Article: Shen L, Shah BR, Reyes EM, et al. Role of diuretics, beta blockers, and statins in increasing the risk of diabetes in patients with impaired glucose tolerance: reanalysis of data from the NAVIGATOR study. BMJ. 2013 Dec 9;347:f6745
OBJECTIVE: To examine the degree to which use of beta blockers, statins, and diuretics in patients with impaired glucose tolerance and other cardiovascular risk factors is associated with new onset diabetes.
DESIGN: Reanalysis of data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial.
SETTING: NAVIGATOR trial.
PARTICIPANTS: Patients who at baseline (enrollment) were treatment naive to beta blockers (n=5640), diuretics (n=6346), statins (n=6146), and calcium channel blockers (n=6294). Use of calcium channel blocker was used as a metabolically neutral control.
MAIN OUTCOME MEASURES: Development of new onset diabetes diagnosed by standard plasma glucose level in all participants and confirmed with glucose tolerance testing within 12 weeks after the increased glucose value was recorded. The relation between each treatment and new onset diabetes was evaluated using marginal structural models for causal inference, to account for time dependent confounding in treatment assignment.
RESULTS: During the median five years of follow-up, beta blockers were started in 915 (16.2%) patients, diuretics in 1316 (20.7%), statins in 1353 (22.0%), and calcium channel blockers in 1171 (18.6%). After adjusting for baseline characteristics and time varying confounders, diuretics and statins were both associated with an increased risk of new onset diabetes (hazard ratio 1.23, 95% confidence interval 1.06 to 1.44, and 1.32, 1.14 to 1.48, respectively), whereas beta blockers and calcium channel blockers were not associated with new onset diabetes (1.10, 0.92 to 1.31, and 0.95, 0.79 to 1.13, respectively).
CONCLUSIONS: Among people with impaired glucose tolerance and other cardiovascular risk factors and with serial glucose measurements, diuretics and statins were associated with an increased risk of new onset diabetes, whereas the effect of beta blockers was non-significant.
TRIAL REGISTRATION(S): ClinicalTrials.gov NCT00097786.
Internal Medicine: This study comprise of a re-analyses of the NAVIGATOR RCT in which patients were randomised to valsartan and nateglinide (a 2×2 factorial design), both of which failed to show any convincing effect in delaying the development of NIDDM in a relatively high risk population. The present BMJ paper is thus only an observational cohort study albeit with some confounder adjustment. I have grave concerns that there may be residual confounding, especially in case of statins. To my knowledge, the association between diuretics and risk of NIDDM is not new. Apart from this general skepticism regarding the design, I also in this context regard NIDDM as a proxy outcome. The beneficial effect on death in risk patients treated with statins is well documented, so although there (eventually) could be a slight increase in risk of NIDDM, statins would probably still save lives.
General Practice(GP)/Family Practice(FP): A large study assessing the risk of developing diabetes in patients taking diuretics, statins and beta blockers with results reflecting a number necessary to harm (NNH) of 17 for diuretics and NNH of 12 for statins respectively.