SGLT2 Inhibitors, GLP-1 Receptor Agonists, or Bariatric Surgery and Risks of All-Cause Mortality, Cardiovascular Diseases, End-Stage Renal Diseases, and Severe Hypoglycemia in Obese Patients with Type 2 Diabetes Mellitus

Background: The risks of all-cause mortality, cardiovascular diseases (CVD), end-stage renal diseases (ESRD), and severe hypoglycaemia (SH) among obese patients with T2DM initiating novel glucose-lowering medications (SGLT2i and GLP-1RA) and those undergoing bariatric surgery were unknown. Methods: This was a population-wide retrospective cohort study. Data were collected from the Hong Kong Hospital Authority database from 2006 to 2017. Generalized matching weights of propensity score was applied to balance out baseline covariates of obese patients with T2DM who underwent bariatric surgery, or initiated SGLT2i or GLP-1RA. Hazard ratios (HRs) for CVD, ESRD, and mortality from any causes were assessed among three groups using Cox proportional hazard models. Findings: Over a median follow-up period of 14 months with 2916·25 person-years, incidence of CVD was the highest in SGLT2i group (7·156/100 person-years). Incidences of ESRD and all-cause mortality were the highest in bariatric surgery group (0·453 and 2·316/100 person-years). SGLT2i users had not significantly lower risk of all-cause mortality (HR=0·343, 95%CI=0·089-1·326, p=0·121), CVD (HR=1·125, 95%CI=0·576-2·198, p=0·729), ESRD (HR=0·480, 95%CI=0·109-2·107, p=0·331) and SH (HR=2·654, 95%CI=0·713-9·871, p=0·145) than bariatric surgery candidates. When comparing with bariatric surgery, GLP-1RA was not associated with significant reduction in risks of all-cause mortality (HR=0·350, 95%CI=0·117-1·045, p=0·060), CVD (HR=0·722, 95%CI=0·327-1·596, p=0·421), ESRD (0·251, 95%CI=0·034-1·836, p=0·173) and SH (1·923, 95%CI=0·418-8·853, p=0·401) events. Patients undergoing bariatric surgery had significantly greater improvement in BMI (-6·879kg/m2 , -0·787kg/m2 , -1·160kg/m2 , p<0·001), HbA1c (-1·723%, -0·875%, -0·607%, p<0·001), fasting glucose (-2·699, -1·345, -0·386, p<0·001) and triglyceride (-0·746, -0·204, -0·007, p<0·001) after 12-month, and higher 12-month cumulative direct healthcare costs (US34,736, US11,266, US10,929, p<0·001) than SGLT2i and GLP-1RA users. Interpretation: Among obese patients with T2DM, risks of all-cause mortality, CVD, ESRD and SH did not differ across three groups over the study period. Beneficial weight loss, metabolic outcomes, and higher direct healthcare costs at 12-month after bariatric surgery were observed. Funding Statement: This study was funded by the Health and Medical Research Fund Research Fellowship Scheme, Food and Health Bureau, Hong Kong SAR (Ref No. #02160087). Declaration of Interests: Dr Wong reports receipt of research funding from the EuroQoL Group Research Foundation, the Hong Kong Research Grants Council, and the Hong Kong Health and Medical Research Fund. Dr Man reports receipt of CW Maplethorpe Fellowship. Dr Chan reports receipt of research funding from Bristol-Myers Squibb, Pfizer, Janssen, Takeda Pharmaceuticals, the Hong Kong Beat Drugs Fund Association, the Hong Kong Research Grants Council, and the Hong Kong Health and Medical Research Fund. Prof Wong reports receipt of research funding from BristolMyers Squibb, Pfizer, Janssen, the Hong Kong Research Grants Council, and the Hong Kong Health and Medical Research Fund. Prof Lam reports receipt of research funding from the Hong Kong Research Grants Council, the Hong Kong Health and Medical Research Fund, and the Kerry Group and Kouk Foundation Endowed Primary Care Research Fund of the University of Hong Kong. No other disclosures were reported. Ethics Approval Statement: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Ethics approval of this study was granted by the Institutional Review Board of the University of Hong Kong /Hospital Authority Hong Kong West Cluster (HKU/HA HKW IRB) (Ref No. UW 16-1018).