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Empagliflozin Produces Liver Fat Reduction in Randomized Control Trial 

Mar 21, 2020
 
Editor: Steve Freed, R.PH., CDE

Author: Mit Suthar, PharmD. Candidate, LECOM School of Pharmacy 

Could empagliflozin contribute to the early treatment of NAFLD in patients with T2DM?  Study finds empagliflozin reduces liver fat.

Sodiumglucose cotransporter 2 inhibitors (SGLT2s) have shown to improve glycemia, reduce body weight, reduce blood pressure, and improve cardiovascular and renal outcomes. 

Weight loss is useful for the treatment of Nonalcoholic Fatty Liver Disease (NAFLD) but for the majority of cases, this is difficult to achieve. Some well-known GLP-1 receptor agonists, TZDs, and novel compounds such as pegbelfermin and elafibranor have shown benefit in patients with T2DM and NAFLD. 

However, currently, there is no widely accepted pharmacologic treatment for patients with diabetes who present with Nonalcoholic Fatty Liver Disease. This is significant because patients with T2DM frequently develop NAFLD. NAFLD is also associated with a doubled risk of incident T2DM, as well as being related to diabetesrelated CKD and retinopathy.  

There are reports of some open-label and placebo-controlled studies finding that canagliflozin and dapagliflozin decrease Liver Fat Content (LFC) compared with placebo. However, this reduction of LFC could be ascribed to the loss of body weight resulting from canagliflozin use. Empagliflozin, though, could improve NAFLD independently of body weight and glycemia.  

The randomized, parallel-group, double-blind, phase 4 trial was executed at five centers in Germany, with a 1:1 allocation to treatment arms. The trial was designed to evaluate if the SGLT2 inhibitor, Empagliflozin, reduces liver fat content in recent-onset and metabolically well-controlled T2DM.  

The participants in the study included well-controlled T2DM patients with short disease duration. These patients with a short disease duration were explicitly included to solve whether or not SGLT2 inhibitors would be effective in early T2DM. This also minimized the effects of additional antihyperglycemic treatments during the intervention.  

Participants had to meet the inclusion criteria: age 18–75 years, BMI <45 kg/m2, known diabetes duration ≤7 years, HbA1c of 6–8%, and no previous antihyperglycemic treatment or a 1-month washout period. The exclusion criteria included: uncontrolled hyperglycemia at screening (fasting blood glucose [FBG] ≥240 mg/dL), liver disease other than NAFLD, previous thiazolidinedione treatment, and use of immunomodulatory, antiobesity, anti-NASH drugs. 

Participants were randomized by stratified computed randomization, which accounted for age, sex, and BMI. Patients were assigned to either 24 weeks with 25mg daily empagliflozin or placebo. Investigators and patients were blinded using identical empagliflozin and placebo tablets. Patients returned to the study center at baseline, and weeks 1, 4, 8, 12, 16, 20, and 24 to assess safety and efficacy. 

The primary endpoint was the difference of the change in Liver Fat Content, which was measured by the magnetic resonance method from the baseline (0 weeks) to 24 weeks between the groups. Visceral Adipose Tissue (VAT), Subcutaneous Adipose Tissue (SCAT) volume, and LFC were assessed at baseline, 12 weeks, and 24 weeks. 
The secondary outcome of tissue-specific insulin sensitivity was assessed by two-step clamps using an isotope dilution technique.  ANCOVA was used for statistical comparison and was adjusted for the baseline values, age, sex, and BMI. 

The EMPA treatment resulted in a placebo-corrected absolute change of −1.8% (95% CI −3.4, −0.2; P = 0.02) and relative change in LFC of −22% (−36, −7; P = 0.009) from baseline to end of treatment, equivalent to a 2.3-fold more significant reduction of LFC.  No placebo-corrected change in tissue-specific insulin sensitivity was observed, and weight loss only occurred with patients on empagliflozin (placebo-corrected change −2.5 kg [−3.7, −1.4]; P < 0.001). 

There were other significant benefits found with empagliflozin use, such as decreasing circulating uric acid levels.  The limitations of the trial included the fact that the results cannot be generalized for the entire population of people with diabetes, since the cohort was explicitly comprised of well-controlled patients with short-known disease duration. Many patients with diabetes may be uncontrolled, have a much longer disease duration, and may also have more severe liver disease. This limitation could be construed as a strength, however, because it shows that empagliflozin reduces LFC even without significant changes in glycemic levels. 

The trial found that empagliflozin reduces hepatic fat in patients with T2DM who have excellent glycemic control and short-known disease duration. Empagliflozin could offer significant benefits as early treatment of Nonalcoholic Fatty Liver Disease in patients with T2DM due to its favorable effects on liver fat and bodyweight. 

Practice Pearls: 

  • Empagliflozin significantly reduces Liver Fat Content compared to placebo. 
  • In other trials, the guideline-based dietary counseling could be responsible for LFC improvement 
  • The absence of head-to-head comparisons with other SGLT2 inhibitors such as canagliflozin, and dapagliflozin does not allow conclusions about drug-specific effects. 

Kahl, Sabine, et al. “Empagliflozin Effectively Lowers Liver Fat Content in Well-Controlled Type 2 Diabetes: A Randomized, Double-Blind, Phase 4, Placebo-Controlled Trial.” Diabetes Care, American Diabetes Association, 1 Feb. 2020, care.diabetesjournals.org/content/43/2/298. 

 

Mit Suthar, PharmD. Candidate, LECOM School of Pharmacy 

 

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