CLINICAL DIABETES
VOL. 17 NO. 3 1999

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LANDMARK STUDIES

What the UKPDS Really Says About Cardiovascular Disease and Glycemic Control

Reviewed by Kenneth E. Robertson, PharmD, and Melvin J. Prince, MD

STUDY
U.K. Prospective Diabetes Group: Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837-53, 1998.

SUMMARY
Objective. To determine whether improved blood glucose control would prevent complications of diabetes and whether there are differences between diet and pharmacologic interventions.

Design. A 20-year, multicenter, randomized investigation that compared the effects of diet to first- and second-generation sulfonylureas or insulin.

Subjects. Subjects included 3,867 newly diagnosed patients with type 2 diabetes, with a median age of 54 years.

Methods. After 3 months of diet treatment, patients with a mean fasting plasma glucose (FPG) between 6.1 and 15.0 mmol/l (110–270 mg/dl) were randomly assigned to treatment with a sulfonylurea, insulin, or diet therapy. The pharmacologic therapy group aimed for FPG < 6 mmol/l (108 mg/dl). The diet group sought the best achievable FPG with diet alone. Medications were added if hyperglycemic symptoms or FPG >15 mmol/l (270 mg/dl) appeared.

Three aggregate endpoints assessed differences between diet and medications: any diabetes-related endpoint, diabetes-related death, and all-cause mortality. All analyses were by intention to treat.

Results. All patient groups were similar at enrollment. The median follow-up for endpoint analyses was 10.0 years and for comparison of diet and medications was 11.1 years. The 10-year median hemoglobin A_1c (HbA_1c) was 7.0% with medications and 7.9% with diet. FPG and HbA_1c in the diet group increased steadily over the 10 years from randomization. FPG and HbA_1c declined during year 1 in the pharmacologic therapy group; subsequent elevations in FPG and HbA_1c were parallel to the diet group. There was no difference in HbA_1c between the pharmacologic agents. At study end, >75% of patients in the diet group required medications to achieve glycemic goals. The risk in the pharmacologic therapy group was 12% lower for any diabetes-related endpoint, 10% lower for any diabetes-related death, and 6% lower for all-cause mortality than the risk in the diet group. Risk reduction in the any-diabetes-related endpoint category was due primarily to a 25% reduction in microvascular endpoints, including retinal photocoagulation. No difference was noted between drug therapies for the three aggregate endpoints.

Conclusion. The UKPDS group concluded that blood glucose control with sulfonylureas or insulin substantially reduces the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes. None of the individual drugs demonstrated an adverse effect on cardiovascular outcomes. Based upon these findings, the UKPDS group concluded that insulin is not atherogenic and that sulfonylureas do not increase the risk of sudden death as previously reported.¹

COMMENTARY
Individuals with type 2 diabetes have a two- to fourfold increased risk of cardiovascular disease (CVD) compared with nondiabetic individuals.^2,3 Several prospective studies associated abnormalities in glucose metabolism with increased CVD and all-cause mortality in patients with diabetes,^4,5 even independent of other cardiovascular risk factors.⁶ Whether improvement in glucose control can modify this increased risk of macrovascular disease remains in question.

Three earlier prospective studies suggested potential benefit with regard to insulin therapy and cardiovascular events: the DCCT,⁷ Kumamoto,⁸ and DIGAMI⁹ studies.

The DCCT compared the effects of conventional insulin therapy to intensive insulin therapy in approximately 1,400 patients with type 1 diabetes mellitus followed for a mean of 6.5 years (3–9 years).⁷ Glycemic control in the intensified regimen group was clinically and statistically improved compared with that in the conventional insulin therapy group (median HbA_1c 7.0% and 8.9%, respectively), resulting in significant reductions in microvascular risk (74%, 35%, and 69% respectively, for retinopathy, nephropathy, and clinical neuropathy) and a 41% decline (P > 0.05) in overall macrovascular risk. The reduction in macrovascular risk was not statistically significant because of the small number of cardiovascular events in this relatively young (15–35 years) patient population with type 1 diabetes followed for a relatively brief period. Notably, with intensified insulin therapy, low-density lipoprotein cholesterol concentrations declined 34% (P < 0.05).

