Trandolapril/verapamil SR v. insulin resistance Lower insulin-resistance risk with Tarka in the STAR trial
While many guidelines recommend thiazide-type diuretics in the first-line treatment of hypertension, a number of studies have shown that their use could increase the risk of new-onset diabetes. Meanwhile, renin-angiotensin blockers and calcium-channel blockers have been shown to lower diabetes risk on top of their blood-pressure-lowering effect. Given these, does combining an RAS blocker with a thiazide translate to glycemic control in this subtype of patients? Or would an ACE inhibitor/calcium-channel blocker do a better job? In 2006 the Study of Trandolapril/Verapamil SR And Insulin Resistance (STAR, Diab Care) trial tried to answer these questions. The angiotensin-converting-enzyme inhibitor (ACEI) trandolapril is known to reduce cardiovascular outcomes as well as thiazides but with metabolically neutral effects. In this study, the trandolapril/verapamil (T/R) combination was compared with losartan/hydrochlorothiazide (L/H) on its effects on glucose tolerance among patients with metabolic syndrome. In an earlier study, the International Verapamil/Trandolapril Study (INVEST, 2003) has already shown the efficacy and safety of a verapamil/trandolapril-based treatment strategy against hypertension and coronary-artery disease. In this randomized, open-label, blindedend- point trial, the regimen was found to be as clinically effective and had similar results as a non-calcium-antagonist strategy (atenolol/hydrochlorothiazide) in achieving two-year pressure control. The primary end points of first occurrence of death (all cause), nonfatal myocardial infarction,or nonfatal stroke were not statistically different between groups, as well as relative risks. Both drug combinations were also well tolerated.
STAR was a multicenter, prospective, randomized, open-label study with blinded outcome evaluation (PROBE). It assessed 276 patients from 30 centers over a 52-week treatment period. Patients included in the study were those 21 years and above diagnosed with metabolic syndrome. After a four-week washout period, they were randomized to a once-daily T/V (2/180 mg) or L/H (50/12.5 mg), with the doses titrated to achieve systolic blood pressure (SBP) of < 130 mm Hg. The primary end point was a difference in glucose tolerance as seen through changes in two-hour postprandial-glucose levels from baseline to week 52 or the final visit. An oral glucose-tolerance test (OGTT) was performed, checking glucose and insulin levels at zero, 30, 60, and 120 minutes. Secondary end points included changes in blood pressure, lipids, and inflammatory markers, insulin sensitivity, and incidence of new-onset diabetes (defined fasting blood sugar = 126 mg/dL or two-hour postprandial glucose = 200 mg/dL). In the primary analysis, both groups were noted to have experienced a change in two-hour OGTT (1.7 + 0.5 mmol/L; p < 0.001). Within-treatment analysis showed that the T/V group showed hardly any difference in two-hour OGTT values (-0.2 + 0.2 mmol/L; p = 0.329), but the L/H group showed an increase (1.4 + 0.4 mmol/L; p < 0.001). Secondary results noted the consistent increases in the twohour OGTT values from baseline to weeks 12 and 52 in the L/H group; this was not seen in the T/V group (treatment differences as 1.0 + 0.3 mmol/L, p < 0.001 for week 12; 1.6 + 0.5 mmol/L, p < 0.001 for week 52). In terms of changes in two-hour OGTT insulin values from baseline to weeks 12 and 52/ study end, the L/H group also exhibited an increase (-30.13 + 38.38 mmol/L v. 84.86 +38.33 mmol/L; p = 0.025). Also noted was a worsening in insulin resistance in the L/H group by week 12 (-0.005 + 0.001; p = 0.016). Also, cases of newonset diabetes in the L/H group were thrice more numerous than the T/V group (21 percent v. seven percent; p = 0.007). STAR showed that in patients with impaired glucose tolerance and metabolic syndrome, a fixed-dose combination of an ACEI and CCB, in this case trandolapril/verapamil SR (Tarka) achieves blood-pressure control and reduces the risk of newonset diabetes compared with a combination angiotensin-receptor blocker and TD, in this case losartan/hydrochlorothiazide. The STAR study may be the first demonstration of the "metabolic consequences" of prolonged (one year and above) use of combination RAS blocker/TD to control blood pressure among patients with greater risk for developing diabetes. M R.Badillo II, MD |
