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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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BackgroundResultSodium–Glucose Cotransporter 2 Inhibitors: A Case Study in Translational Research
Beitelshees, A. L., Leslie, B. R., & Taylor, S. I. (2019) · Diabetes · doi:10.2337/dbi18-0006 · Cited by 73
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“The reduced risks of heart failure and cardiovascular mortality may be explained by the improvement of arrhythmia and myocardial function related to higher levels of glucagon (48-50).”
BackgroundSGLT2 inhibitors: are they safe?
Filippas-Ntekouan, S., Filippatos, T. D., & Elisaf, M. (2017) · Postgraduate Medicine · doi:10.1080/00325481.2018.1394152 · Cited by 72
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“In a fasting and postprandial state in T2DM patients, following administration of empagliflozin or dapagliflozin, paradoxical increase in endogenous glucose production was demonstrated [99].”
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“Secondly, by amelioration of glucotoxicity (achieved through the reduction in plasma glucose concentration secondary to glycosuria) leading to greater insulin sensitivity in peripheral tissues (adipose tissue and skeletal muscle) [20] and enhancement of beta-cell function, with improvements in the first and second pha…”
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Ndefo, U. A., Anidiobi, N. O., Basheer, E., & Eaton, A. (2015) · PubMed Central · Cited by 65
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“It has been demonstrated that two chemically unrelated SGLT2 blockers, dapagliflozin and empagliflozin, despite their glucose lowering effect, increase plasma glucagon levels and raise endogenous glucose production in diabetic subjects 23,24 .”
Chae, H., Augustin, R., Gatineau, E., Mayoux, E., Bensellam, M., Antoine, N., Khattab, F., Lai, B. K., Brusa, D., Stierstorfer, B., et al. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101071 · Cited by 64
“The potential causes of these metabolic responses are the SGLT2i-mediated increase in blood glucagon levels and decrease in blood insulin levels [3,8,10], but themechanisms by which gliflozins increase glucagonemia are highly contested [7,16e18].”
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“The SGLT2 inhibition generates a continuous glucose loss through the kidneys, mimicking a starvation situation, which ultimately increases FA and KB levels in DM patients [16,49].”
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“Consistent with this line of thinking, SGLT2i treatment has been reported to result in increased glucagon levels (5) and decreased insulin secretion (6), most likely mediated by decreased plasma glucose levels (7).”
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Ketones: the double-edged sword of SGLT2 inhibitors?
Lupsa, B. C., Kibbey, R. G., & Inzucchi, S. E. (2022) · Diabetologia · doi:10.1007/s00125-022-05815-1 · Cited by 68
“SGLT2 inhibitors are associated with a transient increase in circulating glucagon levels, which tend to normalise after a few weeks [68, 69].”
BackgroundDapagliflozin modulates glucagon secretion in an SGLT2-independent manner in murine alpha cells
Solini, A., Sebastiani, G., Nigi, L., Santini, E., Rossi, C., & Dotta, F. (2017) · Diabetes & Metabolism · doi:10.1016/j.diabet.2017.04.002 · Cited by 65
“These observations, initially made by two landmark clinical studies [3,4], have cast”
BackgroundSGLT2 inhibitors-induced electrolyte abnormalities: An analysis of the associated mechanisms
Filippatos, T. D., Tsimihodimos, V., Liamis, G. L., & Elisaf, M. (2017) · Diabetes & Metabolic Syndrome Clinical Research & Reviews · doi:10.1016/j.dsx.2017.08.003 · Cited by 62
Comorbidities in Heart Failure
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Mechanisms of Sodium–Glucose Cotransporter 2 Inhibition: Insights From Large-Scale Proteomics
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“persists as long as treatment continues and is reversed on stopping it (3,5,12).”
