C. Glycemic control
2. Glycemic goals in adults
- Lowering A1C to below or around 7% has been shown to reduce microvascular and neuropathic complications of type 1 and type 2 diabetes. Therefore, for microvascular disease prevention, the A1C goal for nonpregnant adults in general is <7%. (A)
- In type 1 and type 2 diabetes, randomized controlled trials of intensive versus standard glycemic control have not shown a significant reduction in CVD outcomes during the randomized portion of the trials. Long-term follow-up of the DCCT and UK Prospective Diabetes Study (UKPDS) cohorts suggests that treatment to A1C targets below or around 7% in the years soon after the diagnosis of diabetes is associated with long-term reduction in risk of macrovascular disease. Until more evidence becomes available, the general goal of <7% appears reasonable for many adults for macrovascular risk reduction. (B)
- Subgroup analyses of clinical trials such as the DCCT and UKPDS and the microvascular evidence from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial suggest a small but incremental benefit in microvascular outcomes with A1C values closer to normal. Therefore, for selected individual patients, providers might reasonably suggest even lower A1C goals than the general goal of <7%, if this can be achieved without significant hypoglycemia or other adverse effects of treatment. Such patients might include those with short duration of diabetes, long life expectancy, and no significant CVD. (B)
- Conversely, less stringent A1C goals than the general goal of <7% may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, and those with longstanding diabetes in whom the general goal is difficult to attain despite DSME, appropriate glucose monitoring, and effective doses of multiple glucose-lowering agents including insulin. (C)
Glycemic control is fundamental to the management of diabetes. The DCCT, a prospective, randomized, controlled trial of intensive versus standard glycemic control in patients with relatively recently diagnosed type 1 diabetes, showed definitively that improved glycemic control is associated with significantly decreased rates of microvascular (retinopathy and nephropathy) as well as neuropathic complications (45
). Follow-up of the DCCT cohorts in the Epidemiology of Diabetes Interventions and Complications (EDIC) study has shown persistence of this effect in previously intensively treated subjects, even though their glycemic control has been equivalent to that of previous standard arm subjects during follow-up (46
In type 2 diabetes, the Kumamoto study (48
) and the UKPDS (49
) demonstrated significant reductions in microvascular and neuropathic complications with intensive therapy. Similar to the DCCT-EDIC findings, long-term follow-up of the UKPDS cohort has recently demonstrated a “legacy effect” of early intensive glycemic control on long-term rates of microvascular complications, even with loss of glycemic separation between the intensive and standard cohorts after the end of the randomized controlled (51
In each of these large randomized prospective clinical trials, treatment regimens that reduced average A1C to ≥7% (≥1% above the upper limits of normal) were associated with fewer long-term microvascular complications; however, intensive control was found to increase the risk of severe hypoglycemia, most notably in the DCCT, and led to weight gain (39
Epidemiological analyses of the DCCT and UKPDS (39
) demonstrate a curvilinear relationship between A1C and microvascular complications. Such analyses suggest that, on a population level, the greatest number of complications will be averted by taking patients from very poor control to fair or good control. These analyses also suggest that further lowering of A1C from 7 to 6% is associated with further reduction in the risk of microvascular complications, albeit the absolute risk reductions become much smaller. Given the substantially increased risk of hypoglycemia (particularly in those with type 1 diabetes) and the relatively much greater effort required to achieve near-normoglycemia, the risks of lower targets may outweigh the potential benefits on microvascular complications on a population level. However, selected individual patients, especially those with little comorbidity and long life expectancy (who may reap the benefits of further lowering of glycemia below 7%) may, at patient and provider judgment, adopt glycemic targets as close to normal as possible as long as significant hypoglycemia does not become a barrier.
