Short- and Long-Term Effects of Intensive Diabetes and Blood Pressure Control

Aparna M. Bhagavat, MD, FACC

Several trials have been conducted, and many more are yet to be completed, that have the goal of addressing whether intensive blood glucose control and intensive blood pressure (BP) control have any long-term benefit on all-cause mortality and major cardiovascular events. Contradictory data have been published with respect to the short- and long-term benefits of aggressive BP and blood glucose control versus conventional treatments for BP and glucose control. This review presents the main points of some of the important trials to date on this subject.

The UK Prospective Diabetes Study (UKPDS),¹ conducted in 1998, was a large study consisting of 3867 patients who were newly diagnosed with type 2 diabetes mellitus (T2DM) and who were randomly assigned to either an intensive oral regimen of insulin or to conventional treatment using dietary and lifestyle changes. There was a significant 25% risk reduction in any diabetes-related aggregate end point, mainly related to microvascular complications. However, the study did not show any benefit to macrovascular complications, which included cardiovascular disease.

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications (DCCT/EDIC) Study evaluated whether intensive therapy reduces cardiovascular events among patients with type 1 diabetes mellitus (T1DM).² Approximately 1400 patients with T1DM were randomized to either intensive glucose therapy or conventional therapy for an initial period of 6.5 years; about 93% of patients were subsequently followed until 2005. During the nearly 17 years of follow-up, intensive treatment reduced by 57% the risk of nonfatal myocardial infarction, stroke, or death from cardiovascular disease.

Contrary to the findings of the UKPDS trial, the DCCT/EDIC trial showed that intensive glucose therapy benefitted cardiovascular event rates when observed over a longer period of time. The possible reasons for the improved cardiovascular event rates in the DCCT/EDIC trial are hypothesized to be a decrease in hemoglobin A1C, which results in both decreased advanced glycation end products andmicrovascular disease, especially renal disease (and thus decreased albuminuria), which has long-term benefits on cardiovascular events.³

Holman et al⁴ conducted a follow-up trial, over a period of nearly 10 years, in which the patients of the UKPDS trial were evaluated to ascertain the continued benefit of intensive blood glucose control on microvascular events and the effect on myocardial infarction and death. The trial showed that intensive glycemic control over a certain period of time has long-term benefits on continued microvascular effects and macrovascular effects. The intensive glucose control was achieved with either metformin or with sulphonylurea and insulin.

In addition to intensive blood glucose control, aggressive blood pressure control in people with T2DM has also been an area of interest.⁵ In the ADVANCE trial,⁵ 11,140 patients with T2DM were randomized to a fixed dose of perindopril/indapamide or placebo. The patients were followed for approximately 4.3 years. A mean reduction of 5 to 6 mm Hg in systolic blood pressure and 2.2 mm Hg in diastolic blood pressure was noted in the treatment group, the relative risk of a major macrovascular or microvascular events was reduced by 9%, the relative risk of death from cardiovascular disease was reduced by 18%, and death from any cause was reduced by 14%. The Advance-ON Collaborative Group,⁶ which followed the same patient population, noted that even though a beneficial effect of intensive blood pressure control on mortality was seen over the long term, the effect was somewhat diminished when compared with a shorter follow up.

This suggests that intensive glucose and blood pressure control for a few years bestows some protected risk in the long term even if the patients are slightly more relaxed in terms of blood pressure and glucose control. However, the study by Holman et al⁷ showed that adequate blood pressure control maintenance was required to continue to see the benefits of blood pressure control on microvascular or macrovascular complications.

After a thorough review of these trials, one can infer that intensive control of blood glucose and blood pressure has beneficial short-term and long-term benefits, though not all the trials were able to show long-term benefits. There is no argument, however, that there is indeed a significant benefit in sustained and continued blood glucose and BP control on microvascular and macrovascular event rate and overall mortality.

References

1. UK Prospective Diabetes Study 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. 1998;352:837-853.

2. Nathan DM, Cleary PA, Backlund JY, et al. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with Type 1 diabetes. N Engl J Med. 2005;353(25):2643-2653.

3. Tuomilehto J, Borch-Jonsenk, Molarius A, et al. Incidence of cardiovascular disease in type 1 (insulin dependent) diabetic subjects with and without diabetic nephropathy in Finland. Diabetologia.1998;41:784-790.

4. Holman RR, Paul SK, Bethel MA, Matthews DR, and Neil HAW. Ten-year follow up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359: 1577-1589.

5. Patel A; Advance Collaborative Group, MacMahon S, Chalmers J, Neal B, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE Trial): a randomized controlled trial. Lancet. 2007;370:829-840.

6. Zoung S, Chelmar J, Neal B, Billot L. Advance-ON Collaborative Group. Follow up of blood pressure lowering and glucose control in type 2 diabetes mellitus. N Engl J Med. 2014;371:1392-1406.

7. Holman RR, Paul SK, Bethel MA, Neil HAW, Matthews DR. Long-term follow-up after tight control of blood pressure in type 2 diabetes. N Engl J Med. 2008;359:1565-1576.