Targets for Glycemic Control

Abstract

Key Messages•Optimal glycemic control is fundamental to the management of diabetes.•Both fasting and postprandial plasma glucose levels correlate with the risk of complications and contribute to the measured glycated hemoglobin (A1C) value.•Glycemic targets should be individualized based on the individual’s age, duration of diabetes, risk of severe hypoglycemia, presence or absence of cardiovascular disease and life expectancy. •Optimal glycemic control is fundamental to the management of diabetes.•Both fasting and postprandial plasma glucose levels correlate with the risk of complications and contribute to the measured glycated hemoglobin (A1C) value.•Glycemic targets should be individualized based on the individual’s age, duration of diabetes, risk of severe hypoglycemia, presence or absence of cardiovascular disease and life expectancy. Optimal glycemic control is fundamental to the management of diabetes. In epidemiological analyses, glycated hemoglobin (A1C) levels >7.0% are associated with a significantly increased risk of both microvascular and macrovascular complications, regardless of underlying treatment (1UK Prospective Diabetes Study (UKPDS) GroupIntensive 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: 837-853Abstract Full Text Full Text PDF PubMed Scopus (18951) Google Scholar, 2The Diabetes Control and Complications Trial Research GroupThe relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial.Diabetes. 1995; 44: 968-983Crossref PubMed Scopus (1322) Google Scholar, 3Stratton I.M. Adler A.I. Neil H.A.W. et al.Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.BMJ. 2000; 321: 405-412Crossref PubMed Scopus (6919) Google Scholar). Data from the Diabetes Control and Complications Trial (DCCT; type 1 diabetes) (2The Diabetes Control and Complications Trial Research GroupThe relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial.Diabetes. 1995; 44: 968-983Crossref PubMed Scopus (1322) Google Scholar) and the United Kingdom Prospective Diabetes Study (UKPDS; type 2 diabetes) (3Stratton I.M. Adler A.I. Neil H.A.W. et al.Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.BMJ. 2000; 321: 405-412Crossref PubMed Scopus (6919) Google Scholar) demonstrated a continuous relationship between A1C and diabetes complications, with no apparent threshold of benefit. In the DCCT, a 10% reduction in A1C was associated with a 40% to 50% lower risk of retinopathy progression, although the absolute reduction in risk was substantially less at lower A1C levels (2The Diabetes Control and Complications Trial Research GroupThe relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial.Diabetes. 1995; 44: 968-983Crossref PubMed Scopus (1322) Google Scholar). In the UKPDS, this relationship was directly linear, with each 1.0% (absolute) reduction in mean A1C associated with a 37% decline in the risk of microvascular complications, a 14% lower rate of myocardial infarction (MI) and a 21% reduction in deaths from diabetes (3Stratton I.M. Adler A.I. Neil H.A.W. et al.Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.BMJ. 2000; 321: 405-412Crossref PubMed Scopus (6919) Google Scholar). Both fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) are directly correlated to the risk of complications, with some evidence that postprandial might constitute a stronger risk factor for cardiovascular (CV) complications (4Service F.J. O'Brien P.C. The relation of glycaemia to the risk of development and progression of retinopathy in the Diabetic Control and Complications Trial.Diabetologia. 2001; 44: 1215-1220Crossref PubMed Scopus (98) Google Scholar, 5Coutinho M. Gerstein H.C. Wang Y. et al.The relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years.Diabetes Care. 1999; 22: 233-240Crossref PubMed Scopus (1530) Google Scholar, 6Levitan E.B. Song Y. Ford E.S. et al.Is nondiabetic hyperglycemia a risk factor for cardiovascular disease?.Arch Intern Med. 2004; 164: 2147-2155Crossref PubMed Scopus (542) Google Scholar, 7DECODE Study Group, European Diabetes Epidemiology GroupIs current definition for diabetes relevant to mortality risk from all causes and cardiovascular and noncardiovascular causes?.Diabetes Care. 2003; 26: 688-696Crossref PubMed Scopus (498) Google Scholar, 8Sorkin J.D. Muller D.C. Fleg J.L. et al.The relation of fasting and 2-h postchallenge plasma glucose to mortality: data from the Baltimore Longitudinal Study of Aging with a critical review of the literature.Diabetes Care. 2005; 28: 2626-2632Crossref PubMed Scopus (172) Google Scholar, 9Cavalot F. Pagliarino A. Valle M. et al.Postprandial blood glucose predicts cardiovascular events and all-cause mortality in type 2 diabetes in a 14-year follow-up: lessons from the San Luigi Gonzaga Diabetes Study.Diabetes Care. 2011; 34: 2237-2243Crossref PubMed Scopus (235) Google Scholar). In a meta-analysis of 102 prospective studies, FPG >5.6 mmol/L was associated with an increased risk of CV events (10The Emerging Risk Factor CollaborationDiabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies.Lancet. 