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 reduce body weight by 1-3 kg in diabetic patients with and without obesity.
“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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“which glycosuria was measured directly in T2DM patients treated with empagliflozin (25 mg/day) (28).”
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The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure
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The Mechanisms and Therapeutic Potential of SGLT2 Inhibitors in Diabetes Mellitus
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“The higher the blood glucose level and GFR, the more glucose is filtered and can be excreted by SGLT2 inhibition (up to its transport maximum), thereby lowering blood glucose levels (13, 26, 27) (Figure 1c and 2).”
BackgroundUpdate on developments with SGLT2 inhibitors in the management of type 2 diabetes
Nauck, M. (2014) · Drug Design, Development and Therapy · doi:10.2147/dddt.s50773 · Cited by 343 · see citing works
“96 Recently published and independent studies using dapagliflozin and empagliflozin in patients with T2DM reported increased insulin sensitivity following SGLT2 inhibitor therapy, 97,98 and empagliflozin-induced UGE also improved beta-cell function.”
Long-Term Efficacy and Safety of Anti-Obesity Treatment: Where Do We Stand?
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Sodium-Glucose Co-transporters and Their Inhibition: Clinical Physiology
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“The improved b cell function documented in studies in patients with type 2 diabetes is most likely the result of the reduced glycemic burden (Ferrannini et al., 2014; DeFronzo et al., 2017; Polidori et al., 2014).”
BackgroundInfluentialSelf-citationDiabetic Ketoacidosis and Related Events in the Canagliflozin Type 2 Diabetes Clinical Program
Erondu, N., Desai, M. G., Ways, K., & Meininger, G. E. (2015) · Diabetes Care · doi:10.2337/dc15-1251 · Cited by 324 · see citing works
SGLT2 Inhibitors: A Review of Their Antidiabetic and Cardioprotective Effects
Tentolouris, A., Vlachakis, P., Tzeravini, E., Eleftheriadou, I., & Tentolouris, N. (2019) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph16162965 · Cited by 300 · see citing works
“SGLT2i do not have effect on resting or postprandial energy expenditure, hence, the difference between expected weight loss and observed weight loss implies gradual compensatory increase in caloric intake [76,77].”
BackgroundSGLT2 Protein Expression Is Increased in Human Diabetic Nephropathy
Wang, X. X., Levi, J., Luo, Y., Myakala, K., Herman‐Edelstein, M., Qiu, L., Wang, D., Peng, Y., Grenz, A., Lucia, S. M., et al. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.779520 · Cited by 307 · see citing works
Emerging role of SGLT-2 inhibitors for the treatment of obesity
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SGLT2 Inhibitors and Cardiovascular Risk: Lessons Learned From the EMPA-REG OUTCOME Study
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“(24) and empagliflozin (25) cause a ro-”
BackgroundInfluentialOelze, M. W., Kröller‐Schön, S., Welschof, P., Jansen, T., Hausding, M., Mikhed, Y., Stamm, P., Mader, M., Zinßius, E., Agdauletova, S., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0112394 · Cited by 293 · see citing works
“Along these lines SGLT2 inhibitors have been demonstrated to be effective in diabetes mellitus type II [35] and are anticipated to be also effective in type 1 diabetic patients.”
BackgroundRosenstock, J., Hansen, L., Zee, P., Li, Y., Cook, W., Hirshberg, B., & Iqbal, N. (2014) · Diabetes Care · doi:10.2337/dc14-1142 · Cited by 291 · see citing works
“Recent studies have shown that the glucosuric effect of SGLT2 inhibitors improves insulin sensitivity and b-cell function in individuals with type 2 diabetes (33,34).”
BackgroundHan, J. H., Oh, T. J., Lee, G., Maeng, H. J., Lee, D. H., Kim, K. M., Choi, S. H., Jang, H. C., Lee, H. S., Park, K. S., et al. (2017) · Diabetologia · doi:10.1007/s00125-016-4158-2 · Cited by 281 · see citing works
“Chronic treatment with SGLT2 inhibitors shifts substrate utilisation from carbohydrates to lipids [26].”