Whereas many epidemiologic studies and meta-analyses (53
) have clearly shown a direct relationship between A1C and CVD, the potential of intensive glycemic control to reduce CVD has been less clearly defined. In the DCCT, there was a trend toward lower risk of CVD events with intensive control (risk reduction 41%, 95% CI 10–68%), but the number of events was small. However, 9-year post-DCCT follow-up of the cohort has shown that participants previously randomized to the intensive arm had a 42% reduction (P
= 0.02) in CVD outcomes and a 57% reduction (P
= 0.02) in the risk of nonfatal myocardial infarction (MI), stroke, or CVD death compared with those previously in the standard arm (55
The UKPDS trial of type 2 diabetes observed a 16% reduction in cardiovascular complications (combined fatal or nonfatal MI and sudden death) in the intensive glycemic control arm, although this difference was not statistically significant (P
= 0.052), and there was no suggestion of benefit on other CVD outcomes such as stroke. In an epidemiologic analysis of the study cohort, a continuous association was observed, such that for every percentage point lower median on-study A1C (e.g., 8 to 7%) there was a statistically significant 18% reduction in CVD events, again with no glycemic threshold. A recent report of 10 years of follow-up of the UKPDS cohort describes, for the participants originally randomized to intensive glycemic control compared with those randomized to conventional glycemic control, long-term reductions in MI (15% with sulfonylurea or insulin as initial pharmacotherapy, 33% with metformin as initial pharmacotherapy, both statistically significant) and in all-cause mortality (13 and 27%, respectively, both statistically significant) (51
Because of ongoing uncertainty regarding whether intensive glycemic control can reduce the increased risk of CVD events in people with type 2 diabetes, several large long-term trials were launched in the past decade to compare the effects of intensive versus standard glycemic control on CVD outcomes in relatively high-risk participants with established type 2 diabetes.
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study randomized 10,251 participants with either history of a CVD event (ages 40–79 years) or significant CVD risk (ages 55–79) to a strategy of intensive glycemic control (target A1C <6.0%) or standard glycemic control (A1C target 7.0–7.9%). Investigators used multiple glycemic medications in both arms. ACCORD participants were on average 62 years old and had a mean duration of diabetes of 10 years, with 35% already treated with insulin at baseline. From a baseline median A1C of 8.1%, the intensive arm reached a median A1C of 6.4% within 12 months of randomization, while the standard group reached a median A1C of 7.5%. Other risk factors were treated aggressively and equally in both groups. The intensive glycemic control group had more use of insulin in combination with multiple oral agents, significantly more weight gain, and more episodes of severe hypoglycemia than the standard group.
In February 2008, the glycemic control study of ACCORD was halted on the recommendation of the study's data safety monitoring board due to the finding of an increased rate of mortality in the intensive arm compared with the standard arm (1.41%/year vs. 1.14%/year; HR 1.22 [95% CI 1.01–1.46]), with a similar increase in cardiovascular deaths. The primary outcome of ACCORD (MI, stroke, or cardiovascular death) was lower in the intensive glycemic control group due to a reduction in nonfatal MI, although this finding was not statistically significant when the study was terminated (HR 0.90 [95% CI 0.78–1.04]; P
= 0.16) (56
Exploratory analyses of the mortality findings of ACCORD (evaluating variables including weight gain, use of any specific drug or drug combination, and hypoglycemia) were reportedly unable to identify an explanation for the excess mortality in the intensive arm. Prespecified subset analyses showed that participants with no previous CVD event and those who had a baseline A1C <8% had a statistically significant reduction in the primary CVD outcome.
The ADVANCE study randomized 11,140 participants to a strategy of intensive glycemic control (with primary therapy being the sulfonylurea gliclizide and additional medications as needed to achieve a target A1C of ≤6.5%) or to standard therapy (in which any medication but gliclizide could be used and the glycemic target was according to “local guidelines”). ADVANCE participants (who had to be at least 55 years of age with either known vascular disease or at least one other vascular risk factor) were slightly older and of similar high CVD risk as those in ACCORD. However, they had an average duration of diabetes 2 years shorter, lower baseline A1C (median 7.2%), and almost no use of insulin at enrollment. The median A1C levels achieved in the intensive and standard arms were 6.3 and 7.0%, respectively, and maximal separation between the arms took several years to achieve. Use of other drugs that favorably impact CVD risk (aspirin, statins, ACE inhibitors) was lower in ADVANCE than in the ACCORD or Veterans Affairs Diabetes Trial (VADT).