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“Adding DPP-4 inhibitors to SGLT2 inhibitors could suppress the production of endogenous glucose secondary to excess excretion of glucose from urine because they can inhibit glucagon and simulate insulin secretion.(2,3) Simultaneously used, SGLT2 inhibitors have been shown to enhance the effect of DPP-4 inhibitors by i…”
BackgroundBlood Sugar Regulation for Cardiovascular Health Promotion and Disease Prevention
Schwarz, P. E. H., Timpel, P., Harst, L., Greaves, C. J., Ali, M. K., Lambert, J. D., Weber, M. B., Almedawar, M. M., & Morawietz, H. (2018) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2018.07.081 · Cited by 66
The Limited Role of Glucagon for Ketogenesis During Fasting or in Response to SGLT2 Inhibition
Capozzi, M. E., Coch, R. W., Koech, J., Astapova, I. I., Wait, J. B., Encisco, S. E., Douros, J. D., EL, K. M., Finan, B., Sloop, K. W., et al. (2020) · Diabetes · doi:10.2337/db19-1216 · Cited by 65
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“Similar predictions come from mathematical models with canagliflozin [15] or empagliflozin [16], showing several-fold increases in calorie intake compared to the adaptation in energy expenditure.”
BackgroundResultOkamoto, A., Yokokawa, H., Sanada, H., & Naito, T. (2016) · Drugs in R&D · doi:10.1007/s40268-016-0137-9 · Cited by 59
“not depend on the amount of insulin secretion [19, 20].”
BackgroundCardiovascular Protection by Sodium Glucose Cotransporter 2 Inhibitors: Potential Mechanisms
Staels, B. (2017) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2017.05.013 · Cited by 59
“Additionally, a metabolic study in patients with T2DM confirmed that lowering elevated blood glucose levels with empagliflozin reduced glucose toxicity and improved b-cell function.(42) This study also demonstrated that insulin sensitivity of tissue glucose uptake was improved.”
BackgroundResultInfluentialMin, S. H., Yoon, J., Moon, S. J., Hahn, S., & Cho, Y. M. (2018) · Scientific Reports · doi:10.1038/s41598-018-22658-2 · Cited by 61
EMPA-REG OUTCOME: The Nephrologist's Point of View
Wanner, C. (2017) · The American Journal of Medicine · doi:10.1016/j.amjmed.2017.04.007 · Cited by 57
“In conclusion, the results from EMPAREG OUTCOME, CANTATA-SU, and the dapagliflozin renal study about renal protective outcomes are encouraging, and indicate that SGLT2 inhibitor agents offer a promising therapeutic option in the future management of patients with T2DM.”
BackgroundInfluentialLee, S. A., & Riella, L. V. (2024) · Kidney International Reports · doi:10.1016/j.ekir.2024.02.1435 · Cited by 65
“67,68 Because elevated insulin levels and insulin resistance can induce in fl ammation, mitochondrial dysfunction, mesangial proliferation, and dysfunction of podocytes and endothelial cells in kidneys, 69 the impact of SGLT2 inhibitors on insulin level and peripheral insulin sensitivity may offer a…”
BackgroundSeufert, J. (2015) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s90662 · Cited by 61
“12 Paradoxically, it has been demonstrated that there is increased glucose reabsorption despite elevated serum glucose levels in patients with T2DM.”
InfluentialPowell, D. R., Zambrowicz, B., Morrow, L., Beysen, C., Hompesch, M., Turner, S., Hellerstein, M. K., Banks, P. L., Strumph, P., & Lapuerta, P. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgz258 · Cited by 60
“Decreased glucose levels with SGLT2 inhibitors are offset by increased EGP, which is observed after single or multiple doses of dapagliflozin (41), empagliflozin (42), and canagliflozin (23,43).”
BackgroundSGLT2 inhibition: efficacy and safety in type 2 diabetes treatment
Scheen, A. J. (2015) · Expert Opinion on Drug Safety · doi:10.1517/14740338.2015.1100167 · Cited by 70
“[94] Although the underlying mechanism is still unclear [96], if confirmed, this adverse event will certainly limit the use of SGLT2 in patients with type 1 diabetes, a population in which these new agents have also the potential to improve glucose control as add-on to insulin therapy.”
