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Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients
Open accessAbstract
BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glycemia by enhancing urinary glucose excretion. The physiologic response to pharmacologically induced acute or chronic glycosuria has not been investigated in human diabetes. METHODS: We evaluated 66 patients with type 2 diabetes (62 ± 7 years, BMI = 31.6 ± 4.6 kg/m(2), HbA1c = 55 ± 8 mmol/mol, mean ± SD) at baseline, after a single dose, and following 4-week treatment with empagliflozin (25 mg). At each time point, patients received a mixed meal coupled with dual-tracer glucose administration and indirect calorimetry. RESULTS: Both single-dose and chronic empagliflozin treatment caused glycosuria during fasting (median, 7.8 [interquartile range {IQR}, 4.4] g/3 hours and 9.2 [IQR, 5.2] g/3 hours) and after meal ingestion (median, 29.0 [IQR, 12.5] g/5 hours and 28.2 [IQR, 15.4] g/5 hours). After 3 hours of fasting, endogenous glucose production (EGP) was increased 25%, while glycemia was 0.9 ± 0.7 mmol/l lower (P < 0.0001 vs. baseline). After meal ingestion, glucose and insulin AUC decreased, whereas the glucagon response increased (all P < 0.001). While oral glucose appearance was unchanged, EGP was increased (median, 40 [IQR, 14] g and 37 [IQR, 11] g vs. 34 [IQR, 11] g, both P < 0.01). Tissue glucose disposal was reduced (median, 75 [IQR, 16] g and 70 [IQR, 21] g vs. 93 [IQR, 18] g, P < 0.0001), due to a decrease in both glucose oxidation and nonoxidative glucose disposal, with a concomitant rise in lipid oxidation after chronic administration (all P < 0.01). β Cell glucose sensitivity increased (median, 55 [IQR, 35] pmol • min(-1) • m(-2) • mM(-1) and 55 [IQR, 39] pmol • min(-1) • m(-2) • mM(-1) vs. 44 [IQR, 32] pmol • min(-1) • m(-2) • mM(-1), P < 0.0001), and insulin sensitivity was improved. Resting energy expenditure rates and those after meal ingestion were unchanged. CONCLUSIONS: In patients with type 2 diabetes, empagliflozin-induced glycosuria improved β cell function and insulin sensitivity, despite the fall in insulin secretion and tissue glucose disposal and the rise in EGP after one dose, thereby lowering fasting and postprandial glycemia. Chronic dosing shifted substrate utilization from carbohydrate to lipid. Trial registration. ClinicalTrials.Gov NCT01248364 (EudraCT no. 2010-018708-99). Funding. This study was funded by Boehringer Ingelheim.
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“Previous RCTs reported that selective SGLT2 inhibitors, a new class of anti-diabetes drugs, have been shown to reduce body weight (1–3 kg reduction) in diabetic patients with and without obesity [99–102].”
From Long-Term Efficacy and Safety of Anti-Obesity Treatment: Where Do We Stand? (2021) · cites this paper as [99]
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“Increased gluconeogenesis and lipolysis are the normal physiological response to secure energy substrate availability for organs such as the brain, and to prevent episodes of hypoglycemia and maintain body energy supply.2 In accordance, a single dose of the SGLT2 inhibitor empagliflozin led to a reduction in insulin s…”
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BackgroundInfluentialEfficacy and safety of empagliflozin for type 2 diabetes: a systematic review and meta‐analysis
Liakos, A., Karagiannis, T., Athanasiadou, E. A., Sarigianni, M., Mainou, M., Papatheodorou, K., Bekiari, E., & Τσάπας, Α. (2014) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12307 · Cited by 218
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“In patients with type 2 diabetes, treatment with canagliflozin at a dose of 300 mg/day increases mean daily UGE by approximately 90 g/day which is sustained at the same level throughout the duration of treatment (9) without directly altering energy expenditure (10,11) or central pathways controlling energy intake and…”
Dapagliflozin Enhances Fat Oxidation and Ketone Production in Patients With Type 2 Diabetes
Daniele, G., Xiong, J., Solis‐Herrera, C., Merovci, A., Eldor, R., Tripathy, D., DeFronzo, R. A., Norton, L., & Abdul‐Ghani, M. A. (2016) · Diabetes Care · doi:10.2337/dc15-2688 · Cited by 215
“Because SGLT2i increase glucagon secretion (3,5), it is not surprising that a reduction in the insulin dose might result in ketoacidosis.”
