The major finding of this report is that despite a more favorable metabolic profile, neither the CCB, nor the ACE-inhibitor, or the alpha-blocker was superior to the thiazide-type diuretic in preventing hard clinical outcomes in hypertensive patients with the metabolic syndrome. The findings by race and MetS status also parallel the findings in the entire cohort and in all other subgroup analyses from the trial.(8
) In no subgroup analysis from ALLHAT has the CCB, ACEI or alpha-blocker been shown thus far to be more effective than the thiazide-type diuretic in preventing either the primary outcome (non-fatal MI or CHD death) or any other major cardiovascular or renal outcome. Note is made of a lower rate of stroke in non-Blacks with MetS assigned to amlodipine compared to those on chlorthalidone. However, this was not seen in Blacks with MetS, in either subgroup without MetS, and did not translate into lower rate of the composite CVD (presumably because of the excess heart failure). Given the number of comparisons and p=.05, the finding is likely due to chance.
The lack of benefit of the agents with the most favorable metabolic profile (i.e., ACE-inhibitors and alpha-blockers) was especially marked in the Black subgroup with MetS. The magnitude of the risk of ESRD (70%), HF (49%), and stroke (37%) and the increased risk of combined CVD and combined CHD, strongly argue against the preference of ACE-inhibitors over diuretics as initial therapy in Blacks with MetS. Similar higher risk was noted for those on the alpha-blocker vs those on the diuretic. While treatment-related differences in cardiovascular and renal outcomes in the lisinopril vs. chlorthalidone comparison may in part be attributed to BP differences in Black participants with MetS, no such attribution can explain the lack of superiority of amlodipine in either race subgroup or of doxazosin or lisinopril in non-Blacks with MetS, as BP differences were minimal.
ALLHAT is not only the first large clinical outcome trial to report on the comparative effects of different classes of antihypertensive drugs on cardiovascular and renal outcomes in patients with the MetS but, remarkably, it is also powered to do so by race, given the large number of participants in ALLHAT meeting the criteria for MetS. Its findings are consistent with published reports from other cohorts (including in diabetics) and with meta-analyses.(18
) This report complements the findings in non-diabetic ALLHAT participants with and without MetS.(25
) In addition, it extends these findings to include the alpha-blocker/diuretic comparison, analyses by race, and it includes diabetics in the definition to be consistent with most definitions of MetS.
The ALLHAT results seem to conflict with expectations. Some have suggested that the follow-up period was too short for the metabolic effects to manifest themselves as clinical outcomes and may not generalize to younger patients, especially those with MetS.(6
) While longer-term treatment effects will be evaluated in an extended morbidity and mortality follow-up of the ALLHAT participants using national databases, until these data are available, little from this or other studies would predict a future reversal of our findings. First, differences in metabolic changes, while statistically significant, are relatively small. The largest difference in mean fasting glucose levels was between the diuretic and the alpha-blocker arms (up to 13 mg/dl). This would represent only a 0.16% lower HbA1c (28
) and thus a small difference in diabetic outcomes.(29
) Secondly, one would also have to assume that the drug-induced increases in glucose levels carry the same risk as a similar increase due to factors such as weight gain, sedentary lifestyle, etc. Although definitive data are not yet available, analyses of a 14+ year extended follow-up of the Systolic Hypertension in the Elderly Program (SHEP) participants showed a significant increase in both cardiovascular and total mortality in participants assigned placebo who developed diabetes during the double-blind phase of the trial.(19
) However, no such increase was seen in those who developed diabetes in the chlorthalidone treatment arm (with atenolol added as needed for blood pressure control). An observational study by Verdecchia et al. reported an increase in CVD event rates associated with new-onset diabetes in hypertensives but the increase in CVD risk was not associated with diuretic therapy.(30
) Furthermore, neither the ALLHAT data nor meta-analyses involving >2,800 CHD events, >5,000 CVD events, and >230,000 patient years (more if the alpha-blockers were to be included) suggest even the slightest signal for a lower rate of cardiovascular events with the ACE-inhibitors or the alpha-blockers, which represent the agents with the most favorable metabolic effects, compared with calcium antagonists and diuretics/beta-blockers. This was shown for individuals both with and without diabetes.(14
) In fact, we have recently reported a similar lack of association between change in glucose and CVD outcomes from ALLHAT in those randomized to chlorthalidone, but interestingly a significantly higher CVD and CHD event rate associated with glucose elevations in those on lisinopril.(31
) Finally, the recently published DREAM trial specifically designed to evaluate the effect ACEI treatment in patients with either impaired fasting glucose or impaired glucose tolerance reported no significant reduction in new-onset diabetes in participants randomized to ramipril compared to placebo.(32
In conclusion, these findings fail to provide support for the selection of alpha-blockers, ACE-inhibitors, or CCBs over thiazide-type diuretics to prevent cardiovascular or renal outcomes in patients with the MetS, despite their more favorable metabolic profiles.