BackgroundHypertension: Current trends and future perspectives
Hunter, P. G., Chapman, F. A., & Dhaun, N. (2021) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.14825 · Cited by 79
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“In a recently published randomized controlled study, the EMPAREG OUTCOME trial, empagliflozin improved cardiovascular outcome, including hospitalization for heart failure and all-cause mortality,2 and was associated with slower progression of kidney disease.8 In the CANVAS programme, another randomized controlled stud…”
BackgroundResultSodium–Glucose Cotransporter–2 (SGLT-2) Inhibitors and the Treatment of Type 2 Diabetes
Kramer, C. K., & Zinman, B. (2018) · Annual Review of Medicine · doi:10.1146/annurev-med-042017-094221 · Cited by 57
Interindividual Heterogeneity of SGLT2 Expression and Function in Human Pancreatic Islets
Saponaro, C., Mühlemann, M., Acosta-Montalvo, A., Piron, A., Gmyr, V., Delalleau, N., Moerman, E., Thévenet, J., Pasquetti, G., Coddeville, A., et al. (2020) · Diabetes · doi:10.2337/db19-0888 · Cited by 57
EMPA-REG OUTCOME: The Nephrologist's Point of View
Wanner, C. (2017) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2017.05.012 · Cited by 57
Hemodynamic Effects of Glucagon: A Literature Review
Petersen, K. M., Bøgevig, S., Holst, J. J., Knop, F. K., & Christensen, M. B. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-00050 · Cited by 68
“SGLT-2 inhibitors and sulfonylurea compounds may, under certain conditions, increase glucagon levels, however, within the physiological range (21, 33).”
Ritu, Sharma, P., Gupta, G., & Asati, V. (2023) · Bioorganic chemistry (Print) · doi:10.1016/j.bioorg.2023.106750 · Cited by 57
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“Previous studies have shown that SGLT2i may improve myocardial energy metabolism [9, 10], suppress inflammation [11], reduce oxidative stress [12], and prevent adverse cardiac remodeling [13, 14].”
BackgroundTakahara, M., Shiraiwa, T., Matsuoka, T., Katakami, N., & Shimomura, I. (2014) · Endocrine Journal · doi:10.1507/endocrj.ej14-0335 · Cited by 55
“A recent single-arm clinical study reported that β cell function, as well as insulin sensitivity, was improved after a 4-week treatment with an SGLT2 inhibitor in patients with type 2 diabetes mellitus [7].”
BackgroundThe renal effects of SGLT2 inhibitors and a mini-review of the literature
Andrianesis, V., Glykofridi, S., & Doupis, J. (2016) · Therapeutic Advances in Endocrinology and Metabolism · doi:10.1177/2042018816676239 · Cited by 56
“Due to their mechanism of action, SGLT2 inhibitors have a very low risk of hypoglycemia [Wilding et al. 2009; Ferrannini et al. 2014; Sarashina et al. 2013; Kaku et al. 2014; Wilding et al. 2013; Rosenstock et al. 2013; Ferrannini et al. 2013a; Kovacs et al. 2013].”
BackgroundKramer, C. K., Zinman, B., Choi, H., Connelly, P. W., & Retnakaran, R. R. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-2725 · Cited by 54
Cardiovascular protection in type 2 diabetes: Insights from recent outcome trials
Bailey, C. J., & Marx, N. (2018) · Diabetes Obesity and Metabolism · doi:10.1111/dom.13492 · Cited by 56
“but the reduction in glucotoxicity has been shown to reduce insulin resistance and improve β-cell responsiveness, the former effect being a potential contributor to reduced CV risk.(85) The weight reduction”
BackgroundEmpagliflozin: A Review of Its Use in Patients with Type 2 Diabetes Mellitus
Scott, L. J. (2014) · Drugs · doi:10.1007/s40265-014-0298-1 · Cited by 58
“Empagliflozin-induced glucosuria after single and multiple doses resulted in improvements in b-cell function and insulin sensitivity, with reductions in insulin secretion and tissue glucose disposal and increases in endogenous glucose production leading to reductions in fasting and postprandial glycaemia [15].”
