Effects of Vitamin E on Cardiovascular and Microvascular Outcomes in High-Risk Patients With Diabetes

Eva Lonn, MD MSC, Salim Yusuf, MBBS, DPHIL, Byrcon Hoogwerf, MD, Janice Pogue, MSC, Qilong Yi, PHD, Bernard Zinman, MD, Jackie Bosch, MSC, Gilles Dagenais, MD, Johannes F.E. Mann, MD, Hertzel C. Gerstein, MD, MSC on behalf of the Heart Outcomes Prevention Evaluation (HOPE) Investigators

Disclosures

Diabetes Care. 2002;25(11) 

In This Article

Results

There were 3,654 patients with diabetes at baseline. Their mean age was 65.4 years, 1,358 (37%) were women, and 2,511 (69%) had a history of CV disease. Baseline characteristics in the vitamin E and placebo groups were similar ( Table 1 ). Compliance with study drug was high and similar in patients randomized to active vitamin E and to placebo. In the vitamin E group, 92.3% of patients were taking study drug at 1 year, 90.3% at 2 years, 87.6% at 3 years, 84.6% at 4 years, and 83.4% at study end. In the placebo group, 90.6% of patients were taking study drug at 1 year, 88.7% at 2 years, 86.1% at 3 years, 83.3% at 4 years, and 81.3% at study end. Use of nonstudy vitamin E was very low, ranging from 0.7 to 3.3% of patients throughout the study, with no differences between the study groups. There were no significant side effects associated with vitamin E use. The most common reason for discontinuation of study drug was physician advice or patient refusal, which accounted for 17 and 19% of all cases of permanent drug discontinuation in the vitamin E and placebo groups, respectively.

Plasma vitamin E levels were similar at baseline: 28.1 ± 9.7 mmol/l in the vitamin E group and 29.8 ± 15.2 mmol/l in the placebo group. At 2 years, plasma vitamin E levels rose significantly in the vitamin E group to 48.7 ± 17.6 mmol/l (P < 0.0001) and remained unchanged in the placebo group (30.4 ± 21.1 mmol/l).

Vital status was ascertained at study end in all patients in the vitamin E group and in 99.9% in the placebo group. There was no significant interaction between the study treatments (ramipril and vitamin E) for the primary (P = 0.93), secondary, and other study outcomes. In the active vitamin E group, 325 (17.7%) people with diabetes had a primary outcome event vs. 313 (17.2%) in the placebo group (RR 1.03, 95% CI 0.88-1.21; P = 0.70). Similarly, there were no significance differences between the study groups in the rates of MI, stroke, CV death, total mortality, and of all other secondary and additional CV outcomes ( Table 2 and Fig. 1). There were also no significant treatment effects of vitamin E in any predefined subgroup. Subgroups analyzed included women, men, patients older and younger than 65 years of age, those with type 1 and with type 2 diabetes, with BMI above and below 27 kg/m2, with and without a history of hypertension, smoking, hypercholesterolemia, microalbuminuria, CV disease, coronary artery disease, MI, stroke, peripheral arterial disease, on various therapies for glycemic control (diet alone, oral hypoglycemic drugs, insulin, or combined therapies) or for the management of CV diseases, hypertension and hypercholesterolemia, and those taking or not taking vitamin C and multivitamin supplements. Some of the pertinent subgroup analyses are illustrated in Fig. 2.

Kaplan-Meier survival curves for the primary CV study outcome, MI, stroke, CV death, and total mortality. The x-axis indicates the duration of follow-up in days.

Kaplan-Meier survival curves for the primary CV study outcome, MI, stroke, CV death, and total mortality. The x-axis indicates the duration of follow-up in days.

Kaplan-Meier survival curves for the primary CV study outcome, MI, stroke, CV death, and total mortality. The x-axis indicates the duration of follow-up in days.

Effect of vitamin E on the primary CV outcome in subgroups. The size of each symbol is proportional to the number of patients in each subgroup. CVD, CV disease.

Urinary albumin-to-creatinine ratio was measured in 3,574 (97.8%) participants at baseline, in 3,140 (88.9% of those alive) at 1 year, and in 2,740 (85.9% of those alive) at study end. The albumin-to-creatinine ratio did not differ significantly between the two study groups at baseline, at 1 year, or at study end. During follow-up, 361 (9.9%) study participants developed an albumin-to-creatinine ratio >36 mg/mmol and were asked to provide a 24-h urine collection to test for overt nephropathy. Results were available for 308 (85.3%) patients. In the vitamin E arm, 146 (7.9%) study participants developed overt nephropathy vs. 131 (7.2%) in the placebo arm (P = 0.37; this analysis uses as a definition of overt nephropathy the presence of significant proteinuria or albuminuria as defined above or albumin-to-creatinine ratio >36 mg/mmol). When a more stringent definition of overt nephropathy was used and the analysis was restricted to people in whom 24-h urine results were available, 120 (6.5%) in the vitamin E group vs. 109 (6.0%) in the placebo group developed nephropathy (P = 0.45). There were also no differences between the study groups in rates of new microalbuminuria, dialysis, history of laser therapy for diabetic retinopathy, combined outcomes related to microvascular disease, history of new cataract or cataract surgery, or hospital admissions for limb infection ( Table 2 ). Serum creatinine was similar at baseline in both study groups ( Table 1 ). The yearly changes in serum creatinine compared with the baseline values did not differ significantly between the study groups. At study end, serum creatinine increased by 1.92 µmol/l in the vitamin E group compared with baseline and by 3.39 µmol/l in the placebo group (P = 0.24).

At baseline, mean HbA1c levels were similar in the vitamin E (7.41%) and the placebo groups (7.50%). Compared with baseline, mean absolute HbA1c values increased by absolute amounts of 1.96% higher than the upper limit of normal in the vitamin E group and of 2% in the placebo group at 1 year (P = 0.89). The change from baseline in HbA1c, was similar for both groups at subsequent visits and at the end of the study (1.32% increase for vitamin E and 1.57% for placebo, respectively, P = 0.78). The number of hospital admissions for hyperglycemia (76 in the vitamin E vs. 76 in the placebo group, P = 0.87), for hypoglycemia (26 in the vitamin E vs. 37 in the placebo group, P = 0.12), and for diabetic ketoacidosis (8 in the vitamin E vs. 4 in the placebo group, P = 0.27) also did not differ significantly.

There were 5,887 HOPE study participants without diabetes at baseline (2,799 in the vitamin E group and 2,827 in the placebo group). A diagnosis of new diabetes by history was obtained in 124 (4.2%) patients on active therapy vs. 137 (4.6%) on placebo (P = 0.55).

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