The importance of glycemic control: how low should we go with HbA1c? Start early, go safe, go low☆

Article Outline

• Abstract
• 1. Introduction
• 2. HbA1c reduction in Type 1 diabetes
• 3. HbA1c reduction in Type 2 diabetes
• 4. How low should we go?
• 5. Conclusion
• References
• Copyright

Abstract 

Epidemiologic data indicate a continuous relationship between hemoglobin A1c (HbA1c) and risk for microvascular and macrovascular complications of diabetes. Intensive glycemic control reduces risk of microvascular complications in Type 1 and Type 2 diabetes, and long-term treatment and follow-up studies have shown that initial intensive control is associated with reduced cardiovascular risk. Recent intervention trials in older, high-risk patients with Type 2 diabetes have not shown a benefit of intensive control in reducing cardiovascular risk over a rather short-term follow-up period of up to 5 years, with some data indicating that intensive control accompanied by hypoglycemia is detrimental in patients with high cardiovascular risk. Indeed, hypoglycemia with current antidiabetic agents—primarily insulin and sulphonylureas—is the main limiting factor in achieving desirable levels of glycemic control. Still, the goal in treating both Type 1 and Type 2 diabetes should be to safely get HbA1c as close to normal as possible. In Type 2 diabetes, this goal should be tempered for the time being in patients with shorter life expectancy or co-existing cardiovascular disease or other co-morbidities, in whom a target of 7.0–7.5% may be advisable until we can demonstrate that lower targets in such patients can be safely achieved. Newer agents with lower risk of hypoglycemia—e.g., insulin analogues, incretin mimetics and incretin enhancers—may form an integral component of strategies for safely achieving lower HbA1c levels.

Keywords: Diabetes, Hypoglycemia, HbA1c, Microvascular complications, Cardiovascular complications

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1. Introduction 

Patients with diabetes are at increased risk of microvascular complications and cardiovascular disease compared with the general population. Compared to those with Type 2 diabetes, patients with Type 1 diabetes have lower rates of such risk factors as obesity, hypertension, and dyslipidemia, and their elevated lifetime cardiovascular risk appears to be more directly related to hyperglycemia. Cardiovascular risk in patients with Type 2 diabetes reflects both the effects of hyperglycemia and a high frequency of such additional risk factors. Available evidence indicates that any increase in hemoglobin A1c (HbA1c) above normal levels is associated with increased risk of microvascular and cardiovascular complications (Fig. 1) (Khaw et al., 2004, Krzentowski et al., 2004, Stratton et al., 2000), providing the rationale for treatment to reduce glucose to normal or near-normal levels. Initial trials of intensive glycemic control showed benefits in reducing microvascular complications in both Type 1 (The Diabetes Control and Complications Trial Research Group, 1993) and Type 2 diabetes (UK Prospective Diabetes Study (UKPDS) Group, 1998a, UK Prospective Diabetes Study (UKPDS) Group, 1998b), with inconclusive evidence regarding prevention of cardiovascular events. Three recently reported trials in Type 2 diabetic patients showed no benefit of intensive control in reducing cardiovascular risk over the short term (The Action to Control Cardiovascular Risk in Diabetes Study Group, 2008, The ADVANCE Collaborative Group, 2008, Duckworth et al., 2009), whereas long-term follow-up studies over 17 years and longer both in Type 1 (The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group, 2005) and Type 2 diabetes (Holman, Paul, Bethel, Matthews, & Neil, 2008) showed significant reductions in cardiovascular risk in patients who had received intensive therapy. When all of these findings are incorporated into the debate over how low we should go with HbA1c, the conclusion that still beckons is that we should go as low as we safely can.

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• Fig. 1. 

  (A) Relationship between updated mean HbA1c and risk for diabetic complications in patients with newly diagnosed Type 2 diabetes in the prospective observational UKPDS-35 study. Each 1% decrease in mean HbA1c was associated with risk reductions of 21% for any diabetes endpoint (P<.0001), 21% for diabetes-related mortality (P<0.0001), 14% for myocardial infarction (MI) (P<.0001) and 37% for microvascular complications (P<.0001) (Stratton et al., 2000). (B) Association between a 1% increase in HbA1c and risk for coronary heart disease, cardiovascular death and all-cause mortality among more than 10,000 men and women aged 45–79 years from the general population in the European Prospective Investigation into Cancer in Norfolk study (Khaw et al., 2004).