BackgroundDeFronzo, R. A., CHILTON, R. J., Norton, L., Clarke, G., Ryder, R. E. J., & Abdul‐Ghani, M. A. (2016) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12652 · Cited by 53
MARTINEZ, R. A., Jobori, H. A., Ali, A. M., Adams, J. M., Abdul-Ghani, M. A., Triplitt, C. L., DeFronzo, R. A., & Cersósimo, E. (2018) · Diabetes · doi:10.2337/db17-1278 · Cited by 53
Novel approaches to restore beta cell function in prediabetes and type 2 diabetes
Salunkhe, V. A., Veluthakal, R., Kahn, S. E., & Thurmond, D. C. (2018) · Diabetologia · doi:10.1007/s00125-018-4658-3 · Cited by 63
“Studies in animals and humans suggest that this approach, by reducing chronic hyperglycaemia, may improve insulin sensitivity and beta cell function [14].”
Blonde, L., Belousova, L., Fainberg, U., Garcia‐Hernandez, P. A., Jain, S. M., Kaltoft, M. S., Mosenzon, O., Nafach, J., Palle, M. S., & Rea, R. (2020) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.13978 · Cited by 54
“Treatment with SGLT2is might be associated with elevations in plasma glucagon concentrations that could sustain endogenous glucose production, offsetting some of the glucose-lowering capacity of these agents.31 In the current trial, fasting glucagon declined in both treatment groups, which was surprising to observe in…”
ResultInfluentialMapping the metabolic reprogramming induced by sodium-glucose cotransporter 2 inhibition
Kogot‐Levin, A., Riahi, Y., Abramovich, I., Mosenzon, O., Agranovich, B., Kadosh, L., Schyr, R. B., Kleiman, D., Hinden, L., Cerasi, E., et al. (2023) · JCI Insight · doi:10.1172/jci.insight.164296 · Cited by 53
“Furthermore, in physiology, excess free fatty acid (FFA) delivery to insulin-sensitive tissues while fasting competes with glucose and causes insulin resistance, whereas treatment with SGLT2i is associated with improved insulin sensitivity (2, 15, 17).”
BackgroundKimura, T., Obata, A., Shimoda, M., Okauchi, S., Kanda‐Kimura, Y., Nogami, Y., Moriuchi, S., Hirukawa, H., Kohara, K., Nakanishi, S., et al. (2018) · Diabetes Obesity and Metabolism · doi:10.1111/dom.13400 · Cited by 52
“Plasma glucagon levels were elevated in all three Luseo groups (Figure 6A,B), as previously reported concerning an SGLT2 inhibitor.(43) It is possible that SGLT2 inhibition directly increased glucagon secretion from α-cells.”
