Glycemic control is critical to the prevention of diabetic complications. The duration and severity of hyperglycemia correlates with both the development and rate of progression of diabetic retinopathy, nephropathy, and neuropathy. The DCCT and the UKPDS established the effectiveness of glycemic control in the prevention of diabetic complications in T1DM and T2DM, respectively, during the 1990s.
The DCCT studied the effect of an intensive insulin regimen on the primary and secondary prevention of diabetic microvascular complications in individuals with T1DM. This prospective study included 1441 individuals with T1DM who were randomized to receive intensive glycemic management or conventional insulin therapy. Those assigned to intensive therapy attempted to achieve and maintain near-normal glucose levels by using > 3 daily insulin injections or an insulin pump, self-monitoring blood glucose levels > 4 times/day, and monthly visits to a multidisciplinary healthcare team. The conventional treatment group continued to use 1-2 injections of daily insulin, daily self-monitoring of blood sugars, and had a routine follow-up visit every 3 months. At study initiation, both groups had a mean HbA1C around 9%. Within 3 months, the intensive group achieved and maintained an average HbA1C of 7%, whereas the mean HbA1C remained at 9% throughout the study in the conventional treatment group.
Intensive therapy reduced the risk for developing retinopathy by 76% (primary prevention) and slowed progression of pre-existing retinopathy by 54%, the incidence of severe retinopathy by 47%, and the need for laser therapy by 56% (secondary prevention). In the primary prevention cohort, the appearance of neuropathy was reduced by 69% at 5 years in subjects on intensive therapy compared with subjects on conventional therapy. In the secondary prevention cohort, intensive therapy reduced the appearance of clinical neuropathy at 5 years by 57%. Furthermore, intensive therapy prevented the development and slowed the progression of diabetic kidney disease by 50%. Intensive therapy, however, was associated with greater weight gain (about 1 kgyear _ 1) and a threefold greater risk of severe hypoglycemia (loss of consciousness or need of second person assistance) compared with conventional therapy.50
The Epidemiology of Diabetes Interventions and Complications (EDIC) study is examining the long-term effects of conventional versus intensive diabetes treatment received during the DCCTon the subsequent development and progression of microvascular, neuropathic, and cardiovascular complications. The previous intensive and conservative treatment arms are combined and have a mean HbA1C of 8%. Results from EDIC indicate that individuals with T1DM have a metabolic memory, where the benefits of a period of good glucose control continue even after HbA1C levels have risen.51 Specifically, DCCT subjects who received intensive therapy have shown a 57% reduction in cardiovascular endpoints (myocardial infarctions and strokes)52 and similar benefits with regards to the development of nephropathy,53 hypertension, and retinopathy.
The UKPDS, conducted from 1977 to 1997 in 23 centers throughout England, Northern Ireland, and Scotland, verified that optimal glycemic control has similar benefits in T2DM. This prospective, randomized intervention trial of 5102 newly diagnosed individuals with T2DM examined the effects of glucose control on cardiovascular and diabetic complications via diet therapy or pharmacologic intervention with sulfonylureas, metformin, or insulin therapy.54 After a 3-month dietary run-in period, subjects with persistent hyperglycemia were randomized to conventional therapy with diet alone (goal FPG <270mgdL_ 1 (15mmolL_ 1)) or intensive therapy (goal FPG <110mgdL_ 1 (6mmolL_ 1)) with pharmacological monotherapy. Subjects receiving pharmacologic intervention were further randomized to receive sulfonylurea, metformin, or insulin therapy. Concurrently, a cohort of the subjects was tested to determine if blood pressure control reduced morbidity and mortality in T2DM. The antihypertensive agents used primarily were the ACE inhibitor, captopril, and the beta blocker, atenolol.
Similarly to the DCCT, the UKPDS found that a reduction in HbA1C resulted in decreased microvascular complications. Over the duration of the study, the intensive group had a mean HbA1C of 7.0% versus 7.9% in the conventional group. Diabetic retinopathy was reduced by 25% and early diabetic nephropathy (defined by the presence of microalbuminuria) by 33%. Overall, a 1% decrement in HbA1C translated to a 35% reduction in risk of diabetic complications. Similar to the DCCT, more frequent hypoglycemia and greater weight gain was observed in the intensive therapy cohort, with the exception of the metformin arm. Independently, improvements in blood pressure control reduced the risk of diabetes-related endpoints by 24%, diabetes-related deaths by 32%, and microvascular endpoints by 37%.
