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Canagliflozin and Hypertension: Is It the Optimal Choice for All Hypertensive Patients?

To the Editor: We have read with great interest the study by Townsend and colleagues, which provided important clinical data on the effect of canagliflozin on blood pressure (BP). Patients with type 2 diabetes are typically a group with difficult-to-control hypertension, most often in need of combination treatment to achieve BP control. The study efficiently demonstrated that canagliflozin seems to actually be an antihypertensive drug, which is in agreement with the results of several studies of impact of sodium-glucose cotransporter 2 (SGLT2) inhibitors on BP. Of note, the study demonstrated almost similar 24-hour ambulatory BP monitoring (ABPM) and office BP reductions, in contrast with data supporting that antihypertensive treatment leads to an ABPM reduction that is usually two-thirds of the office BP decrease. A meta-analysis of 44 studies assessing response to antihypertensive treatment with office and 24-hour BP measurements concluded that the average reductions in 24-hour systolic BP and diastolic BP were 36.5% and 36.8% less than the reduction in the office systolic BP and diastolic BP values, respectively. Therefore, the SGLT2 inhibitor not only demonstrated a decrease in BP but exceeded the expectations for its possible antihypertensive action. The importance of these findings are obvious and we would kindly ask the investigators to provide us with further data that could clarify several important topics on the management of hypertensive patients. First, it would be of interest to provide any differences in the efficacy of canagliflozin according to ethnicity (Hispanic/Latino vs other), especially in African American populations. It is known that patients of African ancestry exhibit greater tendency to retain sodium and have volume-dependent BP elevation. Therefore, diuretics are among the most effective BP-lowering drugs in African Americans. Second, diuretics are very useful in the management of hypertension in obese patients. A subanalysis of the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial revealed that the combination of a calcium channel blocker with an angiotensin-converting enzyme inhibitor provided similar outcome benefits across the baseline adiposity status (lean, overweight, and obese). On the other hand, the combination of a diuretic with an angiotensin-converting enzyme inhibitor was associated with significantly greater benefits in obese patients than in overweight and especially in lean patients. Subsequently, a subanalysis according to baseline body mass index would specify any plausible effects of the diuretic action of the drug on BP in overweight or obese compared with lean patients (body mass index ≤25, 25–30, and >30 kg/m). Third, it is clear that canagliflozin demonstrates an important diuretic effect. Useful information could emerge through the detection of any differences in the efficacy of the drug according to baseline antihypertensive classes used, and especially whether the SGLT2 inhibitor was equally effective in patients already on therapy with diuretics and/or renin-angiotensin system inhibitors. Finally, considering the mechanism of action of canagliflozin, the simultaneous administration of the SGLT2 inhibitor with other antihypertensive agents could explain the occurrence of several adverse events. Did orthostasis, volume depletion, and renal function deterioration occur in patients already treated with diuretics or renin-angiotensin system inhibitors? The additional BP-lowering effect of canagliflozin raises high hopes for the future of this antidiabetic class of drugs. Further understanding of their impact in different subgroups is essential to help physicians individualize treatment options for their patients. Therefore, we would be deeply obliged to the authors for performing the suggested subanalyses.