BackgroundGlucagon Receptor Signaling and Glucagon Resistance
Janah, L., Kjeldsen, S. A. S., Galsgaard, K. D., Winther‐Sørensen, M., Stojanovska, E., Pedersen, J., Knop, F. K., Holst, J. J., & Albrechtsen, N. J. W. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20133314 · Cited by 221
“5 pmol/L) [65,66], and although some have argued for a direct role of SGLT-2 on the alpha cells [67–70], current evidence, which includes the results of glucose clamping, seems to point toward an indirect mechanism by which SGLT-2 inhibition increases renal glucosuria, resulting in significant lowering of blood glucos…”
Backgroundvan Baar, M. J. B., van Ruiten, C. C., Muskiet, M. H. A., van Bloemendaal, L., IJzerman, R. G., & van Raalte, D. H. (2018) · Diabetes Care · doi:10.2337/dc18-0588 · Cited by 208
“Since SGLT2is do not alter resting or postprandial energy expenditure (14), the discrepancy between expected and observed weight loss implies that caloric intake is increased.”
BackgroundGlycemic Variability and Oxidative Stress: A Link between Diabetes and Cardiovascular Disease?
Saisho, Y. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms151018381 · Cited by 204
“secretion [126,127].”
Combination therapy with GLP ‐1 receptor agonist and SGLT2 inhibitor
DeFronzo, R. A. (2017) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.12982 · Cited by 192
Lee, P. C., Ganguly, S., & Goh, S. ‐. (2018) · Obesity Reviews · doi:10.1111/obr.12755 · Cited by 189
“noted a 13% increase in energy intake in patients treated with SGLT2 inhibitors (54).”
BackgroundUse of SGLT2 inhibitors in type 2 diabetes: weighing the risks and benefits
Lupsa, B. C., & Inzucchi, S. E. (2018) · Diabetologia · doi:10.1007/s00125-018-4663-6 · Cited by 200
Marchisello, S., Pino, A. D., Scicali, R., Urbano, F., Piro, S., Purrello, F., & Rabuazzo, A. M. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20081948 · Cited by 202
“The negative energy balance derived from glucose urinary excretion and from the increased glucagon/insulin ratio that promotes substrate utilization shift from carbohydrates to lipids may explain the beneficial role of SGLT2 inhibitors in NAFLD [249,251]; the weight loss and the increased”
BackgroundThe current role of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes mellitus management
Xu, B., Li, S., Kang, B., & Zhou, J. (2022) · Cardiovascular Diabetology · doi:10.1186/s12933-022-01512-w · Cited by 205
“SGLT2 inhibitor-induced glucosuria improved beta-cell function and insulin sensitivity, decreased tissue glucose disposal and increased EGP following administration, thereby reducing fasting and postprandial glycemic [35].”
BackgroundIns and outs of the TCA cycle: the central role of anaplerosis
Inigo, M., Deja, S., & Burgess, S. C. (2021) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-120420-025558 · Cited by 189
Koepsell, H. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.10.017 · Cited by 189
Anti-Obesity Drugs: Long-Term Efficacy and Safety: An Updated Review
Tak, Y. J., & Lee, S. Y. (2020) · The World Journal of Men s Health · doi:10.5534/wjmh.200010 · Cited by 198
“However, in previous clinical studies with diabetic patients, only 2–3 kg weight loss was achieved with such agents; this was attributed to compensatory hyperphagia/increased appetite [75].”
Pathophysiological Association between Diabetes Mellitus and Endothelial Dysfunction
Maruhashi, T., & Higashi, Y. (2021) · Antioxidants · doi:10.3390/antiox10081306 · Cited by 203
Uric acid and the cardio‐renal effects of SGLT2 inhibitors
Bailey, C. J. (2019) · Diabetes Obesity and Metabolism · doi:10.1111/dom.13670 · Cited by 187
“The CV effects emerge too quickly to be explained by decreased body weight, improved insulin sensitivity or reduced atherosclerosis.(13) Haemodynamic effects consequent to the osmotic diuresis, such as lowered blood pressure and decreased intra-vascular volume, are anticipated to play a role in CV and renal effects,(1…”
BackgroundAnti-diabetic drugs and weight loss in patients with type 2 diabetes
Lazzaroni, E., Ben Nasr, M., Loretelli, C., Pastore, I., Plebani, L., Lunati, M. E., Vallone, L., Bolla, A. M., Rossi, A., Montefusco, L., et al. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105782 · Cited by 182
“Pharmacological blockade of renal glucose reabsorption reduces fasting and postprandial glycemia both acutely and chronically without causing hypoglycemia, with improvement of both β cell function and insulin sensitivity [34].”
