In this extension of ALLHAT, analysis by assigned primary antihypertensive medication showed that for participants who developed incident DM versus those with no DM, chlorthalidone had the lowest hazard ratio for CVD mortality. Those treated with chlorthalidone also had the lowest hazard ratio for total mortality, non-CV mortality, CHD, and stroke. For no outcome did incident DM have a significant adverse effect on risk in the chlorthalidone group, despite the much larger sample size compared to the amlodipine and lisinopril groups.
Our findings are consistent with those of our previous ALLHAT report10
and 2 long term post hoc
analyses of trials that examined the impact of diuretic-associated DM on CVD mortality. In the 14-year follow-up of the Systolic Hypertension in Elderly Program (SHEP) study, DM that developed during chlorthalidone therapy did not have a statistically significant impact on CVD mortality (RR 1.04 [0.75, 1.46]; similar to our own result) or on all cause mortality (1.15 [0.92, 1.43]) in contrast to DM that developed while assigned to placebo.11
In a second study, a 14-year follow up of 686 middle-aged adults with hypertension treated with diuretics, incident DM did not have a significant effect on CVD mortality, whereas baseline DM did.12
With regard to fatal/nonfatal stroke, HF and ESRD, randomization to chlorthalidone was associated with a mixed picture. The hazard ratio for stroke was lowest, while for ESRD it was highest, compared to amlodipine or lisinopril. There were fewer ESRD outcomes as compared to stroke outcomes, introducing uncertainty to this comparison and mitigating the absolute impact associated with chlorthalidone for ESRD outcomes. With regard to HF, incident DM in association with chlorthalidone use was associated with a higher risk compared to amlodipine or lisinopril, but interaction terms were not significant, suggesting that the DM-associated risks of HF in the three groups were not statistically different.
Other findings should be noted. First, in almost all instances, participants with baseline DM had a worse outcome than either those with no DM or those with incident DM. Within diabetes subgroups, there were (in general) no differences in hazard ratios whether the participant was treated with chlorthalidone, amlodipine, or lisinopril. Second, our starting point for follow-up was based on incident DM detected at 2 years of in-trial treatment. A higher percent of the incident DM associated with chlorthalidone use was captured during this time period than that associated with amlodipine or lisinopril use. This makes our estimates of the long-term impact of incident DM associated with amlodipine or lisinopril conservative relative to those reported for chlorthalidone.
Third, among chlorthalidone participants, CVD mortality and fatal and non-fatal CHD associated with incident DM closely resembled those with no DM, whereas among amlodipine or lisinopril participants outcomes resembled participants with baseline DM. These findings suggest differences in the nature of amlodipine- and lisinopril-associated DM compared to chlorthalidone-associated DM. We previously hypothesized10
that depletion of potassium plays a role in the excess incidence of DM that is associated with chlorthalidone use (above and beyond the DM that is expected with having hypertension). Depletion of potassium inhibits insulin release from pancreatic beta cells; potassium restoration reverses this effect.13–15
In contrast, DM associated with the use of amlodipine or lisinopril is likely due to progression of insulin resistance that is present despite the glucose-neutral or glucose-protective effects of these agents.
Compared to all other studies, ours has the largest number of participants with incident DM and compares results of randomization to chlorthalidone against other HTN medications. This point is important, since people with HTN are prone to develop DM irrespective of treatment type. Assuming that calcium blockers are metabolically neutral, comparison of DM incidence rates at 2 years of in-trial follow-up for chlorthalidone (7.5%) versus amlodipine (5.6%) suggests that 74.7% of the new-onset DM in the chlorthalidone group is not “caused by” the diuretic, i.e. only about ¼ of cases was diuretic-induced.
This study has several limitations. First, the randomized treatments were discontinued at the conclusion of the trial in 2002. The administrative data used to document extended follow-up do not provide information about medication use during the period of passive observation. Second, glucose levels fluctuate and repeated testing is recommended to confirm glycemic status. This was not done in ALLHAT, a common practice in large trials owing to the inconvenience and cost of re-calling large numbers of participants. Misclassification of DM status would, however, have occurred randomly across treatment groups and should not have impacted our findings. Third, our results present data stratified by post-randomization characteristics (incident DM and no DM), which is the only way of studying the post-randomization effects of randomly assigned drugs, and many participants were excluded. Therefore, the treatment groups may no longer have been balanced on observed and unobserved variables.9
Finally, many participants from the trial were not included in post-trial follow-up due to lack of access to relevant databases.
In conclusion, our findings suggest that thiazide-associated incident DM is associated with lower CVD mortality and morbidity relative to amlodipine- or lisinopril-associated incident DM over an average of 6.9 years. . Therefore concerns regarding potential adverse diabetic effects associated with thiazide-type diuretic therapy should not inhibit its use. In this regard, a recent pooled analysis of 5 statin studies16
showed that incident DM was more common in people treated with intensive-dose therapy versus moderate-dose therapy. Nonetheless, the benefits of reduced cholesterol were deemed to outweigh any possible deleterious effects of incident diabetes on CVD outcomes. Similarly, thiazide-like diuretics have been shown to be highly effective for preventing CVD outcomes through decades of rigorously controlled clinical trials.