Whole-Body Metabolic Response to SGLT2 Inhibition: Benefit or Risk?

Sodium glucose co-transporter-2 (SGLT2) inhibitors, the newest class of antihyperglycemic agents on the market, induce glycosuria by decreasing glucose reabsorption in the proximal renal tubule, thereby lowering blood glucose levels and HbA1c (A1C). Losing glucose through the urine, though, raises the potential for whole-body metabolism to respond with adaptive changes. 

A recent study¹ by researchers in Italy and Germany investigated this possibility by assessing the metabolic response to empagliflozin, a SGLT2 inhibitor currently under development by Boehringer Ingeleheim and Eli Lilly.² Though the study is limited by the absence of a control group, it provides insight into the body’s adaptations to longer-term exposure to SGLT2 inhibitor therapy.

The study in brief:

   -66 participants with T2DM, disease duration of more than 5 years, renal function preserved; mean age 62 years; mean baseline BMI, 31 and  A1C, 7.2

   -32 participants were drug-naïve or free of antihyperglycemic medications, while 34 were on stable doses of metformin. 

   -Open-label design to evaluate specific metabolic measures under 3 conditions: after an overnight fast, after a single dose, and after 4 weeks of empagliflozin 25 mg/day.

   -Assessments consisted of a 5-hour mixed meal tolerance test, followed by a 3-hour fast combined with a double-tracer glucose administration to assess the separate contributions of meal-derived glucose and endogenous glucose production (EGP)

After one dose of empagliflozin:

   -Glycemia decreased, and the amount of glucose lost through the urine (about 8g over 3 hours), was almost exactly balanced by an increase in EGP (about 7g over 3 hours)

   -Insulin secretion was enhanced by about 25%, with improved ß-cell sensitivity

   -Glucagon and GLP-1 levels were significantly increased (p=0.0378 and p=0.0013, respectively)

   -Tissue glucose disposal (TGD) was reduced by 20%, attributed to a decrease in glucose oxidation and nonoxidative glucose disposal, along with a decrease in postprandial suppression of free fatty acids (FFAs)

After 4 weeks of empagliflozin treatment:

   -A1C decreased significantly compared to baseline (6.8 vs. 7.2, respectively; p<.0001)

   -Measures of glycosuria, ß-cell function, and insulin sensitivity were similar to those observed after a single dose

   -Increase in fasting EGP slowed to 3g over 5 hours

   -GLP-1 and glucagon levels remained elevated, but the response was attenuated and no longer significantly different from baseline

   -TGD greatly declined, accompanied by a rise in lipid oxidation and significantly higher FFA concentrations (p<.0001).

The authors estimated that without the rise in EGP, postprandial glucose levels would have decreased by about 50% instead of the 12% found in this study. The decrease in glucose oxidation, they noted, was compensated for by increased lipid oxidation. With chronic dosing, the energy metabolism substrate appeared to shift from carbohydrate to lipid.

Clinical relevance?

Though the observed hyperglucagonemia was attenuated, it was still detectable after 4 weeks of treatment. Whether or not the response will eventually resolve remains to be studied, according to first author Ele Ferrannini, Professor of Medicine at the University of Pisa School of Medicine in Pisa, Italy.

“The SGLT2 inhibitor-induced drop in plasma glucose and insulin concentrations likely contributed to the relative hyperglucagonemia, but other mechanisms may be involved,” Ferrannini explained. “Relative hyperglucagonemia helps toward raising endogenous glucose production. This represents an adaptive physiological response rather than a clinical risk.”

Ferranini mentioned that combining SGLT2 inhibitors with agents that stimulate insulin release (sulfonylureas, DPP4 inhibitors, GLP-1 receptor agonists) or restrain endogenous glucose production (metformin) would likely counter the rise in plasma glucagon.

Should clinicians be concerned about the shift to lipid metabolism and increase in FFA levels in response to empagliflozin therapy?

“The increase in FFA delivery and oxidative usage is the expected response to the decrease in tissue glucose utilization as a result of the loss of glucose through the urine,” commented Ferrannini. Mobilization of fat depots, she explained, is the underlying mechanism for the weight loss associated with SGLT2 inhibitors. So far, observed lipid changes have represented relatively small changes from baseline in LDL cholesterol, HDL cholesterol, and triglyceride levels, according to Ferrannini.

“All in all, available evidence indicates that chronic SGLT2 inhibition is associated with benefits, such as drop in A1c, body weight, and blood pressure, that exceed potential risks such as increases in LDL cholesterol and hemoconcentration,” Ferrannini emphasized. “Obviously, long-term monitoring of the benefit/risk balance is necessary.”

^aIn March 2014, the FDA denied the new drug application for this medication after identifying deficiencies at the facility where it would be manufactured.²

Disclosures:

This study was funded by Boehringer Ingelheim, the maker of empagliflozin.

Dr. Ferrannini reports consulting for various pharmaceutical companies, including Boehringer Ingelheim.

References:

• Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2013;124(2):499–508. doi:10.1172/JCI72227. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904627/pdf/JCI72227.pdf
• U.S. Food and Drug Administration Issues Complete Response Letter for Empagliflozin [press release].  Ridgefield, Conn and Indianapolis, Ind: Boehringer Ingelheim Pharmaceuticals, Inc and Eli Lilly and Company; March 5, 2014. Accessed May 1, 2014 at http://us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2014/03-05-14-us-food-and-drug-administration-issues-complete-response-letter-empagliflozin.html

Additional reading

Merovci A, Solis-Herrara C, Daniele G, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest 2014. DOI: 10.1172/JCI70704.

Cefalu WT. Paradoxical insights into whole body metabolic adaptations following SGLT2 inhibition. J Clin Invest. 2014; DOI: 10.1172/JCI74297.