Type 2 diabetes mellitus (T2DM) is a disease of hyperglycemia with a complex pathology. At its core, insulin resistance with some degree of insulin deficiency is noted. Elevated levels of endogenous glucose production (EGP) in conjunction with hepatic insulin resistance, lowered levels of insulin-stimulated glucose uptake in skeletal muscle, and impaired insulin-mediated suppression of peripheral free fatty acid levels are often documented.¹

There are now many medication classes to treat T2DM, and each affect these pathophysiological abnormalities in unique ways. Much research has been completed on the newer medications to treat T2DM, including sodium glucose cotransporter-2 inhibitors (SGLT2i). By blocking the SGLT2 receptor, SGLT2i's were thought at first to be simple glucodiuretics, with documented urinary glucose excretion of 50-100 g/day more than baseline.² Since then, the direct effect on the kidneys has been confirmed, but indirect effects on the kidneys, and the indirect effects on many other aspects of metabolism have been documented. As their use expands into both diabetes and non-diabetes populations with cardiovascular disease (CVD), chronic kidney disease (CKD), and/or heart failure, the mechanisms underlying their metabolic effects continue to be of interest.

EGP is Increased by SGLT2i's

In humans, Merovci/Solis-Herrera et al. and Ferrannini et al. first published data exploring the mechanisms of how SGLT2i's lower plasma glucose.^2,3 Merovci/Solis-Herrera et al. studied 18 T2DM men (n=12 dapagliflozin 10 mg daily /6 matching placebo) before and after 2 weeks treatment. Despite a lower plasma glucose from increased glucose urinary excretion, dapagliflozin, as measured by glucose tracers, paradoxically increased EGP.² For perspective, with all other classes of T2DM medications, EGP closely follows the change in fasting plasma glucose levels. Ferranini et al. found a similar paradoxical EGP increase after 28 days of empagliflozin treatment when a 5-hour meal tolerance test was performed.² Subsequently, increases in glucagon, decreases in insulin secretion, and higher free fatty acid levels were thought to fully explain this finding^2,3 but further investigation has revealed that other mechanisms involving a renohepatic axis are likely involved.^4-6

Overview of Clinical Trial and Euglycemic Hyperinsulinemic Clamp (EHC) Results

The trial by Op den Camp et al.⁷ further explores the mechanisms of how 5-weeks treatment with dapagliflozin affects metabolic mechanisms of action and caloric expenditure. Twenty-four T2DM subjects (mean age=64, A1C= 6.9%, body mass index [BMI]=28.1kg/m², estimated glomerular filtration rate [eGFR]=141 mL/minute) were included in the double-blind, randomized, placebo-controlled crossover study with a 2-step EHC to explore hepatic and peripheral insulin sensitivity, and uniquely, measurement with a direct calorimetry chamber, the gold standard for caloric expenditure.

The EHC is the gold standard for measurement of insulin sensitivity. Most EHC studies have found that insulin sensitivity improves with SGT2i use.^2,3 Op den Camp et al.⁷ did not document a significant increase in insulin sensitivity, which may be due to the lower insulin doses used in the EHC. Also, it is thought that removal of glucotoxicity by SGLT2i is a major indirect pathway to improve insulin sensitivity, but the Op den Camp et al. study started with an A1C of 6.9%, leaving little room for further plasma glucose improvement. Blood pressure improvements and weight loss have been documented in most SGLT2i studies, though the documented weight loss is less than the expected weight change from urinary glucose excretion. This can be explained in part by the increase in EGP, which offsets urinary caloric loss. In fact, urinary glucose excretion is correlated with the increase in EGP as found by our group⁴ and Op den Camp et al.⁷

Op den Camp et al. similarly documented an increase in EGP with dapagliflozin in conjunction with increased non-esterfied fatty acids (NEFA), fatty acid oxidation, and glycerol levels as seen with other investigations.³ Of interest, EGP was suppressed significantly more versus placebo at both insulin infusion doses and documented improved suppression for NEFA and glycerol. This denotes an improvement in insulin-mediated suppression in the liver and adipocyte, despite basal increases in EGP and fatty acid products. Perhaps in agreement with these changes, intrahepatic lipid content, as measured by magnetic resonance spectroscopy was significantly reduced.

