William C. Cushman, MD presented Management of Hypertension in the Patient with Diabetes at the 76th Scientific Sessions of the American Diabetes Association, June 10–14, 2016. Dr. Cushman is Chief of Preventive Medicine at the Veterans Affairs Medical Center, and is Professor, Preventive Medicine and Physiology at the University of Tennessee Health Science Center in Memphis.
Dr. Cushman began by stating that his presentation addresses two major topics:
Increased Risk of Cardiovascular Death in Hypertensive Patients with Diabetes
1993 Multiple Risk Factor Intervention Trial (MRFIT)
This trial assessed predictors of cardiovascular mortality among men with and without diabetes as well as the independent effect of diabetes on the risk of death from cardiovascular disease. The trial found that elevated systolic blood pressure increases the risk of cardiovascular death almost twofold in diabetic patients vs nondiabetic controls. The results emphasized the importance of rigorous sustained intervention in patients with diabetes not only to control blood pressure, but also to lower serum cholesterol, abolish cigarette smoking, and to consider mass nutritional-lifestyle approaches to prevent diabetes.
Dr. Cushman then reviewed several randomized, controlled trials that evaluated systolic blood pressure goals of <150 and <148 mmHg in hypertensive patients with diabetes. Risk of stroke was reduced by 22% (not significant), of cardiovascular disease by 34%-62%, of myocardial infarction by 50%, of cardiovascular death by 67%, and of coronary heart disease by 56%.
2010 Action to Control Cardiovascular Risk in Diabetes, Blood Pressure (ACCORD)
Dr. Cushman went on to discuss the ACCORD trial, which evaluated the effects of intensive blood pressure control (systolic blood pressure <135–140 mmHg) in patients with type 2 diabetes.
A total of 4,733 participants with type 2 diabetes was randomly assigned to intensive therapy, targeting a systolic pressure <120 mmHg, or standard therapy, targeting a systolic pressure <140 mmHg. The primary composite outcome was nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. Mean follow-up was 4.7 years.
After 1 year, no significant reduction in total mortality, cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was observed with systolic blood pressure targets <120 vs <140 mmHg. Only the incidence of total stroke was reduced significantly with the lower systolic blood pressure target.
Dr. Cushman asserted that though the ACCORD results provided no conclusive evidence that the intensive blood pressure control strategy reduced combined cardiovascular events in high-risk patients with diabetes, the trial was unexpectedly underpowered. ACCORD, therefore, did not prove conclusively that the systolic blood pressure goal of <120 mmHg is not beneficial.
In 2014, 5-year ACCORD outcomes were reported, and these told a very different story from the 1-year results. Risk of the primary composite outcome of deaths due to cardiovascular disease, nonfatal myocardial infarction, and nonfatal stroke was lower in groups intensively treated for glycemia (hazard ratio (HR) 0.67; 95% confidence interval (CI), 0.50-0.91), blood pressure (HR 0.74; 95% CI, 0.55-1.00), or both (HR 0.71; 95% CI, 0.52-0.96) compared with combined standard blood pressure and glycemia treatment.
For secondary outcomes, myocardial infarction was significantly reduced by intensive glycemia treatment, and stroke by intensive blood pressure treatment. Most other hazard ratios were neutral or favored intensive treatment groups.
Dr. Cushman summarized the ACCORD Blood Pressure trial by stating that, compared with combined standard treatment, intensive blood pressure or intensive glycemia treatment alone improved major cardiovascular disease outcomes, without additional benefit from combining the two.
2015 Systolic Blood Pressure Intervention Trial (SPRINT)
The SPRINT trial set out to determine whether a lower recommended blood pressure would decrease stroke, heart disease, progression of chronic kidney disease, and age-related cognitive and memory loss. The cohort included both diabetic and nondiabetic patients, and the endpoints were not related to diabetes.
The trial randomized 9,361 patients with a systolic blood pressure ≥130 mmHg and increased cardiovascular risk to a target <120 mmHg (intensive treatment) or <140 mmHg (standard treatment). Patients with difficult-to-control blood pressure were excluded. Mean blood pressure at baseline was 139.7/78.2 mmHg in the intensive treatment group and 139.7/78.0 mmHg in the standard treatment group. Mean blood pressure at 1 year was 121.4/68.7 and 136.2/76.3 mmHg in the respective groups.