2010; 375: 2215-2222Abstract Full Text Full Text PDF PubMed Scopus (3055) Google Scholar). Postprandial hyperglycemia and the 2-hour post-challenge PG appears to be a better predictor of cardiovascular disease (CVD) and all-cause mortality than FPG (7DECODE Study Group, European Diabetes Epidemiology GroupIs current definition for diabetes relevant to mortality risk from all causes and cardiovascular and noncardiovascular causes?.Diabetes Care. 2003; 26: 688-696Crossref PubMed Scopus (498) Google Scholar). This association between CVD and 2-hour postprandial PG appears to be linear (6Levitan E.B. Song Y. Ford E.S. et al.Is nondiabetic hyperglycemia a risk factor for cardiovascular disease?.Arch Intern Med. 2004; 164: 2147-2155Crossref PubMed Scopus (542) Google Scholar, 7DECODE Study Group, European Diabetes Epidemiology GroupIs current definition for diabetes relevant to mortality risk from all causes and cardiovascular and noncardiovascular causes?.Diabetes Care. 2003; 26: 688-696Crossref PubMed Scopus (498) Google Scholar). Values >7.8 mmol/L are associated with an increase in all-cause mortality (8Sorkin J.D. Muller D.C. Fleg J.L. et al.The relation of fasting and 2-h postchallenge plasma glucose to mortality: data from the Baltimore Longitudinal Study of Aging with a critical review of the literature.Diabetes Care. 2005; 28: 2626-2632Crossref PubMed Scopus (172) Google Scholar), and values >10.0 mmol/L are associated with both microvascular complications (11Ohkubo Y. Kishikawa H. Araki E. et al.Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study.Diabetes Res Clin Pract. 1995; 28: 103-117Abstract Full Text PDF PubMed Scopus (2838) Google Scholar) and the highest risk of MI (12Hanefeld M. Fischer S. Julius U. et al.Risk factors for myocardial infarction and death in newly detected NIDDM: the Diabetes Intervention Study, 11-year follow-up.Diabetologia. 1996; 39: 1577-1583Crossref PubMed Scopus (922) Google Scholar). There is compelling evidence from randomized controlled studies that improved glycemic control reduces the risk of microvascular complications but has no significant effect on macrovascular outcomes in recently diagnosed type 1 (13The Diabetes Control and Complications Trial Research GroupThe 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: 977-986Crossref PubMed Scopus (22705) Google Scholar) and type 2 diabetes (1UK Prospective Diabetes Study (UKPDS) GroupIntensive 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: 837-853Abstract Full Text Full Text PDF PubMed Scopus (18951) Google Scholar, 11Ohkubo Y. Kishikawa H. Araki E. et al.Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study.Diabetes Res Clin Pract. 1995; 28: 103-117Abstract Full Text PDF PubMed Scopus (2838) Google Scholar, 14United Kingdom Prospective Diabetes Study (UKPDS)Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).Lancet. 1998; 352: 854-865Abstract Full Text Full Text PDF PubMed Scopus (7474) Google Scholar), as well as more long-standing type 2 diabetes (15The ADVANCE Collaborative GroupIntensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N Engl J Med. 2008; 358: 2560-2572Crossref PubMed Scopus (5946) Google Scholar, 16Ismail-Beigi F. Craven T. Banerji M.A. et al.ACCORD Trial GroupEffect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomized trial.Lancet. 