The pharmacokinetics and pharmacodynamics of SGLT2 inhibitors for type 2 diabetes mellitus: the latest developments

ABSTRACT

Introduction: Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder associated with high cardiovascular (CV) risk. Some of the therapeutic strategies are contraindicated in patients with concomitant heart disease. However, the newest antidiabetic medications, sodium-glucose cotransporter 2 (SGLT2) inhibitors, have shown to significantly reduce CV mortality and heart failure (HF) hospitalizations. The mechanism behind these surprising cardiac benefits remains unclear.

Areas covered: This article reviews the pharmacokinetic, pharmacodynamics, efficacy, and safety data for the different SGLT2 inhibitors. Specific attention is devoted to the postulated mechanisms of action for their benefit. The therapeutic efficacy and potential use in different indications outside T2DM such as HF, T1DM, and renal disease are also discussed.

Expert opinion: SGLT2 inhibitors have an excellent pharmacokinetic and pharmacodynamic profile. Importantly, SGLT2 inhibitors are a safe and efficacious treatment option for T2DM. Given their cardiac benefits (reduction in HF and death) and the low incidence of adverse events, SGLT2 inhibitors are being currently studied as a treatment for HF also in nondiabetic individuals. These agents seem to represent a shift in the treatment of HF patients regardless their glycemic profile.

KEYWORDS:

• Canagliflozin
• dapagliflozin
• empagliflozin
• heart failure
• pharmacokinetics
• pharmacodynamics
• SGLT2 inhibitors
• type 2 diabetes mellitus

Article highlights

• Type 2 diabetes mellitus (T2DM) increases cardiovascular risk.

• Managing patients with already established heart disease and T2DM is challenging since some of the antidiabetic drugs are contraindicated in such patients.

• Sodium-glucose cotransporter 2 (SGLT2) inhibitors, by blocking renal reabsorption of glucose, are safe and well-tolerated agents to treat diabetic patients.

• SGLT2 inhibitors have significantly shown to reduce mortality and HF hospitalizations in T2DM patients and therefore, they may represent an alternative in these individuals.

• These new drugs also slow down progression of kidney disease, which is a condition frequently associated with diabetes.

• The mechanism behind these surprising findings remains unclear (myocardial ketone utilization? sodium-hydrogen exchanger inhibition? lowering blood pressure and arterial stiffness? diuretic effect?).

This box summarizes key points contained in the article.

Declaration of interest

J Badimon has been awarded an Investigator-Initiated Grant funded by Boehringer-Ingelheim to investigate the mechanism of action of the cardiac benefits of empagliflozin. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.