Similar to the DCCT, the Kumamoto study of 110 Japanese patients with type 2 diabetes and a mean age of 49 years instituted an intensified multiple insulin injection protocol and followed patients for a mean of 6 years.⁸ Significant reductions in HbA_1c (7.1% treatment group, 9.4% control group) and fasting blood glucose (126 ± 36 mg/dl [7 ± 2 mmol/l] treatment group, 164 ± 50 mg/dl [9.1 ± 2.8 mmol/l] control group) resulted in a significant reduction in microvascular risk (76% and 73% for retinopathy and nephropathy, respectively). A 50% reduction in overall macrovascular risk approached, but did not achieve, statistical significance due to the length of study and the small number of cardiovascular events in this group of nonobese patients with type 2 diabetes mellitus.

In the DIGAMI trial, patients with type 1 or type 2 diabetes with suspected myocardial infarction (MI) were randomized to either routine care or a treatment protocol that included intravenous insulin and glucose for at least 24 hours and treatment after discharge with an intensified insulin regimen similar to the DCCT study.⁹ These patients (mean age 68 years) were followed for an average of 3.4 years. Mean HbA_1c at 3 months declined from 8.0% to 7.6% in the control group and from 8.2 to 7.1% in the insulin group, a significant difference between groups (P < 0.0001). Continued follow-up revealed statistically significant reductions in absolute risk of mortality (11%, P < 0.05) and relative risk of mortality at 1 year (30%, P = 0.037) and 3.4 years (28%, P = 0.011). The effect was most apparent in patients who had not previously received insulin treatment and were at a low cardiovascular risk.

In contrast to the above studies, a feasibility trial in a Veteran's Affairs population of type 2 patients followed for an average of 27 months demonstrated a borderline trend (P = 0.1) toward increased cardiovascular events in the intensive insulin therapy group.¹⁰

The UKPDS, because of its length and prospective design, contributes valuable evidence to a discussion of glycemic control and its impact on long-term complications in type 2 diabetes mellitus. In the UKPDS, pharmacologic therapy led to significantly improved glycemic control and a significant decrease in the risk of microvascular complications. The UKPDS confirmed the progressive nature of type 2 diabetes in that the majority of patients required additional therapies, including insulin therapy. Importantly, insulin was associated with no increase in cardiovascular morbidity and mortality despite an increase in weight and hyperinsulinemia in the insulin-treated group. In fact, there was a 16% reduction in the risk of nonfatal and fatal MI that approached statistical significance (P = 0.052). Based on the results of this landmark study, the UKPDS study group concluded that insulin was not atherogenic, as some have previously speculated.

In the UKPDS, the decreased risk of macrovascular endpoints approached, but did not reach, statistical significance. The lack of clear-cut reductions in macrovascular risk may be explained by a number of factors. As with many type 2 patients, 50% of the UKPDS patients had signs of diabetic tissue damage, including cardiovascular complications (8%), at diagnosis.¹¹ Furthermore, despite a median HbA_1c over 10 years of 7.0% in the intensively treated group, there was a steady rise in HbA_1c over the length of the study in both treatment groups. A recent meta-regression analysis demonstrated a progressive relationship between glucose levels (both fasting and postprandial) and cardiovascular risk that extended below the diabetic threshold.¹² Taken together, these data suggest that blood glucose management may need to be more aggressive than previously believed in order to prevent atherosclerosis and CVD.

