# Ketones, Muscle Metabolism, and SGLT2 Inhibitors

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2024 · $25,884

## Abstract

PROJECT SUMMARY/ABSTRACT
Heart failure (HF) affects 6.5 million individuals in the US (87). Diabetes and HF frequently occur
together and each disorder increases the risk for the other. Recent trials (9-16) have
demonstrated that SGLT2 inhibitors (SGLT2i) reduce hospitalization for heart failure and
cardiovascular (CV) mortality. However, the mechanism(s) via which the SGLT2i benefit heart
failure remain to be determined. Following SGLT2i therapy the plasma ketone concentration
rises. Ketones are avidly taken up by the myocardium and, when oxidized, generate more ATP
per molecule of oxygen compared to glucose and fatty acids. Therefore, the SGLT2i-induced rise
in plasma ketones has been suggested to explain the drug’s beneficial effect on the heart. In
Protocol I of the present grant we will examine in type 2 diabetic subjects with HF and reduced
ejection fraction the effect of three infusion rates of beta-hydroxybutyrate (designed to span the
physiologic and pharmacologic range of plasma ketone concentrations) on: (1) LV systolic and
diastolic function using cardiac MRI; (2) myocardial blood flow with PET/15O-H2O; (3) myocardial
glucose uptake with PET/18F-2-DOG ; (4) skeletal muscle glucose and ketone uptake. In Protocol
II we will examine the effect of 3 months of dapagliflozin, an SGLT2i, versus placebo on: (1) LV
systolic and diastolic function using cardiac MRI; (2) myocardial blood flow; (3) myocardial ketone
uptake with PET/11C--OH-B, (4) skeletal muscle glucose and ketone uptake in type 2 diabetic
subjects with HF and reduced ejection fraction. In Protocol III we examine whether inhibition of
the dapagliflozin-induced rise in plasma ketone concentration with acipimox can block the
beneficial effects of dapagliflozin on myocardial function and blood flow. Acipimox, an inhibitor of
lipolysis, reduces the plasma ketone concentration to <0.02 mM and has no other known
metabolic effects.

## Key facts

- **NIH application ID:** 11041199
- **Project number:** 3R01DK107680-08S1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** RALPH A DEFRONZO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $25,884
- **Award type:** 3
- **Project period:** 2016-07-15 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11041199

## Citation

> US National Institutes of Health, RePORTER application 11041199, Ketones, Muscle Metabolism, and SGLT2 Inhibitors (3R01DK107680-08S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11041199. Licensed CC0.

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