The primary outcome of ADVANCE was a combination of microvascular events (nephropathy and retinopathy) and major adverse cardiovascular events (MI, stroke, and cardiovascular death). Intensive glycemic control significantly reduced the primary endpoint (HR 0.90 [95% CI 0.82–0.98]; P
= 0.01), although this was due to a significant reduction in the microvascular outcome (0.86 [0.77–0.97], P
= 0.01), primarily development of macroalbuminuria, with no significant reduction in the macrovascular outcome (0.94 [0.84–1.06]; P
= 0.32). There was no difference in overall or cardiovascular mortality between the intensive and the standard glycemic control arms (57
The VADT randomized 1,791 participants with type 2 diabetes uncontrolled on insulin or maximal dose oral agents (median entry A1C 9.4%) to a strategy of intensive glycemic control (goal A1C <6.0%) or standard glycemic control, with a planned A1C separation of at least 1.5%. Medication treatment algorithms were used to achieve the specified glycemic goals, with a goal of using similar medications in both groups. Median A1C levels of 6.9 and 8.4% were achieved in the intensive and standard arms, respectively, within the first year of the study. Other CVD risk factors were treated aggressively and equally in both groups.
The primary outcome of the VADT was a composite of CVD events (MI, stroke, cardiovascular death, revascularization, hospitalization for heart failure, and amputation for ischemia). During a mean 6-year follow-up period, the cumulative primary outcome was nonsignificantly lower in the intensive arm (HR 0.87 [95% CI 0.73–1.04]; P
= 0.12). There were more CVD deaths in the intensive arm than in the standard arm (40 vs. 33; sudden deaths 11 vs. 4), but the difference was not statistically significant. Post hoc subgroup analyses suggested that duration of diabetes interacted with randomization such that participants with duration of diabetes less than about 12 years appeared to have a CVD benefit of intensive glycemic control while those with longer duration of disease before study entry had a neutral or even adverse effect of intensive glycemic control. Other exploratory analyses suggested that severe hypoglycemia within the past 90 days was a strong predictor of the primary outcome and of CVD mortality (58
The cause of the excess deaths in the intensive glycemic control arm of ACCORD compared with the standard arm has been difficult to pinpoint. By design of the trial, randomization to the intensive arm was associated with or led to many downstream effects, such as higher rates of severe hypoglycemia; more frequent use of insulin, TZDs, other drugs, and drug combinations; and greater weight gain. Such factors may be associated statistically with the higher mortality rate in the intensive arm but may not be causative. It is biologically plausible that severe hypoglycemia could increase the risk of cardiovascular death in participants with high underlying CVD risk. Other plausible mechanisms for the increase in mortality in ACCORD include weight gain, unmeasured drug effects or interactions, or the overall “intensity” of the ACCORD intervention (use of multiple oral glucose-lowering drugs along with multiple doses of insulin, frequent therapy adjustments to push A1C and self-monitored blood glucose to very low targets, and an intense effort to aggressively reduce A1C by ~2% in participants entering the trial with advanced diabetes and multiple comorbidities).
Since the ADVANCE trial did not show any increase in mortality in the intensive glycemic control arm, examining the differences between ADVANCE and ACCORD supports additional hypotheses. ADVANCE participants on average appeared to have earlier or less advanced diabetes, with shorter duration by 2–3 years and lower A1C at entry despite very little use of insulin at baseline. A1C was also lowered less and more gradually in the ADVANCE trial, and there was no significant weight gain with intensive glycemic therapy. Although severe hypoglycemia was defined somewhat differently in the three trials, it appears that this occurred in fewer than 3% of intensively treated ADVANCE participants for the entire study duration (median 5 years) compared with ~16% of intensively treated subjects in ACCORD and 21% in VADT.
It is likely that the increase in mortality in ACCORD was related to the overall treatment strategies for intensifying glycemic control in the study population, not the achieved A1C per se. The ADVANCE study achieved a median A1C in its intensive arm similar to that in the ACCORD study, with no increased mortality hazard. Thus, the ACCORD mortality findings do not imply that patients with type 2 diabetes who can easily achieve or maintain low A1C levels with lifestyle modifications with or without pharmacotherapy are at risk and need to “raise” their A1C.
The three trials compared treatments to A1C levels in the “flatter” part of the observational glycemia-CVD risk curves (median A1C of 6.4–6.9% in the intensive arms compared with 7.0–8.4% in the standard arms). Importantly, their results should not be extrapolated to imply that there would be no cardiovascular benefit of glucose lowering from very poor control (e.g., A1C >9%) to good control (e.g., A1C <7%).