BackgroundFerrannini, E., Baldi, S., Frascerra, S., Astiarraga, B., Barsotti, E., Clerico, A., & Muscelli, E. (2017) · Diabetes Care · doi:10.2337/dc16-2724 · Cited by 190
“cose disposal (2), increased hepatic/ renal extraction (to support the augmentation of gluconeogenic glucose production [2]), and increased renal excretion, in relative proportions that only a combined catheterization/tracer study could quantify.”
BackgroundSelf-citationSotagliflozin, the first dual SGLT inhibitor: current outlook and perspectives
CEFALO, C. M. A., Cinti, F., Moffa, S., Impronta, F., Sorice, G. P., Mezza, T., Pontecorvi, A., & Giaccari, A. (2019) · Cardiovascular Diabetology · doi:10.1186/s12933-019-0828-y · Cited by 188
Extraglycemic Effects of SGLT2 Inhibitors: A Review of the Evidence
Bonora, B. M., Avogaro, A., & Fadini, G. P. (2020) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s233538 · Cited by 199
“61 Moreover, some studies have suggested that SGLT2i may exert a direct stimulatory effect on alfa cells, 62,63 although this fi nding is controversial and has not been consistently replicated in all studies.”
Euglycemic diabetic ketoacidosis
Barski, L., Eshkoli, T., Brandstaetter, E., & Jotkowitz, A. (2019) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2019.03.014 · Cited by 176
Shiba, K., Tsuchiya, K., Komiya, C., Miyachi, Y., Mori, K., Shimazu, N., Yamaguchi, S., Ogasawara, N., Katoh, M., Itoh, M., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-19658-7 · Cited by 177
Renal glucose metabolism in normal physiological conditions and in diabetes
Alsahli, M., & Gerich, J. E. (2017) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2017.07.033 · Cited by 173
Adingupu, D. D., Göpel, S., Grönros, J., Behrendt, M., Soták, M., Miliotis, T., Dahlqvist, U., Gan, L., & Jönsson‐Rylander, A. (2019) · Cardiovascular Diabetology · doi:10.1186/s12933-019-0820-6 · Cited by 176
“SGLT2 inhibitors also mediates a metabolic switch from glucose to lipid utilization [68], and given the bi-directional relationship between fatty liver and CV disease [3], it is plausible that the reduction in hepatic triglyceride we observed in our study contributed in part to the improvement in cardiac contractile f…”
BackgroundByrne, N. J., Parajuli, N., Levasseur, J. L., Boisvenue, J., Beker, D. L., Masson, G., Fedak, P. W. M., Verma, S., & Dyck, J. R. B. (2017) · JACC Basic to Translational Science · doi:10.1016/j.jacbts.2017.07.003 · Cited by 177
“Although it has also been suggested that the glucose-lowering effects of empagliflozin may reduce the cardiac effects of glucotoxicity (19,20), our data suggest that empagliflozin has cardioprotective benefits even in the absence of elevated blood glucose.”
BackgroundSGLT2 inhibition and kidney protection
Nespoux, J., & Vallon, V. (2018) · Clinical Science · doi:10.1042/cs20171298 · Cited by 182
“SGLT2 inhibitors do not increase the hypoglycemia risk due the intact metabolic counter regulation, including up-regulation of hepatic gluconeogenesis [36,37].”
BackgroundYang, X., Liu, Q., Li, Y., Tang, Q., Wu, T., Chen, L., Pu, S., Zhao, Y., Zhang, G., Huang, C., et al. (2020) · Adipocyte · doi:10.1080/21623945.2020.1807850 · Cited by 181
“Previous researches have demonstrated that SGLT2 inhibition results in a progressive shift to enhanced usage of fat [43,44].”
BackgroundObesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease?
Huttasch, M., Roden, M., & Kahl, S. (2024) · Metabolism · doi:10.1016/j.metabol.2024.155937 · Cited by 169
Sodium—Glucose cotransporter inhibitors and oxidative stress: An update
Yaribeygi, H., Atkin, S. L., Butler, A. E., & Sahebkar, A. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.26760 · Cited by 167
Wilding, J. P. H. (2014) · Metabolism · doi:10.1016/j.metabol.2014.06.018 · Cited by 176
“Interestingly, 2 recent studies [75,76] have shown that SGLT2 inhibition decreases plasma insulin secretion and increases”
BackgroundInfluentialMizuno, M., Kuno, A., Yano, T., Miki, T., Oshima, H., Sato, T., Nakata, K., Kimura, Y., Tanno, M., & Miura, T. (2018) · Physiological Reports · doi:10.14814/phy2.13741 · Cited by 172
“Administration of an SGLT2 inhibitor has been reported to increase the plasma level of free fatty acid (FFA) in patients with type 2 diabetes (Ferrannini et al. 2014) and in a high fat-fed rat model (Yokono et al.”
