This article is more than 5 years old. Information may no longer be current.
Dapagliflozin effects may lead to increased ketone production
Click Here to Manage Email Alerts
Insulin sensitivity and glucagon-to-insulin ratio were increased in adults with type 2 diabetes after treatment with dapagliflozin, an SGLT2 inhibitor, study data show.
These changes may provide the metabolic basis for increased ketone production, according to the researchers.
“This study demonstrates that this novel class of drugs exerts many unexpected metabolic effects on glucose, fat and energy metabolism, which require further study,” Muhammad Abdul-Ghani, MD, PhD, professor of medicine at the diabetes division, University of Texas Health Science Center at San Antonio in Texas, told Endocrine Today.
Abdul-Ghani and colleagues evaluated 18 adults with type 2 diabetes randomly assigned to dapagliflozin (Farxiga, AstraZeneca; n = 9) or placebo (n = 9) to determine the effect of dapagliflozin on mitochondrial adenosine triphosphate (ATP) synthesis and rates of substrate oxidation and ketone body production.
An insulin clamp was performed with titrated glucose, indirect calorimetry and muscle biopsies before treatment and 2 weeks after treatment.
In the dapagliflozin group, whole-body insulin-stimulated tissue glucose disposal was significantly increased from baseline and compared with the placebo group (P < .01 for both). After dapagliflozin treatment, glucose oxidation decreased (P < .001), insulin-stimulated nonoxidative glucose disposal increased (P < .001 vs. baseline and P < .01 vs. placebo) and the basal rate of liquid oxidation significantly increased (P < .05). Fasting plasma ketone concentration increased fourfold with dapagliflozin from baseline and compared with placebo (P < .01 for both).
Dapagliflozin increased the basal rate of endogenous glucose production (P < .01 vs. baseline and placebo) and correlated with a significant decrease in fasting plasma insulin (P < .05) and an increase in fasting plasma glucagon (P < .05).
dapagliflozin.
“The increase in fat oxidation is going to have positive effects on glucose and energy metabolism and could explain some of the effects of this class of drugs, like improving insulin sensitivity and beta-cell function, while the drug does not directly affect the liver, skeletal muscle and beta cell,” Abdul-Ghani told Endocrine Today. “The increase in ketone production is not an adverse event which may occur in some patients, but it is part of the mechanism of drug action. In some extreme conditions (eg, reduction in insulin dose, stress, etc.) overproduction of ketones could be detrimental and cause ketoacidosis, which has been reported in association with SGLT2 [inhibitor] use. Thus, clinicians should be aware of these conditions, which may exacerbate ketone production in patients treated with SGLT2 inhibitors. Nonetheless, the increase in plasma ketone concentration has been suggested to have additional positive actions, such as cardioprotection.” – by Amber Cox
For more information:
Muhammad Abdul-Ghani, MD, PhD, can be reached at abdulghani@uthscsa.edu.
Disclosure: Abdul-Ghani reports no relevant financial disclosures. Please see the full study for a list of all other authors’ relevant financial disclosures.
Click Here to Manage Email Alerts