2010; 376: 419-430Abstract Full Text Full Text PDF PubMed Scopus (1026) Google Scholar, 17The Action to Control Cardiovascular Risk in Diabetes Study GroupEffects of intensive glucose lowering in type 2 diabetes.N Eng J Med. 2008; 358: 2545-2559Crossref PubMed Scopus (6456) Google Scholar, 18Duckworth W. Abraira C. Moritz T. et al.VADT InvestigatorsGlucose control and vascular complications in veterans with type 2 diabetes.N Engl J Med. 2009; 360: 129-139Crossref PubMed Scopus (3866) Google Scholar, 19Moritz T. Duckworth W. Abraira C. Veterans Affairs Diabetes Trial: corrections.N Engl J Med. 2009; 361: 1024-1025Crossref PubMed Scopus (52) Google Scholar). The initial prospective randomized controlled trials were conducted in patients with recently diagnosed diabetes. These trials—the DCCT in type 1 diabetes (13The Diabetes Control and Complications Trial Research GroupThe 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: 977-986Crossref PubMed Scopus (22705) Google Scholar) and the Kumamoto (11Ohkubo Y. Kishikawa H. Araki E. et al.Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study.Diabetes Res Clin Pract. 1995; 28: 103-117Abstract Full Text PDF PubMed Scopus (2838) Google Scholar) and the UKPDS (1UK Prospective Diabetes Study (UKPDS) GroupIntensive 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: 837-853Abstract Full Text Full Text PDF PubMed Scopus (18951) Google Scholar, 14United Kingdom Prospective Diabetes Study (UKPDS)Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).Lancet. 1998; 352: 854-865Abstract Full Text Full Text PDF PubMed Scopus (7474) Google Scholar) in type 2 diabetes—confirmed that improved glycemic control significantly reduced the risk of microvascular complications but had no significant effect on macrovascular (particularly CV) outcomes. Subsequent observational data from long-term follow-up of both the DCCT and UKPDS cohorts showed a persistence of significant microvascular benefits in patients who had previously been in the intensively treated groups despite the fact that, during the subsequent follow-up period, their glycemic control became similar to that of patients who were previously in the standard arm (20The Writing Team for the Diabetes Control and Complications Trial / Epidemiology of Diabetes Interventions and Complications Research GroupEffects of intensive therapy on the microvascular complications of type 1 diabetes mellitus.JAMA. 2002; 287: 2563-2569Crossref PubMed Scopus (759) Google Scholar, 21Martin C.L. Albers J. Herman W.H. et al.Neuropathy among the Diabetes Control and Complications Trial cohort 8 Years after trial completion.Diabetes Care. 2006; 29: 340-344Crossref PubMed Scopus (281) Google Scholar, 22Holman R.R. Paul S.K. Bethel M.A. et al.10-Year follow-up of intensive glucose control in type 2 diabetes.N Engl J Med. 2008; 359: 1577-1589Crossref PubMed Scopus (5243) Google Scholar). The follow-up data from these 2 studies also demonstrated a beneficial effect of improved glycemic control on CV outcomes. In the DCCT cohort, there was a significant reduction in CV outcomes (42%) as well as non-fatal MI, stroke and CV death (57%) in previously intensively treated patients compared with those who were previously in the standard arm (23Nathan D.M. Cleary P.A. Backlund J.Y. et al.Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.N Eng J Med. 2005; 353: 2643-2653Crossref PubMed Scopus (4136) Google Scholar). Similarly, there was a significant reduction in MI (15%–33%) and all-cause mortality (13%–27%) in the UKPDS cohort in patients who had been originally randomized to intensive treatment (22Holman R.R. Paul S.K. Bethel M.A. et al.10-Year follow-up of intensive glucose control in type 2 diabetes.N Engl J Med. 2008; 359: 1577-1589Crossref PubMed Scopus (5243) Google Scholar). Three major trials—the Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE), and Veterans Affairs Diabetes Trial (VADT)—looked at the effect of intensive glycemic control on patients with long-standing type 2 diabetes. The ACCORD trial randomly assigned 10 251 patients to intensive therapy targeting an A1C <6.0% or standard therapy targeting an AIC level of 7.0% to 7.9% (17The Action to Control Cardiovascular Risk in Diabetes Study GroupEffects of intensive glucose lowering in type 2 diabetes.N Eng J Med. 2008; 358: 2545-2559Crossref PubMed Scopus (6456) Google Scholar, 24The ACCORD Study Group and ACCORD Eye Study GroupEffects of medical therapies on retinopathy progression in type 2 diabetes.N Engl J Med. 2010; 363: 233-244Crossref PubMed Scopus (964) Google Scholar). Patients included had either a previous history of CVD or multiple risk factors for CVD, and a baseline A1C level ≥7.5%. At inclusion, participants had a mean age of 62 years, diabetes duration of 10 years and a median baseline A1C level of 8.1%. A difference in A1C was