BackgroundIannantuoni, F., M. de Marañon, A., Diaz-Morales, N., Falcon, R., Bañuls, C., Abad-Jimenez, Z., Victor, V. M., Hernandez-Mijares, A., & Rovira-Llopis, S. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8111814 · Cited by 166
“In addition to their antihyperglycaemic effects, iSGLT2s have been shown to improve tissue insulin sensitivity [12,13], increase glucagon secretion by alpha cells in the pancreas [14], prevent obesity by reducing body weight [15], and decrease blood pressure [16].”
BackgroundPieber, T. R., Famulla, S., Eilbracht, J., Cescutti, J., Soleymanlou, N., Johansen, O. E., Woerle, H. J., Broedl, U. C., & Kaspers, S. (2015) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12494 · Cited by 167
“Small increases in mean fasting levels of the ketone body β-hydroxybutyrate were observed with empagliflozin, probably reflecting glucose and calorie loss and a substrate shift from glucose to lipid utilization associated with the mode of action of empagliflozin [24].”
BackgroundSelf-citationRenal sodium-glucose cotransporter inhibition in the management of type 2 diabetes mellitus
Abdul‐Ghani, M. A., Norton, L., & DeFronzo, R. A. (2015) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00267.2015 · Cited by 172
“The increase in 528 fasting plasma glucagon concentration observed in T2DM individuals treated with SGLT2i 529 (13,30,58) would be expected to increase HMGS activity, causing an increase in ketone 530 production.”
BackgroundResultInfluentialMarx, N., & McGuire, D. K. (2016) · European Heart Journal · doi:10.1093/eurheartj/ehw110 · Cited by 166
Gaborit, B., Ancel, P., Abdullah, A., Maurice, F., Abdesselam, I., Calen, A., Soghomonian, A., Houssays, M., Varlet, I., Eisinger, M. J., et al. (2021) · Cardiovascular Diabetology · doi:10.1186/s12933-021-01237-2 · Cited by 174
Euglycemic diabetic ketoacidosis: A missed diagnosis
Nasa, P., CHAUDHARY, S. K., Shrivastava, P. K., & Singh, A. (2021) · World Journal of Diabetes · doi:10.4239/wjd.v12.i5.514 · Cited by 180
Metadata
- Authors
- Ferrannini, E., Muscelli, E., Frascerra, S., Baldi, S., Mari, A., Heise, T., Broedl, U. C., & Woerle, H.-J.
- Affiliations
- University of Pisa (IT)
- National Research Council (IT)
- Profil Institute for Metabolic Research (DE)
- Boehringer Ingelheim (Germany) (DE)
- Corresponding author
- Ferrannini, Ele
- Venue
- Journal of Clinical Investigation
- Published
- 2014-01-27
- Volume
- 124
- Issue
- 2
- Pages
- 499-508
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3904627
- OpenAlex
- W2157405334
- Cited by
- 1,134
- References
- 45
- Citations by year
- 2026: 55 · 2025: 68 · 2024: 80 · 2023: 81 · 2022: 92 · 2021: 117 · 2020: 106 · 2019: 103 · 2018: 97 · 2017: 90 · 2016: 121 · 2015: 83 · 2014: 39
- FWCI
- 89.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Funders
- American Diabetes Association
- Bristol-Myers Squibb
- Eli Lilly and Company
- AstraZeneca
- Sanofi
- Novo Nordisk
- Astellas Pharma
- Daiichi Sankyo Europe
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- SGLT2 inhibitors, empagliflozin, type 2 diabetes, glycosuria, endogenous glucose production, glucose oxidation, nonoxidative glucose disposal, lipid oxidation, beta-cell glucose sensitivity, glucagon response, insulin response, glucose metabolism, indirect calorimetry, mixed meal tolerance, urinary glucose excretion, glucose homeostasis
- MeSH terms
- Sodium-Glucose Transporter 2 Inhibitors, Aged, Benzhydryl Compounds, Blood Glucose, Calorimetry, Diabetes Mellitus, Type 2, Female, Glucose, Glucosides, Glycosuria, Glycated Hemoglobin, Humans, Insulin, Male, Metformin, Middle Aged, Oxygen, Body Mass Index, Postprandial Period, Area Under Curve, Insulin-Secreting Cells, Sodium-Glucose Transporter 2
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