ResultHsu, J., Wang, C., Su, M.-Y. M., Lin, L., & Yang, W. (2019) · Scientific Reports · doi:10.1038/s41598-019-51949-5 · Cited by 52
Ujjawal, A., Schreiber, B., & Verma, A. (2022) · Therapeutic Advances in Endocrinology and Metabolism · doi:10.1177/20420188221090001 · Cited by 53
Mechanistic View on the Effects of SGLT2 Inhibitors on Lipid Metabolism in Diabetic Milieu
Yaribeygi, H., Maleki, M., Reiner, Ž., Jamialahmadi, T., & Sahebkar, A. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11216544 · Cited by 56
Chin, K. L., Ofori‐Asenso, R., Hopper, I., von Lueder, T. G., Reid, C. M., Zoungas, S., Wang, B. H., & Liew, D. (2018) · Cardiovascular Research · doi:10.1093/cvr/cvy295 · Cited by 51
Sheu, W. H., Chan, S. P., Matawaran, B. J., Deerochanawong, C., Mithal, A., Chan, J. C. N., Suastika, K., Khoo, C. M., Nguyen, H. M., Ji, L., et al. (2020) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2019.0208 · Cited by 53
Scheen, A. J. (2016) · Diabetes & Metabolism · doi:10.1016/j.diabet.2015.12.005 · Cited by 50
SGLT2 Inhibitors in Chronic Kidney Disease: From Mechanisms to Clinical Practice
Škrabić, R., Kumrić, M., Vrdoljak, J., Rušić, D., Skrabic, I., Vilović, M., Martinović, D., Duplancic, V., Kurir, T. T., & Božić, J. (2022) · Biomedicines · doi:10.3390/biomedicines10102458 · Cited by 51
Min, S. H., Oh, T. J., Baek, S., Lee, D.-H., Kim, K. M., Moon, J. H., Choi, S. H., Park, K. S., Jang, H. C., & Lim, S. K. (2017) · Diabetes & Metabolism · doi:10.1016/j.diabet.2017.09.006 · Cited by 50
BAJAJ, H. S., Brown, R. E., Bhullar, L., Sohi, N., Kalra, S., & Aronson, R. (2018) · Diabetes & Metabolism · doi:10.1016/j.diabet.2018.08.001 · Cited by 53
Mazumdar, P., Kesuma, H. P., Lau, S.-E., Teo, C. H., & Harikrishna, J. A. (2019) · Trends in Food Science & Technology · doi:10.1016/j.tifs.2019.06.017 · Cited by 50
CHILTON, R. J. (2019) · Diabetes Obesity and Metabolism · doi:10.1111/dom.13854 · Cited by 52
ESTERLINE, R. L., Oscarsson, J., & Burns, J. M. (2020) · International review of neurobiology · doi:10.1016/bs.irn.2020.03.018 · Cited by 51
Kaneto, H., Obata, A., Kimura, T., Shimoda, M., Kinoshita, T., Matsuoka, T., & Kaku, K. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22063062 · Cited by 49
The Insulin:Glucagon Ratio and the Choice of Glucose-Lowering Drugs
Kalra, S., & Gupta, Y. (2016) · Diabetes Therapy · doi:10.1007/s13300-016-0160-4 · Cited by 49
“Similar results have been reported with dapagliflozin (Table 3) [27, 28].”
ResultIshihara, H., Yamaguchi, S., Nakao, I., Okitsu, A., & Asahina, S. (2016) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12745 · Cited by 49
Takebayashi, K., & Inukai, T. (2017) · Journal of Clinical Medicine Research · doi:10.14740/jocmr3112w · Cited by 49
SGLT2 inhibition and glucagon secretion in humans
Saponaro, C., Pattou, F. N., & Bonner, C. (2018) · Diabetes & Metabolism · doi:10.1016/j.diabet.2018.06.005 · Cited by 52
Abdul-Ghani, M. A. (2015) · Diabetes Care · doi:10.2337/dc14-2517 · Cited by 48
“Although the signal responsible for mediating the increase in glucosuria and the increase in EGP remains to be determined, the increase in EGP was accompanied with a small decrease in plasma insulin concentration and a large increase in plasma glucagon concentration (8,9).”
BackgroundInfluentialO’Brien, T. P., Jenkins, E. C., Estes, S. K., Castaneda, A. V., Ueta, K., Farmer, T. D., Puglisi, A. E., Swift, L. L., Printz, R. L., & Shiota, M. (2017) · Diabetes · doi:10.2337/db16-1410 · Cited by 50
“Merovic et al. (13) and Ferrannini et al. (14) reported that SGLT2-I treatment improves whole-body insulin resistance in patients with T2D.”
