Glycemic Control

The Wisconsin Epidemiologic Study^1,2,6–10 demonstrated that in diabetics younger than 30 years and those older than 30 years treated with oral hypoglycemic agents or insulin, baseline hemoglobin A_1c (HbA_1c) level correlated with the incidence of retinopathy, progression of retinopathy, and progression of proliferative retinopathy.

The Diabetes Control and Complications Trial¹¹ (DCCT) enrolled 1441 people with type 1 diabetes. Of these, 726 had no retinopathy, had normal albumin excretion, and had had diabetes for less than 5 years. The other 715 had mild-to-moderate background retinopathy with normal albuminuria or microalbuminuria at baseline.

The subjects received intensive therapy or conventional treatment. The intensive treatment was either given with insulin pumps or multiple daily injections (three or more injections per day.) The insulin dosage was guided by self-monitoring of blood glucose three or four times per day. The participants were seen every month.

The conventional group received no more than two shots per day. Urine and blood glucose were monitored up to two times per day. They had clinic visits every 2 or 3 months over an average of 6.5 years. The average HbA_1c was 9.1% in the conventional group and 7.2% in the intensively treated group throughout the study. Risk reduction was 70% for clinically important sustained retinopathy, 56% for laser photocoagulation, 60% for sustained microalbuminuria, 54% for clinical grade nephropathy, and 64% for clinical neuropathy. Four years after the close of the DCCT, HbA_1c levels in the two groups narrowed to 8.2% in the conventional treatment group and 7.9% in the intensive treatment group. Retinopathic events including proliferative retinopathy, macular edema, and need for laser therapy were 74%, 77%, and 77% lower, respectively, in the intensively treated group. Incidence of microalbuminuria was 53% lower and albuminuria was 86% lower in the intensively treated group.¹²

In the Kumamato trial¹³ in 102 patients with T2DM, intensive therapy with multiple daily injections (preprandial, regular, and bedtime intermediate-acting insulin) compared with once or twice daily insulin injections resulted in a decrease in HbA_1c from 9.4% to 7.1%. Two-step progression of retinopathy decreased 69%, nephropathy progression decreased 70%, and nerve conduction velocities improved.

The United Kingdom Prospective Diabetes Study (UKPDS)^14,15 evaluated 5102 patients with T2DM. The study maintained an average HbA_1c of 7.9% in the conventional treatment group compared to 7% in the intensive treatment group. There was a 27% risk reduction for retinal photocoagulation at 12 years, 33% risk reduction at 12 years for microalbuminuria, and 74% risk reduction for doubling of creatinine at 12 years.

Blood pressure control has been shown to reduce the risk for both retinopathy and nephropathy. The Hypertension and Diabetes Study^16,17 was part of the UKPDS study. The subjects were 1148 patients with T2DM and coexisting hypertension. Tight-control subjects were given a blood pressure goal of lower than 150/85 mm Hg. Most patients were treated with captopril or atenolol. The control group was given a blood pressure goal of lower than 180/105 mm Hg. On average, the tight-control group averaged 144/82 mm Hg and the control group averaged 154/87 mm Hg. The tight-control group had a 35% reduction in retinal photocoagulation (P < 0.025), 34% reduction in two-step deterioration of retinopathy, and 47% risk reduction in three-line deterioration in the ETDRS chart (P < 0.005) over 7.5 years.

The Euclid (EUrodiab Controlled trial of Lisinopril in Insulin-Dependent Diabetes) study¹⁸ in 354 normotensive type 1 diabetics aged 20 to 59 years demonstrated that lisinopril treatment resulted in a 50% reduction in retinopathy progression, 73% reduction in two-grade retinopathy progression, and an 82% reduction in development of proliferative retinopathy.

Several studies have been performed in T1DM and T2DM patients to assess the effects of blood pressure control on nephropathy. Parving¹⁹ demonstrated that blood pressure control in diabetes with nephropathy decreased the albumin excretion rate by 50% and the rate of decline of GFR from 0.29 to 0.1 mL/min/month. A recent meta-analysis²⁰ demonstrated that angiotensin-converting enzyme (ACE) inhibitors can delay progression to overt nephropathy by 62% in type 1 diabetics with microalbuminuria. Many also decreased their albumin excretion rate. No studies in T1DM patients show that starting ACE inhibitors when albumin excretion rate is normal delays the development of microalbuminuria.^21–31 In overt nephropathy, Lewis³² studied 409 type 1 diabetics with protein excretion greater than 500 mg/day and creatinine less than 2.5 mg/dL. Creatinine doubled in 12.1% of the patients receiving captopril and 21.3% in the patients receiving a placebo (a 48% reduction in risk.)

In type 2 diabetic patients with microalbuminuria with or without hypertension, several studies have found that ACE inhibitors delay progression to overt nephropathy, decrease albumin excretion rate, and diminish decline in GFR.^33–40 Only one study has demonstrated that in type 2 diabetics who are normotensive and normoalbuminuric, enalapril attenuates the increase in albumin excretion rate and decreases the likelihood of development of microalbuminuria (a 12.5% risk reduction).⁴¹ Several studies^42–45 using angiotensin II receptor blockers have been published.^36–39 These studies show that in T2DM, there is a slowing of progression of microalbuminuria to overt nephropathy.