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2. HbA1c reduction in Type 1 diabetes 

The Diabetes Control and Complications Trial (DCCT), reported in 1993, demonstrated that intensive glycemic control in patients with newly diagnosed Type 1 diabetes produced a dramatic reduction in risk for microvascular complications—including retinopathy, nephropathy, and neuropathy—compared with conventional insulin treatment over 6.5 years of follow-up (The Diabetes Control and Complications Trial Research Group, 1993). For example, intensive control significantly reduced risk of retinopathy by 76% in the primary prevention cohort; risk of retinopathy progression and development of proliferative or severe non-proliferative retinopathy decreased by 54% and 47%, respectively, in the secondary prevention cohort. For both treatment groups in the study, there was no HbA1c threshold for risk of retinopathy (The Diabetes Control and Complications Trial Research Group, 1996).

There were few macrovascular events in the DCCT trial, limiting the ability to generate conclusions regarding preventive benefit. When all major cardiovascular and peripheral vascular end points were combined, intensive control was associated with a nonsignificant 41% reduction in risk for macrovascular disease during the study period. However, the significant benefit of this initial period of intensive control in reducing cardiovascular risk emerged over long-term follow-up in the DCCT/Epidemiology of Diabetes Interventions and Complications (EDIC) study (The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group, 2005). After 11 years of follow-up, subsequent to the conclusion of the initial study (approximately 17 years total), during which time the difference in HbA1c between the initial intensive control and conventional control groups decreased to 0.2%, and the intensive control group had a significant 42% reduction in risk for any cardiovascular disease (P=.02) and a 57% reduction in risk for nonfatal myocardial infarction, stroke, or cardiovascular mortality (P=.02). On risk factor analysis, this risk reduction was primarily associated with the reduction in HbA1c during DCCT trial treatment; although microalbuminuria and albuminuria were associated with increased risk for cardiovascular disease, the association between the initial HbA1c reduction and reduction in cardiovascular risk remained significant after adjustment for these factors.

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3. HbA1c reduction in Type 2 diabetes 

As shown in Fig. 1, the prospective observational UKPDS-35 study demonstrated a continuous relationship between HbA1c and microvascular and macrovascular risk among patients with newly diagnosed Type 2 diabetes. An epidemiological extrapolation of this study showed that each 1% reduction in mean updated HbA1c was associated with significant decreases in risk for any diabetes end point, diabetes-related mortality, myocardial infarction, and microvascular complications, with no threshold of risk being observed for any end point (Stratton et al., 2000). Risk for complications is shown by HbA1c strata of <6%, 6–<7% and 7–<8% in Fig. 2, with such findings again indicating that having HbA1c as close to normal as possible reduces risk of all complications.

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• Fig. 2. 

  Adjusted rates of diabetes-related morbidity and mortality, all-cause mortality, myocardial infarction (MI), stroke, and microvascular disease according to HbA1c strata in the UKPDS-35 study in Type 2 diabetes. (Stratton et al., 2000)

As did the DCCT trial in patients with Type 1 diabetes, the UKPDS showed that intensive glycemic control significantly reduced the risk of microvascular complications in newly diagnosed patients with Type 2 diabetes. In the UKPDS-33 trial reported in 1998, intensive control with sulphonylureas or insulin was associated with a 25% reduction in risk of microvascular end points (P=.0099) over 10 years compared with conventional control (UK Prospective Diabetes Study (UKPDS) Group, 1998a, UK Prospective Diabetes Study (UKPDS) Group, 1998b).