The goal of diabetic management is to achieve and maintain normal or near-normal fasting, pre-meal and postprandial blood glucose concentrations. The ADA has defined goals as follows: HbA1C <7%, FPG 90-130 mgdL_ 1 (5.0-7.2 mmol L " 1), and a 2hPG <180 mgdL "1 (10mmolL " 1).
The DCCTand UKPDS demonstrated the benefits of glycemic control on the prevention of diabetic microvascular complications and potential benefit in diabetes-associated CVD. Independently, diabetes is a risk factor for CVD morbidity and mortality equivalent to having pre-existing coronary artery disease. Therefore, the treatment goals for modifiable cardiac risk factors, specifically blood pressure and abnormal lipid levels, are more aggressive in individuals with diabetes55 (Table 5). The ADA recommends a goal blood pressure of < 130/80 mmHg, LDL cholesterol of <100mgdL_ 1 (<70mgdL_ 1 in individuals with known coronary artery disease), HDL cholesterol of >40mgdL_ 1 (>50 mgdL_ 1 in women), and triglycerides <150 mgdL_ 1.
The UKPDS study examined the glycemic response to the 3-month dietary run-in subjects completed prior to randomization.56 Only 16% of individuals achieved the glycemic target (FPG <108 mgdL_ 1 (6.0mmolL_ 1)) with
Table 5 Goals for the treatment of type 2 diabetes
Fasting plasma glucose Peak postprandial glucose
Low-density lipoprotein (LDL) cholesterol4 Diabetes + coronary heart disease High density lipoprotein (HDL) cholesterol^ Triglycerides
90-130 mgdL "1 (5.0-7.2 mmol L " 1) <180 mgdL " 1 (< 10.0 mmol L "1)
<100 mgdL " 1 ( <2.6 mmol L "1) <70 mgdL "1
>40 mgdL -1 ( > 1.1 mmol L" 1) <150 mgdL- 1 ( < 1.7 mmol L -1)
Copyright © 2006 American Diabetes Association from Diabetes Care, 2006, 29, S4-S42. Reprinted with permission from the American Diabetes Association.
aHbA1C is the primary target for glycemic control. Glycemic goals should be individualized, with certain populations (children, pregnant women, and elderly) receiving special considerations, and less intensive glycemic goals in patients with severe or frequent hypoglycemia. Normoglycemia (HbA1C <6%) is optimal but increases the risk of hypoglycemic events. b LDL cholesterol goals are lower in patients with overt coronary heart disease. cHDL cholesterol goals are increased by 10mgdL"1 in women.
diet alone. The cohort that achieved the glycemic target lost an average of 15-20 pounds in the 3-month period. At 1-year follow-up only about half (9% of the starting group) maintained the target glycemic control on diet alone.
Sustained lifestyle modification is an essential element of all successful treatment regimens for T2DM. As primary or combined therapy, effective diet and exercise allow individuals with diabetes to utilize endogenous insulin more efficiently, thereby decreasing the amount of medication or supplemental insulin required to achieve euglycemia. The Diabetes Prevention Program (DPP) found that lifestyle interventions alone (goal for weight reduction >7%) decreased the risk of progression from IGT to T2DM by 58%, this being nearly twice as effective as metformin in preventing new cases of diabetes.13
Weight management follows a simple theory. If caloric intake exceeds caloric usage, then weight is accrued. If caloric usage exceeds caloric intake, weight is lost. Once a summative accrual or loss of 3500 calories occurs, 1 pound is gained or lost, respectively. Modest, but consistent, reduction in caloric intake is the key component to sustained weight loss. Increased physical activity plays an important ancillary role in preventing rebound weight gain. Improved glycemic control associated with a hypocaloric diet can be seen before appreciable weight loss occurs. Unfortunately, most efforts to change lifestyle are not sustained. Maintaining a hypocaloric diet and increased physical activity proves to be difficult for most individuals. Bariatric surgery is an option for some severely obese individuals, commonly resulting in dramatic and sustained weight loss.
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