This begs the question: Would a program of earlier screening and diagnosis as suggested by the UKPDS group, with a therapeutic goal of achieving normoglycemia, substantially reduce the risk of macrovascular complications? In the UKPDS, epidemiological analysis of the data demonstrated a continuum link (i.e., no threshold glucose concentration or HbA_1c) between better glycemic control and reduction in macrovascular complications.¹³ Therefore, glucose control is imperative to prevent or delay long-term complications in patients with type 2 diabetes.

The UKPDS extends previous knowledge in that it demonstrates the importance and need for insulin therapy in patients with type 2 diabetes, and documents that insulin therapy is not atherogenic and is, therefore, safe for these patients. Importantly, the Hypertension in Diabetes Study (HDS), embedded within the UKPDS, showed that adequate blood pressure control with either an angiotensin-converting enzyme (ACE) inhibitor (captopril [Capoten]) or a beta-blocker (atenolol [Tenormin]) significantly reduces the risk of both microvascular and macrovascular complications.^14,15 Thus, the UKPDS confirms the need for a multifactorial risk management strategy to improve the prognosis for patients with type 2 diabetes.

ACKNOWLEDGMENT
Appreciation is expressed to Ruby Moaney for editorial assistance with the manuscript.

REFERENCES

¹University Group Diabetes Program: A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. Diabetes 25:1129–53, 1976.

²Kannel WB, McGee DL: Diabetes and cardiovascular disease: the Framingham Study. JAMA 241:2035–38, 1979.

³Stamler J, Vaccaro O, Neaton JD, Wentworth D: Diabetes, other risk factors, and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 16:434–44, 1993.

⁴Kuusisto J, Mykkanen L, Pyorola K, Laakso M: NIDDM and its metabolic control predict coronary heart disease in elderly subjects. Diabetes 43:960–67, 1994.

⁵Klein R: Hyperglycemia and microvascular disease in diabetes. Diabetes Care 18:258–68, 1995.

⁶Lehto S, Ronnemaa T, Haffner SM, Pyorala K, Kallio V, Laakso M: Dyslipidemia and hyperglycemia predict coronary heart disease events in middle-age patients with NIDDM. Diabetes 46:1354–59, 1997.

⁷The DCCT Research Group: 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 329:977–86, 1993.

⁸Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M: 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 28:103–17, 1995.

⁹Malmberg K: Prospective randomised study of intensive insulin treatment on long-term survival after acute myocardial infarction in patients with diabetes mellitus. Br Med J 314:1512–15, 1997.

¹⁰Abraira C, Colwell J, Nuttall F, Sawin CT, Henderson W, Comstock JP, Emanuele NV, Levin SR, Pacold I, Lee HS: Cardiovascular events and correlates in the Veterans Affairs Cooperative Diabetes Feasibility Trial: Veterans Affairs Cooperative Study on glycemic control and complications in type II diabetes. Arch Intern Med 157:181–87, 1997.

¹¹Turner RC: The U.K. Prospective Diabetes Study. Diabetes Care 21 (Suppl. 3):C35–38, 1998.

¹²Coutinho M, Gerstein HC, Wang Y, Yusuf S: The relationship between glucose and incident cardiovascular events. Diabetes Care 22:233–40, 1999.

¹³American Diabetes Association: Implications of the United Kingdom Prospective Diabetes Study. Diabetes Care 22 (Suppl. 1):S27–31, 1999.

¹⁴U.K. Prospective Diabetes Study (UKPDS) Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. Br Med J 317:703–13, 1998.

¹⁵U.K. Prospective Diabetes Study (UKPDS) Group: Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. Br Med J 317:713–20, 1998.

Kenneth E. Robertson, PharmD, is a medical science writer, and Melvin J. Prince, MD, is a senior clinical research physician at Lilly Research Laboratories, Eli Lilly and Company, in Indianapolis, Ind.

Note of disclosure: Dr. Robertson and Dr. Prince are employed by Eli Lilly and Company, which manufactures drugs for the treatment of diabetes.

Copyright © 1999 American Diabetes Association
Updated 7/99
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