As was the case in the DCCT trial, evidence of benefit in preventing cardiovascular events was not straightforward in UKPDS-33, with intensive glycemic control being associated with a borderline significant 16% reduction in risk (P=.052) of myocardial infarction. However, as was also the case in the DCCT/EDIC follow-up study, 10-year follow-up of the UKPDS-33 population after the end of the study showed emergence of significant preventive benefits (Holman et al., 2008). Despite the absence of any difference in HbA1c between the initial intensive control group and the initial conventional control group after 1 year of follow-up after the end of the initial trial, intensive control was associated with a significant 15% reduction in risk for myocardial infarction (P=.01) and a significant 13% reduction in risk for all-cause mortality (P=.007), with the original significant reductions in risk being maintained over follow-up for any diabetes-related end point (9% reduction, P=.04) and microvascular complications (24% reduction, P=.001). The portion of the UKPDS-34 trial comparing intensive control with metformin versus conventional control in newly diagnosed overweight patients had shown significant reductions in risk for any diabetes-related endpoint, all-cause mortality, and myocardial infarction with intensive control (UK Prospective Diabetes Study (UKPDS) Group, 1998a, UK Prospective Diabetes Study (UKPDS) Group, 1998b), and these benefits were maintained over a 10-year follow-up, with risk reductions of 21% (P=.01), 27% (P=.002) and 33% (P=.005) for any diabetes-related endpoint, all-cause mortality and myocardial infarction, respectively (Holman et al., 2008).

The data from the follow-up studies in both Type 1 and Type 2 diabetes indicate that intensive glycemic control soon after diagnosis yields long-term benefits in reducing macrovascular risk. This benefit is probably because of a reduced longterm exposure to hyperglycaemia. A complementary mechanism might be the notion of “metabolic memory,” the idea that early glycemic control is remembered in the different target organs (such as the heart, kidneys and eyes), resulting in a long-term “legacy” benefit of reduced HbA1c. It may be that increased oxidative stress causes irreversible damage in the absence of early control of glycemia. Indeed, the recently reported findings in the observational follow-up of the Steno-2 study confirm the long-term benefits of initial intensive control of cardiovascular risk factors. The Steno-2 study showed that intensive multifactorial intervention with strict glycemic control, blood pressure control and use of aspirin and lipid-lowering therapy led to an approximately 50% reduction in microvascular complications and cardiovascular disease over 7.8 years, including a 53% reduction in risk for cardiovascular disease, compared with conventional control in patients with Type 2 diabetes and microalbuminuria (Gæde et al., 2003). After an additional 5.5 years of observation, during which the difference in risk factor control narrowed primarily due to improved control in the original conventional therapy group, the initial intensive intervention group had a 57% reduction in risk for cardiovascular mortality (P=.04; 13% absolute reduction), a 59% reduction in risk for cardiovascular events (P<.001) and a 46% reduction in risk for any-cause mortality (P=.02; absolute reduction 20%) (Gæde, Lund-Andersen, Parving, & Pedersen, 2008). These findings both confirm that early aggressive control of risk factors produces long-term benefits and suggest that early intensive multifactorial intervention in Type 2 diabetes may be imperative for optimal reduction of cardiovascular risk in the long term.

While these findings support intensive control of glycemia initiated as soon as possible after diagnosis of Type 2 diabetes, the debate over targets in lowering glucose has been fueled by the recent reporting of three large-scale intervention trials—the ACCORD (Action to Control Cardiovascular Risk in Diabetes), ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) and VADT (Veterans Affairs Diabetes Trial) trials (The Action to Control Cardiovascular Risk in Diabetes Study Group, 2008, The ADVANCE Collaborative Group, 2008, Duckworth et al., 2009)—conducted to determine whether reducing HbA1c to near-normal levels can reduce macrovascular complications. These trials compared intensive and standard glycemic control in high-risk populations in which high event rates were expected: patients were on average 60 years or older and had a mean duration of diabetes of approximately 8–12 years; 30–40% had cardiovascular disease at entry. Median follow-up in the trials was 3.5–5.6 years.

While the conclusions from these trials are relevant for the studied populations, care should be exercised in applying them to the broader population of patients with Type 2 diabetes, including lower-risk patients. None of the trials showed benefit in reducing cardiovascular risk for intensive versus standard treatment. The ADVANCE study showed a significant 10% reduction in combined incidence of major microvascular and macrovascular events over 5 years that primarily reflected reduced risk of nephropathy (The ADVANCE Collaborative Group, 2008), supporting the role of intensive control in reducing microvascular risk. Data from the VADT trial indicated an alarming relationship between sudden death and severe hypoglycemia within the prior 3 months of study treatment, re-emphasizing the dangers of hypoglycemia as an adverse effect of glucose-lowering treatment (Duckworth et al., 2009, Abraira, 2008). The ACCORD trial was stopped prematurely after 3.5 years due to increased mortality in the intensive control group (The Action to Control Cardiovascular Risk in Diabetes Study Group, 2008); this group was also characterized by greater use of insulin alone and in combination with oral antidiabetic agents, significantly greater weight gain, and significantly greater frequency of severe hypoglycemia compared with the standard treatment group.