During follow-up, the average difference in systolic pressure was 13.1 mmHg, and the mean number of blood pressure medications was 2.8 in the intensive treatment group and 1.8 in the standard treatment group.
The trial was stopped early, after a median follow-up of 3.26 years. Overall, participants assigned to the intensive treatment group vs the standard treatment group, were at a 25% lower relative risk of major cardiovascular events (95% CI, 11-36%), with consistent results across subgroups defined according to age, sex, race, medical history, and baseline blood pressure. The intensive treatment group was at a 27% lower relative risk of death from any cause (95% CI, 10-40%).
Rates of some serious adverse events, including hypotension and acute kidney injury or failure, were higher in the intensive treatment group than in the standard treatment group, but these higher rates appear unlikely to outweigh the benefits overall.
Dr. Cushman stressed that the SPRINT sample size was about twice that of ACCORD Blood Pressure. Furthermore, guideline committees and the medical community will need to decide whether the SPRINT results should be generalized to patients with hypertension and diabetes.
2007 Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE)
This multicenter trial assessed the effects of the routine administration of an angiotensin-converting enzyme inhibitor—diuretic combination on serious vascular events in patients with diabetes, irrespective of initial blood pressure levels or the use of other blood pressure lowering drugs. A total of 11,140 patients with type 2 diabetes was randomized to the addition of indapamide + perindopril vs placebo on usual therapy.
A significant (14%) reduction in mortality was observed (the trial was stopped early) as well as a 9% reduction of combined macro- and microvascular outcomes. Neither, however, was significant alone. The mean systolic blood pressure in the intensive group was 135 mmHg, similar to the mean systolic blood pressure in the ACCORD standard blood pressure group.
2015 Meta-Analysis by Emdin et al
This meta-analysis of various goal blood pressures in hypertensive patients with type 2 diabetes covered 40 trials involving 100,354 participants. Each 10 mmHg lower systolic blood pressure was associated with a significantly lower risk of mortality, absolute risk reduction in events per 1000 patient-years, cardiovascular events, coronary heart disease, stroke, albuminuria, and retinopathy. The meta-analysis suggested a targeted systolic blood pressure of <130 mmHg.
2010 Avoiding Cardiovascular Events Through COMbination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH)
The ACCOMPLISH trial compared the outcome effects of a renin-angiotensin system blocker, benazepril, combined with amlodipine or hydrochlorothiazide. Diabetic participants were analyzed separately.
In this cohort of patients with diabetes and hypertension, combining a renin-angiotensin system blocker with amlodipine was superior to hydrochlorothiazide in reducing cardiovascular events.
1994-2002 Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
ALLHAT was a randomized, double-blinded, active-controlled trial that set out to determine whether treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor lowers the incidence of coronary heart disease or other cardiovascular disease (events vs treatment with a diuretic). A total of 33,357 patients age 55 years or older with hypertension and at least one other coronary heart disease risk factor from 623 centers in North America participated.
Thiazide-type diuretics proved superior in preventing one or more major forms of cardiovascular disease. Baseline history of diabetes did not affect the outcomes of coronary heart disease, mortality, stroke, heart failure, combined cardiovascular disease, or end-stage renal disease.
2001 Reduction of Endpoints in Non-Insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) and Irbesartan Diabetic Nephropathy Trial (IDNT)
Both trials demonstrated the efficacy of the angiotensin receptor blocker antihypertensive class in conferring significant benefits in patients with diabetic nephropathy.
Dr. Cushman's Conclusions
Cushman WC. Session:Management of Cardiovascular Disease in the Patient with Diabetes: Basic Cardiology for the Diabetologist. 1-AC-SY09 Management of Hypertension in the Patient with Diabetes ADA 2016: 76th Scientific Sessions of the American Diabetes Association, June 10-14, New Orleans, LA.
W.C. Cushman: Research Support; Speaker; Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc.