Risk of orthostatic hypotension associated with sodium-glucose cotransporter-2 inhibitor treatment: A meta-analysis of randomized controlled trials

Abstract

Objective: The aim of this study was to assess the association between sodium-glucose cotransporter-2 (SGLT2) inhibitors and the risk of orthostatic hypotension (OH) in patients with type 2 diabetes mellitus (T2DM). Method: A systematic literature retrieval was performed using PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception up to 16 October 2019. Data for study characteristics and outcomes of interest were extracted from each eligible study. Pooled risk ratios (RRs) with 95% confidence intervals (CI) for OH were calculated using a random-effects model. Result: A total of 16 studies ( n = 12,749) were included in our meta-analysis, with a result of 44 incident OH cases (29 in the SGLT2 inhibitor group, and 15 in the control group). The pooled RR was 1.17 (95% CI: 0.65–2.09). There was no evidence that receiving SGLT2 inhibitors increased the risk of OH, when stratified by age, duration of T2DM, or placebo-control or active-control and baseline blood pressure. Conclusion: This meta-analysis suggested that, in general, SGLPT2 inhibitors did not increase the risk of OH in patients with T2DM. The possibility of OH should be, therefore, considered on an individual basis, especially in patients with a history of OH, long duration of T2DM, or comorbidities.

Prevalence of Admission Hyponatremia in Patients With Diabetes Treated With and Without an SGLT2 inhibitor

“…A first plausible explanation is that we, unfortunately, could not truly differentiate hyponatremia subtypes; in particular, we could not precisely identify hypovolemic hyponatremia, which is one of the most common causes for hyponatremia [ 35 ]. A recent meta-analysis by Rong et al suggested that SGLT2 inhibitors are not associated with orthostatic hypotension [ 36 ]; however, they reduce blood pressure [ 37 ] and induce volume depletion [ 19 ]. In hypovolemic hyponatremia, SGLT2 inhibitors might therefore show no effects or even lower plasma sodium levels through hemodynamic AVP stimulation, and thus counterbalance the benefit of SGLT2 inhibitors on plasma sodium levels in euvolemic and hypervolemic patients in the full dataset.…”

SGLT2 Inhibitors – The New Standard of Care for Cardiovascular, Renal and Metabolic Protection in Type 2 Diabetes: A Narrative Review

“…The decision to use an SGLT2i should consider the possibility of volume depletion and postural hypotension, which may increase the likelihood of falls, particularly in people who are also treated with diuretics or antihypertensives [17,18,53,[63][64][65][66]101]. Older participants (aged > 65 years) included in the CVOT studies typically demonstrated higher rates of volume depletion, compared with younger subgroups, although the overall rates were similar across the treatment and placebo arms in the DECLARE-TIMI (dapagliflozin) and EMPA-REG (empagliflozin) trials [18,53,102]. On the other hand, the CREDENCE and DAPA-CKD studies did not encounter any issues relating to concomitant use of SGLT2is and loop diuretics and some participants in the T2DM subgroups for HF trials (DAPA-HF and EMPEROR-reduced) were taking high-dose diuretics, and no dose reduction was necessary [20,21,28,75,[103][104][105].…”

Physicians’ Considerations and Practice Recommendations Regarding the Use of Sodium-Glucose Cotransporter-2 Inhibitors

“…Prior to SGLT-2i initiation, volume depletion can be addressed by a reduction in the dose of diuretics (based on the individual patient’s volume status) or hypotension-inducing agents (angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker) [ 12 , 39 , 53 ]. Although SGLT-2is do not appear to increase the risk of orthostatic hypotension in randomized controlled trials [ 54 ], volume correction is necessary in patients with volume depletion or existing hypotension to avoid potential orthostatic hypotension upon initiation of SGLT-2i treatment [ 39 ]. After SGLT-2i initiation, close monitoring of body weight, BP, and volume status is recommended, and patients should be counseled about avoiding dehydration and the risk of orthostatic hypotension, particularly in the first week of therapy [ 12 , 40 , 55 ].…”