Although intensive glycemic control was once supported only in theory, several important clinical trials have evaluated the benefits of good glycemic control on the development or progression of long-term microvascular (retinopathy, nephropathy, and neuropathy) complications.
The Diabetes Control and Complications Trial
The first of these trials was the landmark Diabetes Control and Complications Trial (DCCT). This study in 1,441 patients with type 1 diabetes compared the impact of intensive insulin therapy (three to four injections a day or an external pump) with conventional insulin treatment (one or two injections a day) on the risk of development or progression of microvascular complications. The goal was to reduce HbA1c levels to <6%.
Although blood glucose values improved in both treatment groups in the DCCT, mean values for blood glucose over the 6.5 years of followup were 155 mg/dL with intensive treatment and 231 mg/dL after conventional treatment (p<0.001). Mean HbA1c was reduced to 7% after 6 months of intensive therapy (p<0.001), and an average HbA1c of 7.2% was maintained over the 6.5 years of followup. In contrast, little change in HbA1c occurred with conventional treatment, with values approximating the baseline level of 9% throughout the study.
For the 726 patients in the primary prevention cohort with no evidence of retinopathy at baseline, intensive treatment reduced the mean risk for developing retinopathy by 76%; microalbuminuria by 34% (to 2% vs. 3% of patients; p=0.04); and neuropathy by 69% (to 3% vs. 10% of patients; p=0.006). As secondary intervention for the 715 patients with mild retinopathy, intensive treatment slowed progression of retinopathy by 54% (to 4% vs. 8%; p<0.002), reduced the risk of microalbuminuria by 43% (to 4% vs. 6%; p=0.001) and reduced the risk of neuropathy by 57% (to 7% vs. 15%). The most frequent adverse event in the DCCT was severe hypoglycemia, which occurred at a threefold higher rate with intensive than conventional treatment (62 vs. 19 episodes per 100 patient-years). However, no deaths, myocardial infarctions, or strokes in either treatment group could be attributed to severe hypoglycemia.
The Kumamoto Study
This study was designed to evaluate the effect of intensive glycemic control on microvascular complications of type 2 diabetes. Intensive and conventional insulin regimens were compared as primary or secondary prevention in 110 nonobese Japanese patients. The treatment regimen was similar to that in the Diabetes Control and Complications Trial (DCCT), and the goal of intensive treatment was to maintain fasting and postprandial blood glucose levels close to normal and HbA1c levels <7%. For the 102 patients who were evaluated for the entire 6-year followup, mean levels of HbA1c were 7.1% and 9% with intensive and conventional treatment, respectively (p<0.001). The mean HbA1c of 7.1% after intensive treatment represented a decrease of 2.1% for patients in the primary prevention cohort and 2.3% for those in the secondary intervention cohort. Intensive insulin treatment reduced the risk of worsening in retinopathy by 69% (p=0.007), and nephropathy by 70% (p=0.005).9 Microalbuminuria or albuminuria developed in 9.6% of patients on intensive treatment and 30% with conventional treatment (p=0.005). The Kumamoto study also demonstrated significant differences in nerve conduction velocity and vibration thresholds between the intensive and conventional treatment groups (p<0.05) after 6 years. There were no episodes of severe hypoglycemia in the Kumamoto study.
The Veterans Affairs Cooperative Study
In another patient population, the Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes (VA CSDM), evaluated the risks and benefits of intensive treatment compared with standard insulin treatment. The 27-month study evaluated 153 men who had type 2 diabetes that was poorly controlled with insulin or other antihyperglycemic therapy. The patients received intensive therapy (a regimen that progressed as needed from evening insulin to evening insulin plus a sulfonylurea, to two insulin injections alone, to multiple daily injections; n=75) or standard treatment (a single daily injection of insulin in the morning; n=78). With intensive therapy, 41.3% of patients attained normal HbA1c levels, compared with 3.9% of patients who received standard therapy. In the intensive treatment group, most of the decrease in HbA1c occurred with the single evening dose of insulin (from a mean of 9.3% to 7.9%); the addition of daytime glipizide achieved an additional decrease of 0.4% (from a mean of 7.8% to 7.4%, p<0.05). By the end of the study, 64% of the patients in the intensive treatment group required multiple insulin injections to maintain glycemic control. Severe hypoglycemia was rare, occurring in five patients in the intensive treatment group and two in the standard treatment group.
The United Kingdom Prospective Diabetes Study
The United Kingdom Prospective Diabetes Study (UKPDS) is the largest study performed to date in patients with type 2 diabetes and provides substantial evidence of the link between glycemic control and diabetic complications. A total of 4,209 eligible patients were stratified by body weight and assigned to conventional treatment with diet alone (n=1,138) or intensive treatment with insulin or a sulfonylurea (chlorpropamide, glibenclamide, or glipizide) (n=2,729). The remaining 342 patients were overweight and were assigned to treatment with metformin. The goal of conventional treatment was to maintain an FPG <270 mg/dL without symptoms of hyperglycemia, and the goal of intensive treatment was to maintain an FPG <108 mg/dL.
