SGLT2 Inhibitors, GLP-1 RAs Could Lower NAFLD Risk in Type 2 Diabetes

Comparing SGLT2 inhibitor and GLP-1 RA use versus DPP-4 inhibitors in patients with type 2 diabetes, investigators found use of newer glycemic agents could provide protection against NAFLD in addition to their cardiorenal protective benefits.

An analysis of data from more than 250,000 patients with type 2 diabetes is providing clinicians with insight into the effects of newer glycemic agents on the risk of nonalcoholic fatty liver disease (NAFLD).

Results of the new-user, active comparator study, which used data from the UK Clinical Practice Research Datalink, suggests use of SGLT2 inhibitors was associated with a 22% reduction in risk of NAFLD compared with DPP-4 inhibitors while use of GLP-1 RAs was associated with a 14% reduction in risk of NAFLD.

“The results of this large population-based study indicate that the use of SGLT-2 inhibitors, and possibly GLP-1 RA, is associated with a decreased risk of NAFLD compared with the use of DPP-4 inhibitors. In addition, both GLP-1 RA and SGLT2 inhibitors were associated with a decreased risk of hepatic transaminase elevations,” wrote investigators.

As knowledge of the cardiometabolic benefits of newer glycemic agents continues to grow, investigators have turned to retrospective analyses to assess other potential benefits of these agents in addition to their cardioprotective and renoprotective abilities. With this in mind, a team of investigates from McGill University in Canada designed the current study as a population-based cohort study to evaluate whether GLP-1 RA or SGLT2 inhibitors were associated with s decreased risk of NAFLD compared to use of DPP-4 inhibitors.

Using data from the UK Clinical Practice Research Datalink, which pooled data from the GOLD and Aurum databases, investigators identified 2 new-user, active cooperator cohorts for analysis. The first study cohort included new users of GLP-1 RAs and new users of DPP-4 inhibitors who began treatment between January 1, 2007-April 30, 2020. The second cohort included new users of SGLT2 inhibitors and new users of DPP-4 inhibitors who received treatment from January 1, 2013, to April 30, 2020.

DPP-4 inhibitors of interest for the study included alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin. SLGT2 inhibitors included canagliflozin, dapagliflozin, and empagliflozin. GLP-1 RAs included dulaglutide, exenatide, and liraglutide.

For inclusion in either cohort, patients needed to be at least 40 years of age and have at least 1 year of medical history before entry into the Clinical Practice Research Datalink. Investigators used Cox proportional hazards models weighted using propensity score fine stratification to estimate hazard ratios of NAFLD. Investigators pointed out DPP-4 inhibitors were selected as an active comparator because they do not reduce hepatic steatosis.

The cohort of GLP-1 RA users and DPP-4 inhibitor users included 30,291 new GLP-1 RA users and 225,320 new DPP-4 inhibitor users. Before weighting, GLP-1 RA users were younger and more likely to be obese and have microvascular complications than their counterparts using DPP-4 inhibitors. A total of 2144 NAFLD events occurred during a median follow-up of 1.4 years (IQR, 0.5-3.1).

The cohort of SGLT2 inhibitor users and DPP-4 inhibitor users included 41,184 new SGLT2 inhibitor users and 148,421 new DPP-4 inhibitor users. Before weighting, SGLT2 inhibitor users were younger, more likely to be obese, and less likely to have microvascular complications than their counterparts with DPP-4 inhibitors. A total of 1507 NAFLD events occurred during a median follow-up of 1.1 years (IQR, 0.5-2.5).

Results of the investigators’ analyses indicated GLP-1 RA use was associated with a lower incidence of NAFLD when compared with DPP-4 inhibitors, with event rates of 3.9 and 4.6 per 1000 person-years, respectively (HR,0.86 [95% CI, 0.73-1.01]). Similarly, SGLT2 inhibitors use was also associated with a reduction in risk of NAFLD compared with DPP-4 inhibitors, with event rates of 5.4 and 7.0 per 1000 person-years, respectively (HR, 0.78 [95% CI, 0.68-0.89]).

In restricted subcohort analyses, which were designed to assess the impact of residual confounding, results suggested GLP-1RA use was note associated with a decreased risk of NAFLD, but SGLT2 inhibitor use was associated with a 21% reduction in risk of NAFLD (HR, 0.79 [95% CI, 0.64-0.96]). Results also suggested both GLP-1 RA (HR, 0.89 [95% CI, 0.83-0.95]) and SGLT2 inhibitors (HR, 0.66 [95% CI, 0.61-0.71]) use were associated with a decreased risk of hepatic transaminase elevation.

“Given the increased risk of all-cause, liver-related, and cardiovascular mortality associated with NAFLD, and the potential irreversibility of its late-stage complications, therapeutic strategies including SGLT2 inhibitors and GLP-1 RA may reduce the burden of NAFLD among patients with type 2 diabetes,” wrote investigators.

This study, “Glucagon-Like Peptide 1 Receptor Agonists and Sodium–Glucose Cotransporter 2 Inhibitors and Risk of Nonalcoholic Fatty Liver Disease Among Patients With Type 2 Diabetes,” was published in Diabetes Care.