Fat Cell Function with Dapagliflozin

A small, single center study has suggested that the SGLT2 inhibitor dapagluiflozin may improve fat cell function. The findings were published in Drugs in R & D.¹

“In this study, we found that treatment of obese T2D patients with dapagliflozin 5 mg once daily for 12 weeks significantly reduced HbA1c and body weight to the same level as previous reports. Although ketone bodies increased significantly, CRP significantly decreased, and adiponectin significantly increased,” wrote lead author Toshio Naito, MD, PhD of Okamato Medical Clinic (Tokyo, Japan), and colleagues.

Ketone bodies result from fatty acid breakdown and are released from the liver during stressful conditions, such as fasting, carbohydrate restrictive diets, intense exercise, or insufficient insulin levels.  Adiponectin is secreted from fat cells, and increased levels have been associated with weight reduction. CRP is a marker of inflammation. Obesity has been linked to inflammation and elevated CRP levels.  

The study included 27 obese adults with inadequately controlled T2DM (mean BMI 32.7 kg/m², mean age 47.9 years, 63% male). Participants were seen at the Okamoto Medical Clinic (Tokyo, Japan), between June 2014 and December 2014.

Participants received 5 mg/day of dapagliflozin for at least 12 weeks. At the beginning and end of that time, researchers checked HbA1c, body weight, ketone bodies, adiponectin, CRP, and plasminogen activator inhibitor-1 (PAI-1). The last is made by fat cells; levels of PAI-1 increase with obesity, and decrease with weight loss.

Key results after receiving dapagliflozin:

• HbA1c:  Significantly improved from 7.44 to 6.70% (P<0.01)

• Body weight: Significantly decreased from 90.9 kg to 87.1 kg (P<0.01)

• Ketone bodies: Significantly increased

♦ Acetoacetic acid from 22.1 to 35.5 µmol/mL (P<0.01)

♦ 3-hydorxybutyric acid from 38.2 to 73.9 µmol/mL (P<0.01)

♦ Total ketone from 60.3 to 109.4 µmol/mL (P<0.01)

• Adiponectin: Slight but significant increase from 5.1 to 6.7 ug/mL (P<0.01)

• High-sensitivity CRP: Significant decrease from 2410 to 1607 ng/mL (P<0.01)

• PAI-1: No significant change (P=0.07)

The authors pointed out that past studies have suggested that the action of SGLT2 inhibitors might mimic the effects of decreased glucose levels, as in calorie restriction. While weight loss in the initial phases of SGLT2 inhibitor therapy is related to water loss, lower glucose levels during longer term therapy may shift the source of metabolism from glucose to fat. That, in turn, may increase the production of ketone bodies. This may be helpful for weight loss, but at the risk of diabetic ketoacidosis (DKA). Because of past reports of euglycemic DKA associated with SGLT2 inhibitor therapy,² the authors stressed the importance of preventing dehydration in order to prevent DKA.

Nevertheless, while mentioning that larger, longer-term studies are needed, they concluded: “Since adiponectin was significantly associated with changes in HbA1c and body weight, SGLT2 inhibitors may improve adipocyte function. Adipocyte function is closely related to insulin resistance. Thus, dapagliflozin may have mitigated insulin resistance by improving adipocyte function.”

Take-home Points

• A small, single center Japanese study suggests the SGLT2 inhibitor may improve adipocyte function, and possibly insulin resistance.

• After 12 weeks of 5 mg dapagliflozin daily, results of measured adipocyte biomarkers showed significantly increased ketone bodies and adiponectin, significantly decreased CRP, and no change in plasminogen activator inhibitor-1.

The authors report no potential conflicts of interest.

References:

1. Okamoto A, et al. Changes in levels of biomarkers associated with adipocyte function and insulin and glucagon kinetics during treatment with dapagliflozin among obese type 2 diabetes mellitus patients. Drugs R D. 2016 Jun 22. [Epub ahead of print]

2. Peters AL, et al. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 Inhibition. Diabetes Care. 2015 Sep;38(9):1687-1693.