SGLT2 Inhibitors and Weight Loss

Studies have suggested that the weight loss during SGLT2 therapy is much lower than expected given the amount of energy lost through glycosuria. Why?

A new study might explain this phenomenon. Researchers found that actual weight loss was 2.7 times less than predicted in patients with type 2 diabetes (T2DM) on SGLT2 inhibitors. The results suggested that these patients increased their food intake, compensating for some of the energy lost through glycosuria. 

The study included 86 patients with T2DM (39 women, 47 men, age 58 ± 9 years, BMI 29.8 ± 4.5 kg/m², baseline HbA1c 7.8, and estimated glomerular filtration rate (eGFR) 89). Participants were part of the extension phases of two larger phase IIb clinical trials looking at SGLT2 inhibitors as monotherapy in drug naïve patients (n = 46) and as add-on to metformin (n = 40).

Participants took empagliflozin 25 mg/day for 90 weeks, during which time they received 11 assessments for body weight, eGFR, and fasting plasma glucose (FPG). The researchers calculated time-dependent glucose filtration from eGFR and FPG, and estimated time-dependent glucosuria directly. They estimated calorie-to-weight changes using a mathematical model.

Key results at 90 weeks included:

• Average weight loss: -3.2 ± 4.2 kg

• Predicted weight loss: -11.3 ± 3.1 kg

• Observed median calorie deficit: 51 kcal/day

• Observed average calorie loss through glycosuria: 206 kcal/day

• Thinner patients and those with higher eGFRs had larger differences between observed and expected weight loss ( p < 0.01 and p < 0.01, respectively).

• Patients on metformin had significantly greater weight loss (-4.4 kg) than drug-naïve patients (-2.0 kg) (p = 0.024).

• Patients had 13% increase in calorie intake and 2% increase in daily energy expenditure (likely due to diet-induced thermogenesis), which could explain the difference in actual and predicted weight loss.

Past studies have found that empagliflozin does not change resting or postprandial energy expenditure, the authors pointed out, suggesting that the difference between observed and expected weight loss is due to increased energy intake.

The authors speculated that thinner patients may have had less concerns about weight gain, leading them to overcompensate with increased food intake. Moreover, the observed differences in weight loss in subgroups could be explained by greater urinary glucose excretion in those with normal renal function, and the effect of metformin on reducing appetite. They suggested that glycosuria may signal the CNS to change appetite regulation, though this mechanism requires more research.

“These findings indicate that marked, consistent energy loss through the urine triggers an anabolic response by which enhanced appetite and, possibly, carbohydrate craving partially offset glycosuria and defend body weight…” wrote the authors, “… From a clinical standpoint, patients with T2DM could benefit more from SGLT2 treatment in terms of weight loss and glycemic control if more stringent dietary recommendations were implemented to curb appetite and overeating.”

Take-home Points

• Weight loss during SGLT2 therapy is much lower than expected, given the amount of energy lost through glycosuria. 

• A new study of 83 patients with T2DM has suggested that patients on long-term empagliflozin therapy increase their food intake, compensating for some of the energy lost through glycosuria. 

• Glycosuria may signal the CNS to change appetite regulation, though this mechanism requires more research.

• Patients with T2DM might experience more weight loss during SGLT2 inhibitor therapy if they followed stricter dietary recommendations to decrease appetite and overeating.

.Ferrannini G, et al. Energy balance after sodium glucose cotransporter 2 (SGLT2) inhibition. Diabet Care. 2015 Jul 15. [Epub ahead of print]

The clinical trials that provided data for this study were supported by Boehringer Ingelheim and Eli Lilly and Company.