Despite numerous post hoc analyses and speculations (Del Prato, 2009, Lebovitz, 2008, Cukierman-Yaffe et al., 2009), the causes of increased mortality in the intensive control group in the ACCORD trial remain unclear. It is unlikely that the achieved HbA1c is an explanation for the finding, because similar median HbA1c levels were achieved in the ACCORD and ADVANCE studies (6.4% and 6.5%, respectively). However, as noted, findings in these studies should heighten awareness of the possibility that hypoglycemia in high-risk patients may be an important factor in masking the potential benefits of strict glycemic control in the short term. Indeed, findings in these trials have renewed discussion regarding the detrimental effect of hypoglycemia on the already ischemic heart. Many studies have shown that cardiovascular disease can be precipitated by the hemodynamic changes associated with severe hypoglycemia (Cukierman-Yaffe et al., 2009, Tattersall and Gill, 1991, Ewing et al., 1991). The counter-regulatory responses to hypoglycemia, including sympathetic-adrenal activation and catecholamine release, may have hazardous effects including increased risk of localized ischemia and electrolyte disturbances with cardiac arrhythmias, and risk for these events may be greater among patients with preexisting endothelial dysfunction.

Long-term studies of glycemic control, such as the UKPDS, PROactive, ADVANCE, VADT and ACCORD studies, have been completed, and several meta-analyses have recently been published that examine the results of these important studies and the over 30,000 patients with Type 2 diabetes who were enrolled in them (Mannucci et al., 2009, Ray et al., 2009, Standl et al., 2009). In the meta-analyses of all five studies by Mannucci et al., 2009, Ray et al., 2009, it was found that intensified treatment in patients with Type 2 diabetes led to a significant reduction in the occurrence of non-fatal myocardial infarction (17%) and coronary heart disease (15%) but did not have an affect on the occurrence of stroke and cardiovascular mortality. These meta-analyses found that intensive glycemic control significantly reduced coronary events without an increased risk of death but were associated with weight gain and an increase in hypoglycemic risk in patients with Type 2 diabetes. In the meta-analysis from Standl et al. (2009), which only examined the VADT, ADVANCE and ACCORD studies, cardiovascular events were reduced by approximately 10–15% per 1% of absolute reduction of HbA1c. Comparing only the ACCORD and ADVANCE studies led to the belief that the overaggressive treatment enforced in the ACCORD study, which targeted an HbA1c goal of ≤6.0%, may have had the unintended result of increasing the mortality rate in some patients. In these two studies, the target HbA1c levels were <6.0% (ACCORD) vs ≤ 6.5% (ADVANCE) and the hazard ratios were 1.22 vs 0.93, respectively. These three meta-analyses point to the effect that the speed and extent of HbA1c reduction can have on mortality rates in different populations, especially those with pre-existing macrovascular disease and Type 2 diabetes (Mannucci et al., 2009, Ray et al., 2009, Standl et al., 2009.

This is in agreement with a recent cohort study of patients aged 50 years or older with Type 2 diabetes, who showed that not only high, but also low mean HbA1c values were associated with increased all cause mortality and cardiac events. The lowest risk was seen at a HbA1c of about 7.5% (Currie et al., 2010). Considering the fact that these observations were even stronger when studying the insulin-treated subgroup, hypoglycemia as cause for this excess morbidity and mortality comes into the picture.

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4. How low should we go? 

The answer to the question “How low should we go?” in HbA1c lowering would seem to be “As close to normal as possible” when considering epidemiologic data showing the relationship between HbA1c and microvascular and macrovascular risk, as well as clinical trial data showing reduction of microvascular risk with intensive glycemic control in both Type 1 and Type 2 diabetes. Existing clinical trial data also clearly support the benefits of intensive control initiated soon after diagnosis in reducing cardiovascular risk over the long term in Type 1 diabetes. It seems clear that we should aim to lower HbA1c as much as possible as soon as possible after diagnosis in patients with Type 1 diabetes.

