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Two studies examine metabolic adaptations to SGLT2 inhibitors
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Two studies published simultaneously this week in the Journal of Clinical Investigation examine the metabolic responses to two sodium-glucose cotransporter 2 inhibitors — empagliflozin and dapagliflozin — in patients with type 2 diabetes.
In the first study, patients who were administered dapagliflozin (Farxiga, Bristol-Myers Squibb/AstraZeneca) demonstrated glucosuria and significant reductions in fasting plasma glucose. This effect improved tissue sensitivity to insulin, resulting in glucotoxicity.
The endogenous glucose production (EGP) increased significantly after the beginning of dapagliflozin therapy and was accompanied by an increase in FPG concentration, according to researchers from the University of Texas Health Science Center in San Antonio.
Patients were randomly assigned to either dapagliflozin (n=12) or placebo (n=6) for 2 weeks, according to study data.
Dapagliflozin caused a significant increase in urinary glucose excretion to 78 g/day on day 2 and 91 g/day on day 3 (P<.0001), and this was maintained at day 14 (75 g/day), according to data.
Those in the placebo group displayed baseline urinary glucose excretion of 1 g/day, with no significant changes days 2, 3 and 14, according to data.
After 14 days of dapagliflozin, whole-body glucose disposal during the insulin clamp increased to 5.7 mg/kg/minute and remained unchanged in the placebo group (4.2 mg/kg/minute; P<.05 vs. baseline vs. placebo), according to data.
“Insulin-mediated tissue glucose disposal increased by approximately 18% after 2 weeks of dapgagliflozin treatment, while placebo-treated subjects had no change in insulin sensitivity,” researchers wrote.
In a related article, Ele Ferrannini, MD, PhD, of the department of clinical and experimental medicine at the University of Pisa School of Medicine in Italy, and colleagues demonstrated that empagliflozin (Boehringer Ingelheim and Eli Lilly and Company)-induced glycosuria improved beta-cell function and insulin sensitivity.
This effect occurred despite the reduction in insulin secretion and tissue glucose disposal, and a rise in EGP after one dose. This lowered fasting and postprandial glycemia, according to data.
The researchers examined 66 patients with type 2 diabetes (aged 62 years; BMI, 31.6; HbA1c, 7.2%) at baseline, after a single dose, and after a 4-week empagliflozin 25-mg treatment period.
They found that both single-dose and chronic empagliflozin treatment led to glycosuria during fasting (median, 7.8 g every 3 hours and 9.2 g every 3 hours, respectively) and after meal ingestion (median, 29 g every 5 hours and 28.2 g every 5 hours, respectively).
EGP increased 25% after 3 hours of fasting, whereas glycemia was 0.9 mmol/L lower (P<.0001) compared with baseline results.
Furthermore, glucose and insulin area under the curve levels decreased after meal consumption. However, the glucagon response increased (P<.001), researchers wrote. The EGP increased and oral glucose did not appear to change (P<.01).
In addition, tissue glucose disposal decreased due to a decrease in both glucose oxidation and nonoxidative glucose disposal (P<.0001), researchers wrote. This effect happened while a rise in lipid oxidation occurred after chronic administration (P<.01).
Moreover, beta-cell glucose sensitivity increased (P<.0001) and insulin sensitivity improved, researchers wrote.
In an accompanying commentary, William T. Cefalu, MD, of Pennington Biomedical Research Center in Baton Rouge, La., wrote that articles such as those cited here contribute to the literature and clinical medicine by providing a better appreciation of the independent effects of glucose on peripheral insulin action.
“Together, these studies provide new information on whole body metabolic adaptations to SGLT2 inhibition and lay the groundwork for additional research, particularly relating to the paradoxical rise in EGP,” Cefalu wrote.
For more information:
Cefalu WT. J Clin Invest. 2014; 124:485-487.
Ferrannini E. J Clin Invest. 2014; 124:499-508.
Merovci A. J Clin Invest. 2014; 124:509-514.
Disclosure: Ferrannini has served as an ad hoc consultant and occasional speaker for Boehringer Ingelheim, Merck, Sanofi, Eli Lilly and Company, Johnson and Johnson, Astellas, Daiichi Sankyo, Bristol-Myers Squibb/AstraZeneca and Novartis. Cefalu reports ties with Intarcia Therapeutics Inc., Shire, Novo Nordisk, Johnson and Johnson, GlaxoSmithKline, Lexicon Pharmaceuticals, MannKind Corporation and Sanofi-Aventis. For a complete list of relevant disclosures, see the full studies and commentary.
Perspective
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George Grunberger, MD, FACP, FACE
The studies investigating metabolic consequences of two different SGLT2 inhibitors in patients with type 2 diabetes published back-to-back in the February 2014 issue of Journal of Clinical Investigation provide sophisticated insights. The accompanying excellent editorial by Will Cefalu nicely summarizes both the appreciation of the well-done work by two very experienced groups of investigators (Ferrannini and colleagues; DeFronzo and colleagues) and the surprise at the paradoxical finding of increased endogenous glucose production in the face of glycosuria produced by these two agents (empagliflozin and dapagliflozin). Clearly, we have much to learn yet about the human response to drug-induced glycosuria and the clinical implications of this finding. The suggestion that seeing increased glucagon secretion (and subsequent enhanced EGP) in response to SGLT2 inhibitors should lead to clinical evaluation of combining those drugs with GLP-1 receptor agonists is ripe for investigations which could lead to a new paradigm in our approach to patients with type 2 diabetes.Click Here to Manage Email Alerts