All three trials were carried out in participants with established diabetes (mean duration 8–11 years) and either known CVD or multiple risk factors suggesting the presence of established atherosclerosis. Subset analyses of the three trials suggested a significant benefit of intensive glycemic control on CVD in participants with shorter duration of diabetes, lower A1C at entry, and/or or absence of known CVD. The DCCT-EDIC study and the long-term follow-up of the UKPDS cohort both suggest that intensive glycemic control initiated soon after diagnosis of diabetes in patients with a lower level of CVD risk may impart long-term protection from CVD events. As is the case with microvascular complications, it may be that glycemic control plays a greater role before macrovascular disease is well developed and minimal or no role when it is advanced.
The benefits of intensive glycemic control on microvascular and neuropathic complications are well established for both type 1 and type 2 diabetes. The ADVANCE trial has added to that evidence base by demonstrating a significant reduction in the risk of new or worsening albuminuria when A1C was lowered to 6.3% compared with standard glycemic control achieving an A1C of 7.0%. The lack of significant reduction in CVD events with intensive glycemic control in ACCORD, ADVANCE, and VADT should not lead clinicians to abandon the general target of an A1C <7.0% and thereby discount the benefit of good control on what are serious and debilitating microvascular complications.
The evidence for a cardiovascular benefit of intensive glycemic control primarily rests on long-term follow-up of study cohorts treated early in the course of type 1 and type 2 diabetes and subset analyses of ACCORD, ADVANCE, and VADT. Conversely, the mortality findings in ACCORD suggest that the potential risks of very intensive glycemic control may outweigh its benefits in some patients, such as those with very long duration of diabetes, known history of severe hypoglycemia, advanced atherosclerosis, and advanced age/frailty. Certainly, providers should be vigilant in preventing severe hypoglycemia in patients with advanced disease and should not aggressively attempt to achieve near-normal A1C levels in patients in whom such a target cannot be reasonably easily and safely achieved.
Recommended glycemic goals for nonpregnant adults are shown in . The recommendations are based on those for A1C, with listed blood glucose levels that appear to correlate with achievement of an A1C of <7%. The issue of pre- versus postprandial SMBG targets is complex (59
). Elevated postchallenge (2-h OGTT) glucose values have been associated with increased cardiovascular risk independent of FPG in some epidemiological studies. In diabetic subjects, some surrogate measures of vascular pathology, such as endothelial dysfunction, are negatively affected by postprandial hyperglycemia (60
). It is clear that postprandial hyperglycemia, like preprandial hyperglycemia, contributes to elevated A1C levels, with its relative contribution being higher at A1C levels that are closer to 7%. However, outcome studies have clearly shown A1C to be the primary predictor of complications, and landmark glycemic control trials such as the DCCT and UKPDS relied overwhelmingly on preprandial SMBG. Additionally, a randomized controlled trial presented at the 68th Scientific Sessions of the American Diabetes Association in June 2008 found no CVD benefit of insulin regimens targeting postprandial glucose compared with those targeting preprandial glucose. A reasonable recommendation for postprandial testing and targets is that for individuals who have premeal glucose values within target but have A1C values above target, monitoring postprandial plasma glucose (PPG) 1–2 h after the start of the meal and treatment aimed at reducing PPG values to <180 mg/dl may help lower A1C.
Summary of glycemic recommendations for non-pregnant adults with diabetes
As noted above, less stringent treatment goals may be appropriate for adults with limited life expectancies or advanced vascular disease. Glycemic goals for children are provided in Section VII.A.1.a. Severe or frequent hypoglycemia is an absolute indication for the modification of treatment regimens, including setting higher glycemic goals.
Regarding goals for glycemic control for women with GDM, recommendations from the Fifth International Workshop-Conference on Gestational Diabetes Mellitus (61
) were to target the following maternal capillary glucose concentrations:
- preprandial: ≤95 mg/dl (5.3 mmol/l) and either
- 1-h postmeal: ≤140 mg/dl (7.8 mmol/l) or
- 2-h postmeal: ≤120 mg/dl (6.7 mmol/l)
For women with preexisting type 1 or type 2 diabetes who become pregnant, a recent consensus statement (62
) recommended the following as optimal glycemic goals, if they can be achieved without excessive hypoglycemia:
- premeal, bedtime, and overnight glucose 60–99 mg/dl
- peak postprandial glucose 100–129 mg/dl
- A1C <6.0%