BackgroundResultHenry, R. R., Thakkar, P., Tong, C., Polidori, D., & Alba, M. (2015) · Diabetes Care · doi:10.2337/dc15-1730 · Cited by 286 · see citing works
Sodium-Glucose Cotransporter 2 Inhibitors Mechanisms of Action: A Review
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Islet α cells and glucagon--critical regulators of energy homeostasis
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Ketoacidosis associated with SGLT2 inhibitor treatment: analysis of FAERS data
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Sodium–glucose cotransporter type 2 inhibitors for the treatment of type 2 diabetes mellitus
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Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes
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Self-citationAn Overview of the Cardiorenal Protective Mechanisms of SGLT2 Inhibitors
Salvatore, T., Galiero, R., Caturano, A., Rinaldi, L., Martino, A. D., Albanese, G., Salvo, J. D., Epifani, R., Marfella, R., Docimo, G., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073651 · Cited by 266 · see citing works
Latva-Rasku, A., Honka, M.-J., Kullberg, J., Mononen, N., Lehtimäki, T., Saltevo, J., Kirjavainen, A. K., Saunavaara, V., Iozzo, P., Johansson, L., et al. (2019) · Diabetes Care · doi:10.2337/dc18-1569 · Cited by 253 · see citing works
“Except from reduced body weight, an alternative hypothesis explaining loss of liver fat is the metabolic substrate shift fromglucose to fatty acids (5,6,26) and possibly increased fatty acid oxidation in the liver presumed to be associated with reduced nighttime he-”
BackgroundMaack, C., Lehrke, M., Backs, J., Heinzel, F. R., Hulot, J., Marx, N., Paulus, W. J., Rossignol, P., Taegtmeyer, H., Bauersachs, J. K., et al. (2018) · European Heart Journal · doi:10.1093/eurheartj/ehy596 · Cited by 250 · see citing works
“In addition, SGLT2 inhibition increases endogenous glucose production, which partly compensates glucose excretion, preventing hypoglycaemia.(124,125) Through early diuretic and longer-term metabolic effects, SGLT2-inhibitors reduce body weight.”
BackgroundBrown, A. J. M., Gandy, S. J., McCrimmon, R. J., Houston, J. G., Struthers, A. D., & Lang, C. C. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehaa419 · Cited by 245 · see citing works
“Finally, SGLT2i-induced glycosuria has been shown to improve b cell function and insulin sensitivity and this improvement in insulin sensitivity could have mediated the LVM regression.(55,56) Insulin resistance is thought to contribute to changes in cardiac tissue seen in LVH.”
BackgroundStorgaard, H., Gluud, L. L., Bennett, C., Grøndahl, M. F. G., Christensen, M., Knop, F. K., & Vilsbøll, T. (2016) · PLoS ONE · doi:10.1371/journal.pone.0166125 · Cited by 240 · see citing works
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“plasma glucagon and endogenous glucose production in subjects with T2DM [33, 34].”
BackgroundSGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms
Osataphan, S. A., Macchi, C., Singhal, G., CHIMENE-WEISS, J. I., Sales, V., Kozuka, C., Dreyfuss, J. M., Pan, H., Tangcharoenpaisan, Y., Morningstar, J. E., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.123130 · Cited by 229 · see citing works
“SGLT2i treatment increases glucagon levels in humans with T2D, potentially via direct effects in α cells (5, 8, 28).”
BackgroundQiu, H., Novikov, A., & Vallon, V. (2017) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.2886 · Cited by 226 · see citing works
“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…”
BackgroundInfluentialSodium–Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal Glucose Transport
Mudaliar, S., Polidori, D., Zambrowicz, B., & Henry, R. R. (2015) · Diabetes Care · doi:10.2337/dc15-0642 · Cited by 225 · see citing works
“EGP increased after a single dose of canagliflozin in healthy subjects (14) and increased by ;17–25% after single and multiple doses of empagliflozin and dapagliflozin in patients with T2D (38,41).”
BackgroundInfluentialBrown, E. E., Wilding, J. P. H., Barber, T. M., Alam, U., & Cuthbertson, D. J. (2019) · Obesity Reviews · doi:10.1111/obr.12841 · Cited by 222 · see citing works
“Mathematical models based on studies of SGLT2i in patients with T2DM predict that energy intake after weight loss because of urinary glucose excretion (UGE) may exceed adaptions in energy expenditure, contributing to difficulties with sustained weight loss.(108,109) In one study, weight loss was less than a third of t…”
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 · see citing works
Polidori, D., Sanghvi, A., Seeley, R. J., & Hall, K. D. (2016) · Obesity · doi:10.1002/oby.21653 · Cited by 209 · see citing works
“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 · see citing works
“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 205 · see citing works
“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 201 · see citing works
“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 200 · see citing works
“secretion [126,127].”
Combination therapy with <scp>GLP</scp> ‐1 receptor agonist and <scp>SGLT2</scp> inhibitor
DeFronzo, R. A. (2017) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.12982 · Cited by 192 · see citing works
Lee, P. C., Ganguly, S., & Goh, S. ‐. (2018) · Obesity Reviews · doi:10.1111/obr.12755 · Cited by 189 · see citing works
“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 191 · see citing works
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 194 · see citing works
“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 192 · see citing works
“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 · see citing works
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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 190 · see citing works
“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 194 · see citing works
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 183 · see citing works
“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 · see citing works
“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 182 · see citing works
“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 180 · see citing works
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 177 · see citing works
“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 · see citing works
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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 · see citing works
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 173 · see citing works
“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 172 · see citing works
“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 172 · see citing works
“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 178 · see citing works
“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 · see citing works
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 · see citing works
Wilding, J. P. H. (2014) · Metabolism · doi:10.1016/j.metabol.2014.06.018 · Cited by 169 · see citing works
“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 169 · see citing works
“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 · see citing works
“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 · see citing works
“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 166 · see citing works
“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 165 · see citing works
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 169 · see citing works
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 165 · see citing works
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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