Recent evidence suggests that long term use of diuretics, β blockers, and statins may increase the risk of diabetes. However, these studies reported investigator or patient reported data or claims-related data on new onset diabetes. Given the limited number of large studies, the current analysis used data from the NAVIGATOR (Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research) study to examine the relation between risk of new onset diabetes and use of these drugs in treatment naïve patients.
NAVIGATOR was a multinational, randomised, double blinded, placebo controlled trial examining the effects of valsartan and nateglinide on conversion to type 2 diabetes mellitus and cardiovascular outcomes in patients with impaired glucose tolerance and other cardiovascular risk factors. The trial used standard methods of identifying diabetes (serial glucose measurements) that enhanced detection of risk for new onset diabetes in a high risk population with impaired glucose tolerance. Since this cohort represented a heterogeneous group, only patients that were treatment naïve to each class of drug at baseline were selected for the current analysis. Thus, of 9306 patients enrolled in NAVIGATOR, 915 (16.2%) of 5640 who were β blocker naïve at baseline started β blocker treatment during follow-up, 1316 (20.7%) of 6346 who were diuretic naïve started diuretic treatment, 1353 (22.0%) of 6146 who were statin naïve started statin treatment, and 1171 (18.6%) of 6294 who were calcium channel blocker naïve started calcium channel blocker treatment (calcium channel blocker was used as a metabolically neutral control).
The primary outcome measure was new onset diabetes, defined by a fasting plasma glucose level ≥ 7.0 mmol/L or a glucose level 11.1 mmol/L two hours after an oral glucose tolerance test, confirmed by a repeat oral glucose tolerance test within 12 weeks.
During the median five years of follow-up, the following results were reported (After adjusting for baseline characteristics and time varying confounders):
• The adjusted hazard ratio for new onset diabetes in patients treated with diuretics compared with those who were not was 1.23 (95% confidence interval 1.06 to 1.44); the number needed to harm was 17 (95% confidence interval 9 to 68).
• Likewise, the hazard ratio for new onset diabetes in the statin treated group, compared with the non-treated group, was 1.32 (1.14 to 1.48); the number needed to harm was 12 (8 to 29).
• For the β blockers group, the risk of new onset diabetes was numerically higher but non-significant (hazard ratio 1.10, 0.92 to 1.31).
• No association was found between calcium channel blocker use and development of new onset diabetes (hazard ratio 0.95, 0.79 to 1.13).
The authors noted that there were several limitations to their findings:
• Since this was a reanalysis of a clinical trial, selection bias due to the observational nature of treatment assignment is possible.
• They did not explore differential effects according to the duration of use but estimated the effect averaged over duration. Therefore they could not determine if there was a dose or category response for these drugs, especially when previous studies have showed that diuretic and β blocker effect can vary within these classes of drugs, and intensive dose (versus lower dose) statins may be associated with an increased risk of new onset diabetes.
• Finally, they did not examine the effect of new onset diabetes on cardiovascular disease outcomes, so they could not determine the effect of increased rate of diabetes on major outcomes in this population at high risk for cardiovascular disease.
Overall, they conclude that their findings suggest that glycaemia should be better monitored when these drugs are initiated in high risk patients. Further, these findings should be confirmed in subsequent prospectively randomised studies in patients at high risk of diabetes.