rapidly obtained and maintained throughout the trial at 6.4% and 7.5% in the intensive and standard therapy groups, respectively. The primary outcome of this study was a composite of major CV events: non-fatal MI, nonfatal stroke or death from CV causes. The intensive glucose control arm was prematurely terminated after 3.5 years due to higher mortality associated with assignment to this treatment (17The Action to Control Cardiovascular Risk in Diabetes Study GroupEffects of intensive glucose lowering in type 2 diabetes.N Eng J Med. 2008; 358: 2545-2559Crossref PubMed Scopus (6456) Google Scholar, 24The ACCORD Study Group and ACCORD Eye Study GroupEffects of medical therapies on retinopathy progression in type 2 diabetes.N Engl J Med. 2010; 363: 233-244Crossref PubMed Scopus (964) Google Scholar). The ADVANCE trial randomly assigned 11 140 patients to standard (targeting A1C based on local guidelines) or intensive glucose control therapy aimed at reducing A1C levels to ≤6.5% (15The ADVANCE Collaborative GroupIntensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N Engl J Med. 2008; 358: 2560-2572Crossref PubMed Scopus (5946) Google Scholar). Patients were at least 55 years old with a history of major macrovascular or microvascular disease or at least 1 other risk factor for vascular disease. Median baseline A1C level and diabetes duration were lower than in the ACCORD trial at 7.2% and 8 years, respectively, whereas mean age was slightly higher at 66 years. The difference in A1C in both arms was obtained less rapidly, and, after a 5-year follow-up, mean A1C was 6.5% in the intensive group and 7.3% in the standard group. The primary outcome in the ADVANCE trial was a composite of microvascular events (nephropathy and retinopathy) and macrovascular disease defined by major adverse CV events. VADT randomly assigned 1791 United States military veterans with poor glycemic control (≥7.5%) to either standard or intensive glucose therapy, which aimed for an overall reduction in A1C levels by 1.5% (18Duckworth W. Abraira C. Moritz T. et al.VADT InvestigatorsGlucose control and vascular complications in veterans with type 2 diabetes.N Engl J Med. 2009; 360: 129-139Crossref PubMed Scopus (3866) Google Scholar, 19Moritz T. Duckworth W. Abraira C. Veterans Affairs Diabetes Trial: corrections.N Engl J Med. 2009; 361: 1024-1025Crossref PubMed Scopus (52) Google Scholar). Following a median follow-up of 5.6 years, A1C levels were 8.4% and 6.9% in the standard and intensive therapy groups, respectively. The primary outcome of the study was the time from randomization to the first occurrence of a major CV event (18Duckworth W. Abraira C. Moritz T. et al.VADT InvestigatorsGlucose control and vascular complications in veterans with type 2 diabetes.N Engl J Med. 2009; 360: 129-139Crossref PubMed Scopus (3866) Google Scholar, 19Moritz T. Duckworth W. Abraira C. Veterans Affairs Diabetes Trial: corrections.N Engl J Med. 2009; 361: 1024-1025Crossref PubMed Scopus (52) Google Scholar). These 3 trials confirmed the benefit of intensive glycemic control on microvascular outcomes. In the VADT study, the progression to albuminuria was significantly reduced in the intensive-treatment patients, with 9.1% of patients having significantly reduced progression compared to 13.8% in the standard therapy group (19Moritz T. Duckworth W. Abraira C. Veterans Affairs Diabetes Trial: corrections.N Engl J Med. 2009; 361: 1024-1025Crossref PubMed Scopus (52) Google Scholar). Similarly, intensive therapy in ACCORD patients showed a favourable effect on microvascular outcomes, particularly albuminuria and diabetic retinopathy (16Ismail-Beigi F. Craven T. Banerji M.A. et al.ACCORD Trial GroupEffect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomized trial.Lancet. 2010; 376: 419-430Abstract Full Text Full Text PDF PubMed Scopus (1026) Google Scholar). In ADVANCE, patients in the intensive control group demonstrated a reduction in the incidence of major microvascular events, mainly through a 21% relative reduction in nephropathy (15The ADVANCE Collaborative GroupIntensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N Engl J Med. 2008; 358: 2560-2572Crossref PubMed Scopus (5946) Google Scholar). A recent meta-analysis confirmed the positive impact of intensive glycemic control on microalbuminuria (25Boussageon R. Bejan-Angoulvant T. Saadatian-Elahi M. et al.Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials.BMJ. 2011; 343: d4169Crossref PubMed Scopus (593) Google Scholar). None of the above studies independently confirmed a significant benefit of tight glycemic control on macrovascular outcomes. However, meta-analysis of clinical trials designed to assess differences in CV outcomes in patients who had achieved lower versus higher levels of glycemia demonstrated that those treated with more intensive therapy, compared to less intensive glycemic control, were found to have a 10% to 15% reduction in the risk of major CV events, primarily because of a 15% reduced risk of MI, but with no effect on stroke, CV death or all cause mortality (26Hemmingsen B. Lund S.S. Gluud C. et al.Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus.Cochrane Database Syst Rev. 2011; 6: CD008143PubMed Google Scholar). Intensive glycemic control, however, was associated with more than a 2-fold increase in the risk of severe hypoglycemia (25Boussageon R. Bejan-Angoulvant T. Saadatian-Elahi M. et al.Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials.BMJ. 2011; 343: d4169Crossref PubMed Scopus (593) Google Scholar). The unexpected higher mortality rates seen in the intensive arm of the ACCORD study and the lack of clear macrovascular benefit in the ADVANCE and VADT trials have been further reviewed. Several potential reasons for these findings have been suggested, including patient age, duration of diabetes, presence of CVD, history of severe hypoglycemic events, weight gain and the rapid decrease in A1C values. Increased mortality associated with intensive treatment could not be explained by the type of pharmacological treatment, rapidity to implement the intensive strategy or weight gain (24The ACCORD Study Group and ACCORD Eye Study GroupEffects of medical therapies on retinopathy progression in type 2 diabetes.N Engl J Med. 2010; 363: 233-244Crossref PubMed Scopus (964) Google Scholar). Hypothesis-generating secondary analysis from the ACCORD trial reported a nonsignificant trend toward lower all-cause mortality in individuals assigned to the standard arm who were younger than 65 years at baseline (27Calles-Escandón J. Lovato L.C. Simons-Morton D.G. et al.Effect of intensive compared with standard glycemia treatment strategies on mortality by baseline subgroup characteristics: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.Diabetes Care. 2010; 33: 721-727Crossref PubMed Scopus (141) Google Scholar). Similarly, the ADVANCE trial also reported a nonsignificant trend toward fewer events among younger patients in the intensive therapy group (15The ADVANCE Collaborative GroupIntensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N Engl J Med. 2008; 358: 2560-2572Crossref PubMed Scopus (5946) Google Scholar). Duration of diabetes also may have played a role. Compared with the UKPDS and the DCCT, which were conducted in younger individuals with recent-onset diabetes, the duration of diabetes in the ACCORD, ADVANCE and VADT trials ranged from 8 to 11.5 years. Further emphasis of the importance of duration of diabetes was identified in a substudy of the VADT patients when measurement of the coronary calcium score, utilizing computed tomography, revealed fewer CVD events in these younger patients enrolled in the intensive treatment arm (28Reaven P.D. Moritz T.E. Schwenke D.C. et al.Intensive glucose-lowering therapy reduces cardiovascular disease events in veterans affairs diabetes trial participants with lower calcified coronary atherosclerosis.Diabetes. 2009; 58: 2642-2648Crossref PubMed Scopus (147) Google Scholar). The frequency of severe hypoglycemia in these trials was 2 to 3 times higher in the intensive therapy groups, and a higher mortality was reported in participants with 1 or more episodes of severe hypoglycemia in both the ACCORD (29Bonds D.E. Miller M.E. Bergenstal R.M. et al.The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study.BMJ. 2010; 340: 4909Crossref PubMed Scopus (758) Google Scholar) and the ADVANCE (30Zoungas S. Patel A. Chalmers J. et al.Severe hypoglycemia and risks of vascular events and death.N Eng J Med. 2010; 363: 1410-1418Crossref PubMed Scopus (1169) Google Scholar) trials, irrespective of the different treatment arms in which individual patients were allocated. However, these subanalyses confirmed that hypoglycemic events could not account for the difference in mortality between the intensive and standard therapy