Results from a six-month extension study have shown that impairment in glycemic control after one year of diuretic-based combination treatment is reversible by switching to treatment not involving a diuretic, in this case, an ACE inhibitor and calcium-channel blocker.1 Dr George Bakris (University of Chicago, IL), commented that, “When we looked at who developed new-onset diabetes, the plan was to then switch these patients over to the ACE-inhibitor/calcium-channel-blocker combination to see whether we could regress or bring back to baseline these metabolic changes.” “This effect of new-onset diabetes, at least if you intervene within a short time of starting the therapy, does not appear to be permanent.”
The hypothesis-generating study, an extension of the Study of Trandolapril/Verapamil SR And Insulin Resistance (STAR), was presented last week at the American Society of Hypertension 2007 Scientific Sessions. In the original STAR study, published in 2006, investigators showed that in patients with impaired glucose tolerance, normal kidney function, and hypertension, the fixed-dose combination of trandolapril and verapamil reduces the risk of new-onset diabetes compared with a losartan/hydrochlorothiazide-based therapy.
Dr. Bakris said clinicians previously believed marrying diuretic therapy to an ACE inhibitor or angiotensin receptor blocker (ARB) might provide protection from new-onset diabetes, although this turned out not to be true. The risk of new-onset diabetes is also dose dependent, he said, such that at 25-mg hydrochlorothiazide (HCTZ) there is substantial risk of impairing the glucose response.
Testing the hypothesis that impaired glycemic control might be reversible early in the diuretic/losartan-combination treatment by switching to an ACE-inhibitor/calcium-channel-blocker combination, investigators assessed glycemic changes after six months of additional treatment with trandolapril and verapamil in both treatment groups in the STAR study. Bakris noted that only 53% of the original cohort stayed in the extension trial, although there were no statistically significant demographic differences between those who stayed and those who did not continue in the trial.
Those patients switching from losartan/HCTZ to trandolapril/verapamil experienced greater improvements in glucose and insulin response. The primary outcome measure, change in two-hour glucose using the oral glucose tolerance test (OGTT), decreased from 154 mg/dL at baseline to 131 mg/dL at six months in those who switched from the diuretic to the ACE-inhibitor/calcium-channel-blocker combination. At baseline, 10 patients in the losartan/HCTZ-treatment arm had diabetes, but six months after they switched to trandolapril/verapamil, this number was cut in half.
Blood pressure was sacrificed to some degree, noted Bakris, increasing from 128 mm Hg systolic at baseline to 137 mm Hg at six months. He said that while diuretics are cheap and have decades of outcomes data to support their use, clinicians might decide the cost of using the drug with respect to new-onset diabetes is too high.
“Looking at this overall, from a cost perspective, from a morbidity perspective, and from a patient perspective, why would you use a therapy to treat one condition only to express another condition that now requires additional medicine and has a potentially greater cardiovascular risk?” he said.
1. Bakris G, Molitch M, Sowers J et al. Reversal of new onset diabetes by nondiuretic based fixed dose antihypertensive drug combinations? Results of the STAR 6-month extension (STAR-LET). American Society of Hypertension 2007 Scientific Sessions; May 20, 2007; Chicago, IL.