Avoid inducing diabetes in hypertensive patients

When we first read the ALLHAT study (do a search for multiple rants), one problem that bothered me was the increased incidence of diabetes mellitus. This article expands on that concern – Adverse prognostic significance of new diabetes in treated hypertensive subjects

Diabetes may develop in nondiabetic hypertensive subjects during treatment, but the long-term cardiovascular implications of this phenomenon are not clear. We determined the prognostic value of new diabetes in hypertensive subjects. In a long-term cohort study, 795 initially untreated hypertensive subjects, 6.5% of whom with type 2 diabetes, underwent diagnostic procedures including 24-hour ambulatory blood pressure (BP) monitoring and electrocardiography (ECG). Procedures were repeated after a median of 3.1 years in the absence of cardiovascular events. Follow-up duration was 1 to 16 years (median 6.0). New diabetes occurred in 5.8% of subjects initially without diabetes. Antihypertensive treatment included a diuretic in 53.5% of these subjects, versus 30.4% of those in whom diabetes did not develop (P=0.002). Plasma glucose at entry (P=0.0001) and diuretic treatment on follow-up (P=0.004) were independent predictors of new diabetes. Subsequent to the follow-up visit, a first cardiovascular event occurred in 63 subjects. Event rate in nondiabetic subjects at both visits, new diabetes, and diabetes at entry were 0.97, 3.90, and 4.70×100 person-years, respectively (P=0.0001). After adjustment for several confounders, including 24-hour ambulatory BP, the relative risk of events was 2.92 (95% CI: 1.33 to 6.41; P=0.007) in the group with new diabetes and 3.57 (95% CI: 1.65 to 7.73; P=0.001) in the group with previous diabetes, when compared with the group persistently free of diabetes. In treated hypertensive subjects, occurrence of new diabetes portends a risk for subsequent cardiovascular disease that is not dissimilar from that of previously known diabetes.

theheart.org has a long post on this issue (theheart.org does not have links to individual posts).

In their editorial, Drs George L Bakris (Rush University Medical Center, Chicago, IL) and James R Sowers (University of Missouri-Columbia Health Sciences Center, Columbia) point out that observations from recent large trials, including LIFE, ALLHAT, CONVINCE, and INVEST, have suggested that both diuretics and beta blockers increase the risk for new-onset diabetes.

The current report by Verdecchia et al shows that the accelerated development of diabetes associated with antihypertensive therapy further enhances the risk of CVD in these patients, although the risk was not appreciated for an average of six years, a much longer period than in clinical trials, they write. The study also confirms that those with elevated fasting glucose are at particularly high risk for new diabetes with its attendant cardiovascular risk. “Collectively, these observations suggest that thiazide diuretics and beta blockers should be initiated cautiously in hypertensive patients with elevated fasting glucose, ie, above 100 mg/dL, or those who have a body mass index of >30,” they conclude. “Further, the risks of new-onset diabetes and associated CVD risk should be factored into further recommendations of antihypertensive therapy.”

Both Bakris and Sowers were coauthors of the JNC 7 guidelines that currently recommend diuretics as the drug of first choice in most patients with hypertension. In an interview, Bakris told heartwire that these new findingswhich, he noted, were observational and, at the longest follow-up, based on small numbersdon’t change that recommendation substantially and cautioned against them being used to argue against any use of diuretics.

“There is a happy medium that you can meet with these guidelines,” he said. For many patients, diuretics are fine as first-line therapy, but “if you have a compelling indication for another class of drugs, you can use another class of drugs,” particularly in patients with metabolic syndrome, preexisting diabetes, kidney disease, or a family history of diabetes. In these patients, he said, the totality of the evidence suggests they are going to need multiple drugs. “ACE inhibitors and angiotensin receptor blockers (ARBs) are indicated as first-line therapy in those patients, and then if you need more help, you should consider a diuretic from the data.”

Those who interpret the guidelines more absolutely in terms of diuretics first, he added, “need to back off, and that was the message of this.”

Well said. These data add much to our knowledge. ALLHAT, despite good intentions and much money, did not answer the right questions. We need more data to understand how to best individualize antihypertensive therapy.