Median levels of HbA1c over the 10-year follow-up period were significantly lower with intensive treatment (7.0%) than with conventional treatment (7.9%), representing an 11% reduction (p<0.0001). Improved glycemic control with intensive treatment significantly reduced the risk of microvascular complications by 25% (p=0.0099), progression of retinopathy by 21% (p=0.015), and microalbuminuria by 34% (p=0.000054). In the UKPDS, intensive treatment with a sulfonylurea or insulin was associated a higher incidence of hypoglycemic episodes (10% vs. 15% with conventional treatment) and greater weight gain (mean of 3.1 kg).
Considering the results of these large, well-controlled, randomized clinical trials, utilizing intensive therapy to strive for normoglycemia in patients with type 2 diabetes appears to reduce diabetes-related complications (Table 2). Understanding current strategies and emerging treatment approaches is necessary if these therapies are to be successful in reducing the retinopathy, nephropathy, and neuropathy associated with type 2 diabetes.
| Table 2 Key Results of Clinical Trials of Intensive Glycemic Control in Patients with Diabetes | ||||
| Follow up | Conventional Therapy | |||
| No. of Patients (M/F) | HbA1c Baseline/Final | Severe Hypoglycemia | ||
| DCCT (n=1441)* Primary Prevention Secondary Intervention | 6.5 yr | 726 378 (54% M) 348 (49% M) | 8.8%/NS 8.8%/NS | 62/100 patient-yr |
| Kumamoto (n=110)† Primary Prevention Secondary Intervention | 6 yr | 25 (12/13) 25 (11/14) | ~9.0%/9.4% | None |
| VA CSDM (n=151)† | 27 mo | 78 (100% M) | NS/NS | 0.01 per patient-yr |
| UKPDS (n=4209)†‡ | 10 yr | 1138 (705/433) | 7.05%/7.9% | 0.7% per year |
| *Type 1 diabetes †Type 2 diabetes ‡1,138 of the 4,209 eligible patients were randomized to conventional treatment; 1,573 of 2,729 patients randomized to intensive treatment were treated with a sulfonylurea and 1156 were treated with insulin; 342 of the 4,209 eligible patients were overweight and assigned to intensive treatment with metformin | ||||
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| Table 2 (continued) Key Results of Clinical Trials of Intensive Glycemic Control in Patients with Diabetes | |||
| Intensive Therapy | |||
| No. of Patients (M/F) | HbA1c Baseline/Final | Severe Hypoglycemia | |
| DCCT (n=1441)* Primary Prevention Secondary Intervention | 715 352 (54% M) 363 (53% M) | 8.9%/NS 9.0%/NS | 19/100 patient-yr |
| Kumamoto (n=110)† Primary Prevention Secondary Intervention | 26 (14/12) 26 (12/14) | None ~9.3%/7.1% | |
| VA CSDM (n=151)† | 75 (100% M) | 9.3%/6.9% | 0.03 per patient-yr |
| UKPDS (n=4209)†‡ | 2729 (649/444) | 7.09%/7.0% | <2% per year |
| *Type 1 diabetes †Type 2 diabetes ‡1,138 of the 4,209 eligible patients were randomized to conventional treatment; 1,573 of 2,729 patients randomized to intensive treatment were treated with a sulfonylurea and 1156 were treated with insulin; 342 of the 4,209 eligible patients were overweight and assigned to intensive treatment with metformin | |||
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| Table 2 (continued) Key Results of Clinical Trials of Intensive Glycemic Control in Patients with Diabetes | |||
| Other Clinical Benefits of Intensive Therapy | |||
| DCCT (n=1441)* Primary Prevention Secondary Intervention | 76% RR in development of retinopathy 76% RR in development of retinopathy 47% RR in development of proliferative/ severe nonproliferative retinopathy 39% RR in microalbuminuria 54% RR in albuminuria 60% RR in clinical neuropathy | ||
| Kumamoto (n=110)† Primary Prevention Secondary Intervention | Development/progression of retinopathy: 32% CT vs. 8% IT with PP; 44% CT vs. 19% IT with SI Development/progression of nephropathy: 28% CT vs. 8% IT with PP; 32% CT vs. 12% IT with SI Improvement in nerve conduction velocities | ||
| VA CSDM (n=151)† | No weight gain, hypertension, dyslipidemia | ||
| UKPDS (n=4209)† ‡ | 12% RR for any diabetes-related endpoint 10% RR for diabetes-related death 6% RR in all-cause mortality 25% RR in microvascular endpoints | ||
| *Type 1 diabetes †Type 2 diabetes ‡1,138 of the 4,209 eligible patients were randomized to conventional treatment; 1,573 of 2,729 patients randomized to intensive treatment were treated with a sulfonylurea and 1156 were treated with insulin; 342 of the 4,209 eligible patients were overweight and assigned to intensive treatment with metformin Final mean blood glucose levels were 8.6 mmol/L (155 mg/dL) for the intensive treatment group and 12.8 mmol/L (231 mg/dL) for the conventional treatment group. DCCT = Diabetes Control and Complications Trial; VA CSDM = Veterans Administration Cooperative Study of Diabetes Mellitus; UKPDS = United Kingdom Prospective Diabetes Study; RR = risk reduction; NS = not stated; CT = conventional therapy; IT = intensive therapy; PP = primary prevention; SI = secondary intervention | |||