SGLT2i's Convert Back to Fasting Metabolic Profile Sooner than Placebo

The weight loss reported (-1.26kg) was accompanied by no change in 24-hour energy expenditure reinforcing that urinary glucose loss is the major mechanism of caloric loss. An increase in fatty acid oxidation and a decrease in carbohydrate oxidation was documented, like past studies by Ferrannini et al.³ In addition, over a 24-hour period versus placebo, the SGLT2i converted the respiratory exchange ratio (RER) back to a fasting profile sooner. This effect was seen first in the afternoon/evening resulting in a significant RER reduction during the daytime but was most marked overnight. Practically, we can say that dapagliflozin converted the subject back toward a mild caloric restriction or intermittent fasting state sooner than placebo.

The definition of intermittent fasting is still not well defined, though some extended period without substantial caloric intake is implied. Importantly, the benefits of intermittent fasting beyond weight loss are not well documented, but have been hypothesized to reduce oxidative stress, provide ketones as an improved source of fuel, and reset the circadian rhythm for improved energy metabolism.⁸ SGLT2i's clearly have documented less oxidative stress and are well known to increase ketones.^9,10 Mild continuous caloric restriction may provide similar benefits.¹¹ A recent Cochrane review found no cardiovascular outcome data to report on intermittent fasting¹² and little evidence exists for improved renal outcomes from intermittent fasting, unlike the well documented cardiovascular and renal outcome data for SGLT2i's.

For cardiologists, this study should add to the complex potential mechanisms of how an SGLT2i may be beneficial to a T2DM patient at high risk of CVD, including their benefits on all types of heart failure.

References

1. DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009;58:773-95.  
2. Merovci A, Solis-Herrera C, Daniele G, et al. Dapaglflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest 2014;124:509-14.
3. Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter-2 inhibition in type 2 diabetes. J Clin Invest 2014;124:499-508.
4. Solis-Herrera C, Daniele G, Alatrach M, et al. Increase in endogenous glucose production with SGLT2 inhibition is unchanged by renal denervation and correlates strongly with the increase in urinary glucose excretion. Diabetes Care 2020;43:1065-69.
5. Daniele G, Solis-Herrera C, Dardano A, et al. Increase in endogenous glucose production with SGLT2 inhibition is attenuated in individuals who underwent kidney transplantation and bilateral native nephrectomy. Diabetologia 2020;63:2423-33.
6. Alatrach M, Laichuthai N, Martinez R, et al. Evidence against an important role of insulin and glucagon concentrations in the increase in EGP caused by SGLT2 inhibitors. Diabetes 2020;69:681-88.
7. Op den Camp YJM, de Ligt M, Dautzenberg B, et al. Effects of the SGLT2 inhibitor dapagliflozin on energy metabolism in patients with type 2 diabetes: a randomized, double-blind crossover trial. Diabetes Care 2021;44:1334-43.
8. Dong TA, Sandesara PB, Dhindsa DS, et al. Intermittent fasting: a heart healthy dietary pattern? Am J Med 2020;133:901-07.
9. Li C, Zhang J, Xue M, et al. SGLT2 inhibition with empagliflozin attenuates myocardial oxidative stress and fibrosis in diabetic mice heart. Cardiovasc Diabetol 2019;18:15.
10. Al Jabori H, Daniele G, Adams J, et al. Determinants of increase ketone concentration during SGLT2 inhibition in NGT, IFG, and T2DM patients. Diabetes Obes Metab 2017;19:809-13.
11. Schübel R, Nattenmüller J, Sookthai D, et al. Effects of intermittent and continuous calorie restriction on bodyweight and metabolism over 50 wk: a randomized controlled trial. Am J Clin Nutr 2018;108:933-45.
12. Allaf M, Elghazaly H, Mohamed OG, et al. Intermittent fasting for the prevention of cardiovascular disease. Cochrane Database Syst Rev 2021;1:CD013496.

Clinical Topics: Cardiovascular Care Team, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Lipid Metabolism, Acute Heart Failure, Diet, Stress, Diabetes and Cardiometabolic Disease

Keywords: Fatty Acids, Nonesterified, Glucagon, Insulin Resistance, Fasting, Diabetes Mellitus, Type 2, Body Mass Index, Blood Glucose, Glycerol, Sodium-Glucose Transporter 2 Inhibitors, Cross-Over Studies, Glycated Hemoglobin A, Insulin, Insulin Secretion, Sodium-Glucose Transporter 2, Glucose, Caloric Restriction, Glomerular Filtration Rate, Weight Loss, Metabolome, Cardiovascular Diseases, Circadian Rhythm, Fatty Acids, Double-Blind Method, Ketones, Health Expenditures, Blood Pressure, Hyperglycemia, Liver, Muscle, Skeletal, Energy Metabolism, Heart Failure, Adipocytes, Oxidative Stress, Renal Insufficiency, Chronic, Magnetic Resonance Spectroscopy, Calorimetry, Reference Standards

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