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What You Need to Know About SGLT2i Use in Obesity

Feb 24, 2018
 

Therapy offers beneficial weight loss in treatment of diabetes, but which agent in the class leads to the greatest body weight reduction?  

Obesity is highly widespread in patients with diabetes; excess weight leads to difficulty with controlling HbA1c levels and increases the risk of diabetes-related complications.

Although lifestyle modifications, including exercise and behavior change, are crucial for shedding off the excess pounds, certain medications for the treatment of diabetes may be to blame for struggles with weight loss. Recently, an article in Diabetologia was published that outlines the common therapies used in the treatment of diabetes and distinguishes their influence on obesity and weight management. Along with GLP-1 agonists, the author lists SGLT2 inhibitors as one of the most beneficial weight-loss–causing antidiabetic drugs. Applications of SGLT2-i use and weight loss benefits are presented below.

SGLT2i work by hindering renal glucose transport and promoting the excretion of glucose in urine. The quantity of glucose excreted in urine corresponds to approximately 75 grams, or ~300 kcal, and as a consequence, reduction in body weight is seen.  However, owing to the compensatory increase in food intake by the individual, the weight loss that occurs with the use SGLT2s is restricted. Following the AACE guidelines, individuals in need of a combination antihyperglycemic therapy and who wish to lose weight are usually treated with metformin and an SGLT2i or a GLP-1 agonist. Data supporting the combination therapy with all three medication classes is limited. On the other hand, there have been studies conducted that endorse the use of dual-therapy with SGLT2i and GLP-1 agonists. More specifically, a combination study with exenatide and dapagliflozin therapy is advantageous because it leads to an average weight loss of 3.4 kg.

The use of insulin in the treatment of both type 1 and type 2 diabetes may result in weight gain. In type 2, the addition of SGLT2 inhibitors to insulin may improve glycemic control, lessen the amount of insulin needed, and alleviate the insulin-related weight gain. Nonetheless, current guidelines support the addition of metformin, not an SGLT2 inhibitor, to insulin in individuals whose glycemic levels are not controlled despite proper insulin use. While there was some appeal in utilizing SGLT2 inhibitors in the treatment of type 1 diabetes to control the weight gain commonly seen in this population, the advantage was short lived due to the exposure of ketoacidosis risk seen with SGLT2i use.

Currently, various studies are under investigation that are exploring the utilization of anorectic drugs to combat the compensatory mechanisms of increased food intake seen with SGLT2 inhibitors in the treatment of obesity. By increasing energy wastage, the combination of the two different classes of medication may prove a beneficial and sustained weight loss. One such study has recently reported its results: combination therapy with phentermine and canagliflozin has showed an overall 7.5% decrease in weight, single agent phentermine decreased weight by 4.1%, and canagliflozin lead to 1.9% decrease in body weight.  However, these results have not been replicated in patients with diabetes.

SGLT2 application in the treatment of obesity in diabetes is extensive. Although current guidelines do not recommend their use over metformin in certain situations, SGLT2 inhibitors lead to a modest reduction is body weight. Given the remarkable effect on weight loss the combination therapy of SGLT2i and anorectics offers, SGLT2 relevance in treatment of individuals with obesity and diabetes is likely to magnify if similar results are replicated in individuals with diabetes.

Choosing the right agent in the class for your patient may be challenging. To help, we have outlined the average body weight loss seen with each of the SGLT2 inhibitors.

Drug Name Weight Loss Effect
Empagliflozin 1.5 – 2.1 kg
Dapagliflozin 0.46 – 2.16 kg
Canagliflozin 2 – 2.4 kg
Ertugliflozin 1.76 – 2.16 kg

Practice Pearls:

  • On average, SGLT2 inhibitors lead to weight loss of ~2 kilograms.
  • SGLT2 inhibitors’ weight loss is limited if there is a compensatory increase in food intake by an individual.
  • Combination therapy with SGLT2 inhibitors and anorexinogenic drugs may prove effective for weight loss in diabetes, however, future studies are needed to establish the benefit.

Resources:

John Wilding. “Medication use for the treatment of diabetes in obese individuals.” Diabetologia. 2018.  https://link.springer.com/article/10.1007%2Fs00125-017-4288-1. Accessed on Jan 2018.

Juan Frias, et al. “Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial.” The Lancet. 2016.  http://www.thelancet.com/journals/landia/article/PIIS2213-8587(16)30267-4/fulltext.  Accessed on Jan 2018.

Ian Neeland, et al. “Empagliflozin reduces body weight and indices of adipose distribution in patients with type 2 diabetes mellitus.” Diabetes and Vascular Disease Research. Mar 2016.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4768401/. Accessed on Jan 2018.

Susan Grandy, et al. “Changes in weight loss-related quality of life among type 2 diabetes mellitus patients treated with dapagliflozin.” Diabetes, Obesity and Metabolism.  Feb 2014.   http://onlinelibrary.wiley.com/doi/10.1111/dom.12263/abstract.  Accessed on Jan 2018.

Julio Rosenstock, et al. Dose-Ranging Effects of Canagliflozin, a Sodium-Glucose Cotransporter 2 Inhibitor, as Add-On to Metformin in Subjects With Type 2 Diabetes. American Diabetes Association. Jun 2012. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3357223/. Accessed on Jan 2018.

Lamija Zimic, PharmD(c), University of South Florida, College of Pharmacy