groups. Finally, in the ACCORD trial, mortality was increased in patients randomized in the intensive arm but who failed to reduce their A1C despite treatment intensification (31Riddle M.C. Ambrosius W.T. Brillo D.J. et al.Action to Control Cardiovascular Risk in Diabetes (ACCORD) InvestigatorsEpidemiologic relationships between A1C and all-cause mortality during a median 3.4-year follow-up of glycemic treatment in the ACCORD trial.Diabetes Care. 2010; 33: 983-990Crossref PubMed Scopus (353) Google Scholar). These findings suggest that microvascular and macrovascular events may be reduced by intensifying therapy targeting an A1C <7.0% in younger patients with recently diagnosed diabetes and a lower initial A1C value but with an increased risk of hypoglycemic risk. Individualized and higher A1C targets may be indicated in older type 2 patients with longer duration of diabetes, established CV risk factors, severe hypoglycemia episodes and/or without A1C reduction despite treatment intensification. Similarly, individualization of A1C targets may be needed in some patients with type 1 diabetes who are unable to achieve an A1C <7.0% without being at increased risk of severe hypoglycemia. It also must be recognized that A1C measurement is a component of both the FPG and PPG. When A1C values are higher, the major contribution is the FPG levels, but as the A1C value approaches the target value of ≤7.0%, there is a greater contribution from PPG values (32Monnier L. Lapinski H. Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA1c.Diabetes Care. 2003; 26: 881-885Crossref PubMed Scopus (1273) Google Scholar, 33Woerle H.H.J. Neumann C. Zschau S. et al.Impact of fasting and postprandial glycemia on overall glycemic control in type 2 diabetes. Importance of postprandial glycemia to achieve target HbA1c levels.Diabetes Res Clin Pract. 2007; 77: 280-285Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar). Another study using continuous glucose monitoring demonstrated that a 2-hour postprandial PG <8.0 mmol/L correlates best with A1C <7.0% (34Monnier L. Colette C. Dunseath G.J. et al.The loss of postprandial glycemic control precedes stepwise deterioration of fasting with worsening diabetes.Diabetes Care. 2007; 30: 263-269Crossref PubMed Scopus (396) Google Scholar). In view of this, if A1C targets cannot be achieved with a postprandial target of 5.0 to 10.0 mmol/L, further postprandial BG lowering to 5.0 to 8.0 mmol/L can be considered. The role of pre- vs. postprandial glucose control on reducing CV outcomes has been controversial (35Esposito K. Giugliano D. Nappo F. et al.Campanian Postprandial Hyperglycemia Study GroupRegression of carotid atherosclerosis by control of postprandial hyperglycemia in type 2 diabetes mellitus.Circulation. 2004; 110: 214-219Crossref PubMed Scopus (369) Google Scholar, 36Raz I. Wilson P.W.F. Strojek K. et al.Effects of prandial versus fasting glycemia on cardiovascular outcomes in type 2 Diabetes: the HEART2D trial.Diabetes Care. 2009; 32: 381-386Crossref PubMed Scopus (287) Google Scholar). A major difficulty in attempting to use evidence-based observations to determine the value of tighter postprandial glucose control has been the lack of well-designed, long-term outcome studies where assessing postprandial glucose values is the major objective of the study. Most of the large outcome trials conducted so far have been mostly based on preprandial glucose and A1C targets. Although there is evidence in type 2 diabetes that targeting postprandial hyperglycemia to <8.0 mmol/L reduces progression of carotid atherosclerosis (35Esposito K. Giugliano D. Nappo F. et al.Campanian Postprandial Hyperglycemia Study GroupRegression of carotid atherosclerosis by control of postprandial hyperglycemia in type 2 diabetes mellitus.Circulation. 