Cardiovascular Benefits of Intensive Antihypertensive Treatment in Patients with Diabetes

Specific intensive antihypertensive treatment goals in high-risk patients are a widely controversial topic; which type of patient with diabetes benefits most from blood pressure lowering medications?

Many medical practice guidelines exist that state differing blood pressure goals for patients with diabetes mellitus. Patients with diabetes are already at a higher risk for future cardiovascular complications compared to those patients without diabetes. Understanding which blood pressure threshold in which to begin specific antihypertensive regimens, and target once on these regimens, can reduce long-term complications that come with secondary cardiovascular disease. Previous studies have shown that targeting a lower systolic blood pressure goal (<120mmHg compared to <140mmHg) results in a lower incidence of death and negative cardiovascular outcomes; however, patients with diabetes mellitus were excluded from these studies or were found in very small percentages population wise. In another trial that tried to replicate these outcomes in patients with diabetes mellitus, there were no statistically significant differences in the composite primary cardiovascular outcomes between patients randomized to a systolic blood pressure goal of <120mmHg and <140mmHg, warranting the need for further studies.

A recent multicentered, randomized, placebo controlled study, the ADVANCE trial, aimed to determine the cardiovascular effects associated with antihypertensive treatments in patients with diabetes based on differing baseline systolic blood pressures, diastolic blood pressures, or estimated cardiovascular risks. The primary efficacy outcome that was observed in this study was the composite incidence of major vascular events, including but not limited to nephropathy, retinopathy, cardiovascular death, or nonfatal acute coronary syndrome. Primary safety endpoints were also observed and included composite incidence of serious events that resulted in treatment discontinuation.

Patients were enrolled into this study if they had a history of type 2 diabetes mellitus and either cardiovascular disease or at least one risk factor for cardiovascular disease. A total of 10,948 patients were included in primary analysis of composite incidence of major vascular events; about half of the enrolled patients were randomized to receive perindopril-indapamide 4mg-1.25mg while the other half were randomized to receive placebo during the treatment period.

Baseline study characteristics showed that patients with a higher baseline 10-year ASCVD risk score (>20%) were more likely to be men who are current smokers and already receiving antihypertensive treatment as compared to those with a lower ASCVD risk score (<20%). Cox proportional hazard regression was used by a third party adjudication committee to analyze and report primary safety and efficacy data stratified by baseline systolic blood pressure, diastolic blood pressure, or estimated cardiovascular risk.

A total of 837 deaths and 966 major vascular events were recorded throughout a mean follow up period of just over 4 years. Analysis of results from the ADVANCE trial demonstrated that antihypertensive treatment with perindopril and indapamide resulted in a reduced incidence of both major vascular events (0.91; 95% CI 0.83-0.997) and all-cause mortality (0.86; 95% CI 0.75-0.99) than placebo in the treatment of patients with diabetes, regardless of baseline systolic blood pressure, diastolic blood pressure, and estimated 10 year cardiovascular risk. Differences in overall cardiovascular benefits between stratified groups of patients with diabetes with a systolic blood pressure of >140 or <140 at baseline were not observed within this study, indicating that treatment with antihypertensive therapy should be initiated as soon as possible.

The debate for specific blood pressure goals among patients with diabetes is still controversial, though results from this study correlate to the current American College of Cardiology/ American Heart Association guideline directed goal of <130/80 mmHg. Future studies observing the incidence of cardiovascular outcomes in patients with diabetes treated to a blood pressure goal of either <140/90 mmHg or <130/80 mmHg are warranted.

Practice Pearls

• Intensive antihypertensive treatment resulted in a 9% reduced risk of major vascular events and a 14% reduced risk of all-cause mortality in patients with diabetes, as compared to placebo, regardless of baseline blood pressure of estimated 10 year ASCVD risk.
• The results of the ADVANCE trial do not find heterogeneity of primary efficacy and safety outcomes between patients with lower or higher blood pressures or estimated cardiovascular risk at baseline.
• The authors suggest that future trials are warranted on the association of cardiovascular outcomes and specific blood pressure goals to determine which guideline-directed goal is best for patients with diabetes.

Rahman F, McEvoy JW, Ohkuma T, et al. Effects of blood pressure lowering on clinical outcomes according to baseline blood pressure and cardiovascular risk in patients with type 2 diabetes mellitus: the ADVANCE trial. Hypertension 2019; 73(6):1291-1299. DOI: 10.1161/HYPERTENSIONAHA.118.12414

Adam Chalela, B.S. Doctor of Pharmacy Candidate USF College of Pharmacy