Glycemic control and vascular complications in type 2 diabetes mellitus
- David K McCulloch, MD
David K McCulloch, MD
- Washington Permanente Medical Group
The importance of tight glycemic control for protection against microvascular and cardiovascular disease (CVD) in diabetes was established in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study for type 1 diabetes [1,2]. Although the role of glycemic control on microvascular disease in type 2 diabetes was documented in the United Kingdom Prospective Diabetes Study (UKPDS), its role in reducing cardiovascular risk has not been established as clearly for type 2 diabetes.
The effects of glycemic control on microvascular and macrovascular complications in type 2 diabetes will be reviewed here. Glycemic control and vascular complications in type 1 diabetes, the mechanism by which hyperglycemia might cause these complications, and an overview of the treatment of diabetes are discussed separately. (See "Glycemic control and vascular complications in type 1 diabetes mellitus" and "Overview of medical care in adults with diabetes mellitus".)
Hyperglycemia is an important risk factor for the development of microvascular disease in patients with type 2 diabetes, as it is in patients with type 1 diabetes. This has been shown in several observational studies [3,4]. In addition, improving glycemic control improves microvascular outcomes, as illustrated by the findings of a meta-analysis of randomized trials (34,912 participants) . There was a reduction in the risk of microvascular complications (a composite outcome including progression of nephropathy, manifestation and progression of retinopathy, and retinal photocoagulation) in the intensive compared with standard glycemic control group (relative risk [RR] 0.88, 95% CI 0.82-0.95). There were significant reductions in risk for each of the individual components.
In another meta-analysis of seven trials (28,065 adults) evaluating the benefits of intensive versus conventional glycemic control specifically on renal outcomes, there was a statistically significant reduction in the risk of microalbuminuria and macroalbuminuria in patients randomly assigned to intensive glycemic control (risk ratios of 0.86 and 0.74, respectively) . The reduction in risk of end-stage renal disease did not reach statistical significance (RR 0.69, 95% CI 0.46-1.05). There was no reduction in the risk of doubling of the serum creatinine level or death from renal disease (RRs 1.06 and 0.99, respectively). Of note, the majority of the trials in the meta-analysis were not of long enough duration to show a beneficial effect of glycemic control on end-stage renal disease, which typically manifests after 10 to 20 years of diabetes duration . In the trials included in the meta-analysis, the absolute rates of severe renal outcomes were low in both the intensive- and conventional-therapy groups, reducing the ability of the analysis to demonstrate a benefit, if one exists. In the one trial with longer-term follow-up (United Kingdom Prospective Diabetes Study [UKPDS] cohort followed for 22 years), there was a beneficial effect of intensive therapy on the development of more advanced clinical outcomes, including renal disease . (See 'Post-trial monitoring' below.)
The major trials are described below:
- Diabetes Control and Complications Trial Research Group, Nathan DM, Genuth S, et al. 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; 329:977.
- 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; 353:2643.
- Klein R, Klein BE, Moss SE, Cruickshanks KJ. Relationship of hyperglycemia to the long-term incidence and progression of diabetic retinopathy. Arch Intern Med 1994; 154:2169.
- Bash LD, Selvin E, Steffes M, et al. Poor glycemic control in diabetes and the risk of incident chronic kidney disease even in the absence of albuminuria and retinopathy: Atherosclerosis Risk in Communities (ARIC) Study. Arch Intern Med 2008; 168:2440.
- Hemmingsen B, Lund SS, Gluud C, et al. Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus. Cochrane Database Syst Rev 2013; :CD008143.
- Coca SG, Ismail-Beigi F, Haq N, et al. Role of intensive glucose control in development of renal end points in type 2 diabetes mellitus: systematic review and meta-analysis intensive glucose control in type 2 diabetes. Arch Intern Med 2012; 172:761.
- Nathan DM. Understanding the long-term benefits and dangers of intensive therapy of diabetes. Arch Intern Med 2012; 172:769.
- Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359:1577.
- Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:837.
- United Kingdom Prospective Diabetes Study (UKPDS). 13: Relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years. BMJ 1995; 310:83.
- Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:854.
- Ohkubo 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.
- ADVANCE Collaborative Group, Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358:2560.
- Zoungas S, Chalmers J, Neal B, et al. Follow-up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med 2014; 371:1392.
- Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; 360:129.
- Ismail-Beigi F, Craven T, Banerji MA, et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet 2010; 376:419.
- ACCORD Study Group, ACCORD Eye Study Group, Chew EY, et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010; 363:233.
- Khaw KT, Wareham N, Bingham S, et al. Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk. Ann Intern Med 2004; 141:413.
- Kuusisto J, Mykkänen L, Pyörälä K, Laakso M. NIDDM and its metabolic control predict coronary heart disease in elderly subjects. Diabetes 1994; 43:960.
- Selvin E, Marinopoulos S, Berkenblit G, et al. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med 2004; 141:421.
- Selvin E, Steffes MW, Zhu H, et al. Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults. N Engl J Med 2010; 362:800.
- Selvin E, Coresh J, Golden SH, et al. Glycemic control, atherosclerosis, and risk factors for cardiovascular disease in individuals with diabetes: the atherosclerosis risk in communities study. Diabetes Care 2005; 28:1965.
- Meigs JB, Singer DE, Sullivan LM, et al. Metabolic control and prevalent cardiovascular disease in non-insulin-dependent diabetes mellitus (NIDDM): The NIDDM Patient Outcome Research Team. Am J Med 1997; 102:38.
- Ray KK, Seshasai SR, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet 2009; 373:1765.
- Kelly TN, Bazzano LA, Fonseca VA, et al. Systematic review: glucose control and cardiovascular disease in type 2 diabetes. Ann Intern Med 2009; 151:394.
- Boussageon 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:d4169.
- Hemmingsen B, Lund SS, Gluud C, et al. Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials. BMJ 2011; 343:d6898.
- Abraira C, Colwell J, Nuttall F, et al. Cardiovascular events and correlates in the Veterans Affairs Diabetes Feasibility Trial. Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes. Arch Intern Med 1997; 157:181.
- Abraira C, Duckworth WC, Moritz T, VADT Group. Glycaemic separation and risk factor control in the Veterans Affairs Diabetes Trial: an interim report. Diabetes Obes Metab 2009; 11:150.
- Hayward RA, Reaven PD, Wiitala WL, et al. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015; 372:2197.
- Gerstein HC, Riddle MC, Kendall DM, et al. Glycemia treatment strategies in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Am J Cardiol 2007; 99:34i.
- ACCORD Study Group, Buse JB, Bigger JT, et al. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. Am J Cardiol 2007; 99:21i.
- The National Heart, Lung, and Blood Institute. Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial: Questions and Answers about the ACCORD Trial. http://www.nhlbi.nih.gov/health/prof/heart/other/accord/ (Accessed on February 14, 2008).
- Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358:2545.
- Bonds DE, Miller ME, Bergenstal RM, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ 2010; 340:b4909.
- ACCORD Study Group, Gerstein HC, Miller ME, et al. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med 2011; 364:818.
- Zoungas S, Patel A, Chalmers J, et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med 2010; 363:1410.
- American Diabetes Association. 6. Glycemic Targets. Diabetes Care 2017; 40:S48.
- Huang ES, Zhang Q, Gandra N, et al. The effect of comorbid illness and functional status on the expected benefits of intensive glucose control in older patients with type 2 diabetes: a decision analysis. Ann Intern Med 2008; 149:11.
- Currie CJ, Peters JR, Tynan A, et al. Survival as a function of HbA(1c) in people with type 2 diabetes: a retrospective cohort study. Lancet 2010; 375:481.
- Shurraw S, Hemmelgarn B, Lin M, et al. Association between glycemic control and adverse outcomes in people with diabetes mellitus and chronic kidney disease: a population-based cohort study. Arch Intern Med 2011; 171:1920.
- Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015; 38:140.
- Gray A, Raikou M, McGuire A, et al. Cost effectiveness of an intensive blood glucose control policy in patients with type 2 diabetes: economic analysis alongside randomised controlled trial (UKPDS 41). United Kingdom Prospective Diabetes Study Group. BMJ 2000; 320:1373.
- Eastman RC, Javitt JC, Herman WH, et al. Model of complications of NIDDM. I. Model construction and assumptions. Diabetes Care 1997; 20:725.
- Eastman RC, Javitt JC, Herman WH, et al. Model of complications of NIDDM. II. Analysis of the health benefits and cost-effectiveness of treating NIDDM with the goal of normoglycemia. Diabetes Care 1997; 20:735.
- Vijan S, Hofer TP, Hayward RA. Estimated benefits of glycemic control in microvascular complications in type 2 diabetes. Ann Intern Med 1997; 127:788.
- MICROVASCULAR DISEASE
- United Kingdom Prospective Diabetes Study
- - Post-trial monitoring
- Kumamoto study
- ADVANCE trial
- Veterans Affairs Diabetes Trial
- ACCORD trial
- Microvascular summary
- MACROVASCULAR DISEASE
- Intensive therapy
- - UKPDS
- - VACSDM/VADT
- - ACCORD
- - ADVANCE
- - Macrovascular summary
- GLYCEMIC TARGETS
- COST OF INTENSIVE THERAPY
- SOCIETY GUIDELINE LINKS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS
- Microvascular complications
- Macrovascular complications
- Target A1C
- Multifactorial risk reduction