2004; 110: 214-219Crossref PubMed Scopus (369) Google Scholar), a randomized controlled trial of type 2 diabetes patients treated with insulin therapy after acute MI showed no benefit of insulin regimen targeting postprandial hyperglycemia compared with the regimen targeting preprandial glucose (36Raz I. Wilson P.W.F. Strojek K. et al.Effects of prandial versus fasting glycemia on cardiovascular outcomes in type 2 Diabetes: the HEART2D trial.Diabetes Care. 2009; 32: 381-386Crossref PubMed Scopus (287) Google Scholar). Contrasting results from recent studies should not discourage physicians from controlling blood glucose levels. Intensive glucose control, lowering A1C values to ≤7% in both type 1 and type 2 diabetes, provides strong benefits for microvascular complications and, if achieved early in the disease, might also provide a significant macrovascular benefit, especially as part of a multifactorial treatment approach. More intensive glucose control, A1C ≤6.5%, may be sought in patients with a shorter duration of diabetes, no evidence of significant CVD and longer life expectancy, provided this does not result in a significant increase in hypoglycemia. An A1C target ≤8.5% may be more appropriate in type 1 and type 2 patients with limited life expectancy, higher level of functional dependency, a history of severe hypoglycemia, advanced comorbidities, and a failure to attain established glucose targets despite treatment intensification (Figure 1).Recommendations1.Glycemic targets should be individualized based on age, duration of diabetes, risk of severe hypoglycemia, presence or absence of cardiovascular disease, and life expectancy [Grade D, Consensus].2.Therapy in most individuals with type 1 or type 2 diabetes should be targeted to achieve an A1C ≤7.0% in order to reduce the risk of microvascular [Grade A, Level 1A (1UK Prospective Diabetes Study (UKPDS) GroupIntensive 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: 837-853Abstract Full Text Full Text PDF PubMed Scopus (18951) Google Scholar, 2The Diabetes Control and Complications Trial Research GroupThe relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial.Diabetes. 1995; 44: 968-983Crossref PubMed Scopus (1322) Google Scholar)] and, if implemented early in the course of disease, macrovascular complications [Grade B, Level 3 (22Holman R.R. Paul S.K. Bethel M.A. et al.10-Year follow-up of intensive glucose control in type 2 diabetes.N Engl J Med. 2008; 359: 1577-1589Crossref PubMed Scopus (5243) Google Scholar, 23Nathan D.M. Cleary P.A. Backlund J.Y. et al.Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.N Eng J Med. 2005; 353: 2643-2653Crossref PubMed Scopus (4136) Google Scholar)].3.An A1C ≤6.5% may be targeted in some patients with type 2 diabetes to further lower the risk of nephropathy [Grade A, Level 1 (15The ADVANCE Collaborative GroupIntensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N Engl J Med. 2008; 358: 2560-2572Crossref PubMed Scopus (5946) Google Scholar)] and retinopathy [Grade A, Level 1 (24The ACCORD Study Group and ACCORD Eye Study GroupEffects of medical therapies on retinopathy progression in type 2 diabetes.N Engl J Med. 2010; 363: 233-244Crossref PubMed Scopus (964) Google Scholar), but this must be balanced against the risk of hypoglycemia [Grade A, Level 1 (15The ADVANCE Collaborative GroupIntensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N Engl J Med. 2008; 358: 2560-2572Crossref PubMed Scopus (5946) Google Scholar)].4.Less stringent A1C targets (7.1%–8.5% in most cases) may be appropriate in patients with type 1 or type 2 diabetes with any of the following [Grade D, Consensus]:a)Limited life expectancyb)High level of functional dependencyc)Extensive coronary artery disease at high risk of ischemic eventsd)Multiple comorbiditiese)History of recurrent severe hypoglycemiaf)Hypoglycemia unawarenessg)Longstanding diabetes for whom it is difficult to achieve an A1C ≤7.0% despite effective doses of multiple antihyperglycemic agents, including intensified basal-bolus insulin therapy5.In order to achieve an A1C ≤7.0%, people with diabetes should aim for:•FPG or preprandial PG target of 4.0–7.0 mmol/L and a 2-hour PPG target of 5.0–10.0 mmol/L [Grade B, Level 2 (2The Diabetes Control and Complications Trial Research GroupThe relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial.Diabetes. 1995; 44: 968-983Crossref PubMed Scopus (1322) Google Scholar) for type 1; Grade B, Level 2 (1UK Prospective Diabetes Study (UKPDS) GroupIntensive 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: 837-853Abstract Full Text Full Text PDF PubMed Scopus (18951) Google Scholar, 11Ohkubo Y. 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Importance of postprandial glycemia to achieve target HbA1c levels.Diabetes Res Clin Pract. 2007; 77: 280-285Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar) for type 2 diabetes].Abbreviations:A1C, glycated hemoglobin; BG, blood glucose; FPG, fasting plasma glucose; PG, plasma glucose; PPG, postprandial plasma glucose.