But how should the data from the recently reported studies in Type 2 diabetes be integrated into recommendations regarding treatment targets? The failure of the ACCORD, ADVANCE, and VADT trials to show any benefit of intensive glycemic control in reducing cardiovascular risk may imply that such disadvantages as weight gain and increased frequency of severe hypoglycemia counterbalance potential advantages in the short-term in patients with more advanced Type 2 diabetes. The UKPDS-33 follow-up study, on the other hand, showed that intensive control started soon after diagnosis and sustained over many years leads to benefits in reducing microvascular and macrovascular complications, as well as overall mortality risk over the long term. It may be that, in addition to indicating elevated risk of poor outcome associated with hypoglycemia and other adverse effects of antidiabetic agents in higher-risk patients, the three recent intervention studies highlight the importance of the stage of disease at which intervention is initiated in predicting potential benefit. Indeed, the aforementioned trials, as well as their subset analyses, suggest a significant benefit of intensive glycemic control in reducing cardiovascular disease risk in patients with shorter duration of diabetes, lower HbA1c at entry and/or absence of known cardiovascular disease at entry. And finally, assessing those studies in several meta-analyses together with other randomized trials achieving at a difference of HbA1c lowering of at least 0.5% clearly showed a significant reduction of especially myocardial infarction in general and at least a neutral effect on mortality over the mean observation period of 5 years.

Taken together, these considerations suggest that intensive glycemic control soon after the diagnosis of Type 2 diabetes has a positive effect on cardiovascular risk, although—as indicated by the findings in the UKPDS-33 and Steno-2 follow-up studies—the benefit may become apparent only after 10 or more years of follow-up.

Treatment should be started as soon as possible after diagnosis. In patients with a good life expectancy (eg, >10 years), shorter duration of diabetes, and no preexisting cardiovascular complications, we should aim at the lowest possible HbA1c. For the present, less-stringent HbA1c targets (>7.0–7.5%) may be advisable in patients with shorter life expectancy (eg, older patients, those with co-morbidities) and those with established cardiovascular complications. Individualisation of care is important. The best practice is to agree with the patient what the most appropriate HbA1c target is in that particular setting. This will depend on a whole range of patient and disease characteristics. It is equally important to agree then with the patient what the best way is to achive this and what measures of success might be.

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5. Conclusion 

At present, the limitations in achieving low HbA1c are largely imposed by the side effects of existing medications. An additional consideration, as seen from the ACCORD study, is that the rate and target level of HbA1c reduction should be tailored to each patient. For many widely used drugs, particularly sulphonylureas and insulin, the major concerns in this regard are hypoglycemia and weight gain. The introduction of insulin analogues with a similar potential for glycemic control but a lower risk for hypoglycemia compared with human insulin was an important step in the treatment of patients with Type 1 diabetes and those with Type 2 diabetes on insulin therapy. The development of new antidiabetic agents based on the incretin system, such as the incretin mimetics (eg, exenatide, liraglutide) and dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g., sitagliptin, vildagliptin, saxagliptin), present new options and potential strategies for safely achieving glucose targets. These drugs reduce hyperglycemia in a glucose-dependent manner and thus pose little risk of hypoglycemia; they are also associated with weight loss (incretin mimetics) or a weight neutral effect (DPP-4 inhibitors).

The goal in treating hyperglycemia in diabetes is to start treatment early and reduce HbA1c to as close to normal as is safely possible. We have the tools to begin to devise strategies to accomplish this objective in the form of lifestyle intervention and antidiabetic agents that avoid the risks associated with hypoglycemia and weight gain—e.g., metformin and incretin-based agents. The overall goal in treating diabetes is to reduce risk of microvascular and macrovascular complications, and glycemic control is an important component of efforts to achieve this goal. Optimal prevention of diabetic complications likely requires a multifactorial intervention strategy—eg, glycemic, blood pressure and lipid control—initiated early in the course of disease. The UKPDS, PROactive, ADVANCE, VADT and ACCORD studies have yielded large amounts of useful data for consideration, but further randomized trials are urgently needed to investigate the best approach to lowering HbA1c levels in patients with Type 2 diabetes who also have pre-existing macrovascular disease.

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