Canagliflozin vs. Sotagliflozin for Stroke Prevention in Patients with T2D and CKD

SGLT2 inhibitors –a.k.a. gliflozins — are not created equal, as patient-specific characteristics and comorbidities like CKD need to be considered for best efficacy.

SGLT2 inhibitors are recommended for patients with T2D based on their cardiovascular benefits. These medication guidelines stemmed from data found in large, randomized trials examining major adverse cardiovascular events (MACE) and heart failure (HF). These trials were not powered to measure SGLT2 inhibitor capacity to increase or decrease the risk of stroke. A meta-analysis was conducted and found no significant association between gliflozins and the incidence of stroke. However, it failed to look at various subgroups. This trial looked at individuals with T2D alongside CKD, HF, or ASCVD. Researchers also collected data from newly published research, including the SOLOIST-WHF, SCORED, and VERTIS CV trials.

This meta-analysis included randomized trials that compared gliflozin to placebo in preventing cardiovascular and cerebrovascular outcomes among patients with or without T2D.  The primary outcome was a fatal or nonfatal and ischemic or hemorrhagic stroke. The secondary outcome was MACE, which included stroke, myocardial infarction, or cardiovascular death. The extracted data included patient characteristics, trial type, intervention type, and control type. Participants with T2D were divided into groups: those with/without CKD, HF, or ASCVD. Treatment outcomes were listed as hazard ratios (HR) and 95% confidence intervals (CI). The quality of the trials was assessed using the Cochrane risk of the bias assessment tool. I2 statistics were computed to evaluate heterogeneity, in which substantial heterogeneity was defined as an I2 of >50%.

This meta-analysis included information taken from 9 randomized trials. Each trial enrolled more than one thousand participants and had a long follow-up period (0.8- 4.2 years). The participants had varying proportions of CKD, HF, and ASCVD. Individuals with T2D and CKD had a significantly lower risk of stroke (HR 0.68, CI 0.55–0.84, I2 = 49.0%) and MACE (HR 0.77, 95% CI 0.69–0.86) when taking gliflozins compared to placebo. Patients with T2D without CKD did not have a significantly lower risk of stroke (HR 1.00, CI 0.86–1.16, I2 = 0%) and MACE (HR 0.94, 95CI 0.86–1.02) when taking gliflozins compared to placebo. Individuals with T2D on gliflozins did not significantly lower stroke risk (HR 0.94, CI 0.82–1.07), regardless of HF (Psubgroup = .684) and ASCVD (Psubgroup = .915) status. Those with T2D taking gliflozins had a significantly lower MACE (HR 0.89, 95% CI 0.83–0.96), regardless of HF (Psubgroup = .428) and ASCVD (Psubgroup = .423) status. 

Canagliflozin (HR 0.84, 95% CI 0.69–1.01) reduced stroke risk and sotagliflozin (HR 0.73, 95% CI 0.54–0.98) significantly lowered stroke risk when compared to placebo. Empagliflozin (HR 1.18, 95% CI 0.89–1.56; I2 = 0%), dapagliflozin (HR 0.99, 95% CI 0.84–1.16; I2 = 0%) and ertugliflozin (HR 1.06, 95% CI 0.82–1.37; I2 = 0%) had no significant effects on stroke risk. Ertugliflozin (HR 0.97, 95% CI 0.85–1.11) had no significant effects on the MACE risk. Empagliflozin (HR 0.86, 95% CI 0.74–0.99; I2 = 0%), canagliflozin (HR 0.84, 95% CI 0.76–0.93; I2 = 0%), dapagliflozin (HR 0.90, 95% CI 0.83–0.97; I2 = 0%), and sotagliflozin (HR 0.81, 95% CI 0.70–0.95; I2 = 53.9%) significantly lowered the MACE risk versus placebo.

Previous meta-analyses found that SGLT2 inhibitors were not associated with an increased risk of stroke in patients with T2D, overlooking the effects of CKD, HF, and ASCVD. This study was more comprehensive since it included data on CKD, HF, and ASCVD. Weaknesses of the trial include substantial heterogeneity among some subgroups, inadequate power for the T2D subgroup with ASCVD alongside CKD, and inadequate power for the T2D subgroup with CKD and ASCVD without CKD. The study also failed to look at confounding factors and hypertension status. Future studies are needed to study these subgroups so that better guidelines can be made. 

 Practice Pearls:

• Individuals with T2D and CKD taking gliflozins had a significantly lower risk of stroke and MACE than those taking the placebo. However, there was no significant reduction in stroke and MACE with patients who had diabetes without CKD.
• Individuals with T2D on gliflozins did not significantly lower stroke risk, regardless of HF and ASCVD status. However, those with T2D taking gliflozins had a significantly lower MACE risk, regardless of HF and ASCVD status.
• Sotagliflozin significantly lowered stroke risk, and canagliflozin lowered stroke risk when compared to placebo. Empagliflozin, dapagliflozin, and ertugliflozin had no significant effects on stroke risk. Empagliflozin, canagliflozin, dapagliflozin, and sotagliflozin significantly lowered MACE risk versus placebo. Ertugliflozin had no significant effects on MACE risk.

Guo M, Ding J, Li J, et al. SGLT2 inhibitors and risk of stroke in patients with type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab 2018;20:1977–82.

Zhao LM, Huang JN, Qiu M, Ding LL, Zhan ZL, Ning J. Gliflozins for the prevention of stroke in diabetes and cardiorenal diseases: A meta-analysis of cardiovascular outcome trials. Medicine (Baltimore). 2021 Oct 1;100(39):e27362. doi: 10.1097/MD.0000000000027362. PMID: 34596148.

Kornelia Ilias, Pharm.D. Candidate, Creighton University School of Pharmacy and Health Professions