BackgroundVeelen, A., Erazo‐Tapia, E., Oscarsson, J., & Schrauwen, P. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101158 · Cited by 50
Veelen, A., Andriessen, C., den Kamp, Y. J. M. O., Erazo‐Tapia, E., de Ligt, M., Mevenkamp, J., Jörgensen, J. A., Moonen‐Kornips, E., Schaart, G., ESTERLINE, R. L., et al. (2022) · Metabolism · doi:10.1016/j.metabol.2022.155396 · Cited by 48
SGLT-2 inhibition and glucagon: Cause for alarm?
Kibbey, R. G. (2015) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2015.05.011 · Cited by 47
“After 28 days of treatment, although EGP remained elevated, glucagon had normalized, identifying a potential disconnect [2].”
BackgroundMcGill, J. B. (2014) · Diabetes Therapy · doi:10.1007/s13300-014-0063-1 · Cited by 47
“The metabolic response to empagliflozin has been studied in patients with T2DM [15].”
BackgroundStein, P., Berg, J. K., Morrow, L., Polidori, D., Artis, E., Rusch, S., Vaccaro, N. M., & Devineni, D. (2014) · Metabolism · doi:10.1016/j.metabol.2014.07.003 · Cited by 47
“[15] Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, et al.”
BackgroundResultMerovci, A., Abdul‐Ghani, M. A., Mari, A., Solis‐Herrera, C., Xiong, J., Daniele, G., Tripathy, D., & DeFronzo, R. A. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-2597 · Cited by 48
Self-citationRahman, A., Hitomi, H., & Nishiyama, A. (2017) · Hypertension Research · doi:10.1038/hr.2016.193 · Cited by 47
Euglycemic Diabetic Ketoacidosis
Plewa, M. C., Bryant, M. G., & King-Thiele, R. (2021) · StatPearls · Cited by 47
Yang, Y., Zhao, C., Ye, Y., Yu, M., & Qu, X. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00190 · Cited by 50
“reported that a single dosage of empagliflozin enhanced glycosuria and resulted in improved insulin sensitivity and β-cell function for tissue glucose uptake (32).”
Backgroundde Leeuw, A. E., & de Boer, R. A. (2016) · European Heart Journal - Cardiovascular Pharmacotherapy · doi:10.1093/ehjcvp/pvw009 · Cited by 46
“Other beneficial findings on SGLT2 inhibition are improvement of pancreatic b-cell function concerning glucose sensitivity,(91) cell mass and overall function,(91) – 95 and improvement in insulin sensitivity and associated peripheral glucose uptake.(91,93,96,97) SGLT2 inhibition also appears to directly affect pancrea…”
BackgroundLee, J.-Y., Lee, M., Lee, J. Y., Bae, J., Shin, E., Lee, Y., Lee, B., Kang, E. S., & Soo, B. (2021) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2020.0187 · Cited by 47
“This was reported to be due to a decrease in the plasma insulin levels because of glu-cosuria [22].”
Cardiometabolic and renal benefits of sodium–glucose cotransporter 2 inhibitors
Lee, Y., Lim, S. K., & Davies, M. J. (2025) · Nature Reviews Endocrinology · doi:10.1038/s41574-025-01170-4 · Cited by 56
“They require less oxygen to produce the same amount of energy as glucose, which could enhance organ function under conditions of stress or ischaemia 85 , contributing to the observed cardiovascular and renal benefits 21 .”
InfluentialParadoxical insights into whole body metabolic adaptations following SGLT2 inhibition
Cefalu, W. T. (2014) · Journal of Clinical Investigation · doi:10.1172/jci74297 · Cited by 46
“…Ferrannini et al. are examples of classic, in-depth human metabolic research and provide important contributions to sitivity and an estimated insulin sensitivity that was significantly increased during the acute study and “was at least maintained as compared to baseline” in the chronic study (7).”
BackgroundResultInfluentialType 2 Diabetes, SGLT2 Inhibitors, and Glucose Secretion
Hattersley, A. T., & Thorens, B. (2015) · New England Journal of Medicine · doi:10.1056/nejmcibr1506573 · Cited by 46
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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