINSKA-ZIOLKIEWICZ
MD, PhD
Department of Internal Medicine and
Diabetology
Poznan University of Medical Sciences
Raszeja Hospital
Poznan, POLAND
(email: zozula@box43.pl)div style= »clear: both; »>

Obtaining good glycemic control from the diagnosis of diabetes is fundamental to the management of the disease. Glycated hemoglobin (HbA1c) is still an indicator for both glycemic control and the efficacy of hyperglycemia treatment in patients with diabetes. The overall objective recommended by most diabetes guidelines, regardless of the type of diabetes, is <7%.1,2 This target makes biological sense because this value indicates that glycemia is below the renal threshold. Good glycemic control plays a crucial role in the prevention of late complications. In the last decade, the HbA1c targets for type 2 diabetes have become individualized, and are based on the patient’s age, duration of diabetes, risk of severe hypoglycemia, presence or absence of cardiovascular disease, and life expectancy.3 According to the various recommendations, HbA1c targets range from <6.0% to 8.5%.4

The inconsistency in the statements from various associations and institutions on HbA1c targets for patients with type 2 diabetes has led to discrepancies in clinical study results. Much discussion has taken place after the publication of the results of three studies—ACCORD (Action to Control CardiOvascular Risk in Diabetes), VADT (Veterans Affairs Diabetes Trial), and ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation)—on the efficacy of antihyperglycemic treatments regarding safety, ie, a low risk for hypoglycemia. Focusing treatments on lowering blood glucose levels effectively, while minimizing the risk of hypoglycemia, enforces common-sense individualization of glycemic targets. When setting individual HbA1c targets for patients with type 2 diabetes, we should not only take into account patient age, duration, and extent of the current glycemic control, presence and severity of chronic diabetes complications, and the risk of hypoglycemia, but also for the quality of life. Both the results from clinical trials and their meta-analyses indicate that the HbA1c target should be <7%. However, clinical practice, experience, and expert opinions indicate that individualized glycemic goals are needed for patients with type 2 diabetes. Patients with type 2 diabetes at an early stage, without symptoms, and in whom antihyperglycemic therapy does not induce hypoglycemia should achieve normoglycemia, expressed as HbA1c <6.5%, while the overwhelming number of patients with type 2 diabetes should strive to maintain an HbA1c level <7%.

Factors that can be used to determine which patients should achieve less strict HbA1c targets primarily include those associated with hypoglycemia, particularly in patients in whom hypoglycemia may increase the risk of sudden death. The available data indicate that higher HbA1c levels in patients with type 2 diabetes treated with glucose-lowering drugs do not protect against hypoglycemia or vice versa. Less stringent HbA1c targets (7.1% to 8.5%) may be appropriate in patients with type 2 diabetes if their life expectancy is limited due to advanced age or comorbidities, especially when the treatment of hyperglycemia is based on insulin.

Personally, I believe that relaxing the HbA1c target to 8% is desirable in some situations, but higher values are already a dangerous exaggeration. When we look at the real world, unfortunately we conclude that most patients with type 2 diabetes do not achieve the recommended HbA1c targets. Basically, having a single HbA1c target—and even individualized HbA1c targets—is the “theory” and we need to find solutions to put the recommendations in practice.■

References
1. American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care. 2016;37(suppl 1):S14-S80.
2. Kloos C, Müller N, Hartmann P, et al. High quality of diabetes care based upon individualized treatment goals – a cross sectional study in 4784 patients in Germany. Exp Clin Endocrinol Diabetes. 2016;124(5):294-299.
3. 2015 Guidelines on the management of diabetic patients: a position of diabetes Poland. Clin Diabetol. 2015;4(suppl A):A7.
4. O’Hare JP, Millar-Jones D, Hanif W, et al. The revised NICE draft guideline for type 2 diabetes: still a long way to go. Lancet Diabetes Endocrinol. 2015;3(9): 679-680.