The DOI matches its Crossref record; 45 of the 45 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
The theoretical bases of indirect calorimetry: A review
Ferrannini, E. (1988) · Metabolism · doi:10.1016/0026-0495(88)90110-2 · Cited by 1,604
Self-citationWatson, P. E., Watson, I. D., & Rd, B. (1980) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/33.1.27 · Cited by 1,477
Biology of Human Sodium Glucose Transporters
Wright, E. M., Loo, D. D. F., & Hirayama, B. A. (2011) · Physiological Reviews · doi:10.1152/physrev.00055.2009 · Cited by 1,430
Effect of fatty acids on glucose production and utilization in man.
Ferrannini, E., Barrett, E. J., Bevilacqua, S., & DeFronzo, R. A. (1983) · Journal of Clinical Investigation · doi:10.1172/jci111133 · Cited by 1,050
Self-citationINDOCYANINE GREEN: OBSERVATIONS ON ITS PHYSICAL PROPERTIES, PLASMA DECAY, AND HEPATIC EXTRACTION*
Cherrick, G. R., Stein, S. W., Leevy, C. M., & Davidson, C. S. (1960) · Journal of Clinical Investigation · doi:10.1172/jci104072 · Cited by 978
Sodium–Glucose Cotransporter 2 Inhibitors for Type 2 Diabetes: A Systematic Review and Meta-analysis
Vasilakou, D., Karagiannis, T., Athanasiadou, E., Mainou, M., Liakos, A., Bekiari, E., Sarigianni, M., Matthews, D. R., & Tsapas, A. (2013) · Annals of Internal Medicine · doi:10.7326/0003-4819-159-4-201308200-00007 · Cited by 911
Cauter, E. V., Mestrez, F., Sturis, J., & Polonsky, K. S. (1992) · Diabetes · doi:10.2337/diab.41.3.368 · Cited by 887
Rossetti, L., Smith, D. J., Shulman, G. I., Papachristou, D. N., & DeFronzo, R. A. (1987) · Journal of Clinical Investigation · doi:10.1172/jci112981 · Cited by 824
SGLT2 Mediates Glucose Reabsorption in the Early Proximal Tubule
Vallon, V., Platt, K. A., Cunard, R. A., Schroth, J., Whaley, J. M., Thomson, S. C., Koepsell, H., & Rieg, T. (2010) · Journal of the American Society of Nephrology · doi:10.1681/asn.2010030246 · Cited by 565
Bolinder, J., Ljunggren, Ö., Johansson, L. O. M., Wilding, J. P. H., Langkilde, A., Sjöström, C. D., Sugg, J. E., & Parikh, S. J. (2013) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12189 · Cited by 492
Research works printed but not linked: 1
- Yki-Järvinen, 1992, Endocr Rev., 13, 415
Cited by
Sorted by citations
Items 701–800 of 999
Ueno, H., Nakazato, H., Ebihara, E., Noma, K., Kawano, T., Nagamine, K., Sakoda, H., & Nakazato, M. (2018) · Diabetes Therapy · doi:10.1007/s13300-018-0366-8 · Cited by 10
“Of the eight previous studies mentioned above, four studies lacked a description of their glucagon measuring methods [11, 13, 14, 17], and the remaining four used radioimmunoassay (RIA) for glucagon measurement [9, 12, 15, 16].”
BackgroundMethodParadigm shift in heart failure treatment: are cardiologists ready to use gliflozins?
Correale, M., Petroni, R., Coiro, S., Antohi, E., Monitillo, F., Leone, M., Triggiani, M., Ishihara, S., Düngen, H., Sarwar, C. M. S., et al. (2021) · Heart Failure Reviews · doi:10.1007/s10741-021-10107-8 · Cited by 10
Where to for precision treatment of HNF1A-MODY?
Bonner, C., & Saponaro, C. (2022) · Diabetologia · doi:10.1007/s00125-022-05696-4 · Cited by 10
“improving beta cell function, to shifting substrate utilisation from carbohydrates to lipids by inducing plasma glucagonlike peptide-1 (GLP1) and increasing glucagon levels [22, 23, 49, 50].”
BackgroundFortin, E., Lundin, M., Mellbin, L., Norhammar, A., Näsman, P., Smetana, S., Sörensson, P., Ferrannini, E., Rydén, L., & Ferrannini, G. (2023) · Cardiovascular Diabetology · doi:10.1186/s12933-023-01950-0 · Cited by 11
“This effect has been suggested to partly be attributed to improvement of insulin resistance in the failing heart [6] and in patients with T2DM [7].”
BackgroundSelf-citationKorkmaz, Y., & Dik, B. (2023) · Fundamental and Clinical Pharmacology · doi:10.1111/fcp.12975 · Cited by 11
“The glucosuric effect of empagliflozin reduces glucose toxicity and hyperglycemia and indirectly contributes to the reduction in β -cell damage and the improvement of insulin secretion [53 – 57].”
EMPA-REG: Glucose excretion and lipid mobilization – not storage – saves lives
Jørgensen, N. B., Pedersen, J., & Vaag, A. A. (2016) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2016.02.015 · Cited by 10
“Consequently, and in marked contrast to conventional glucose lowering agents, empagliflozin does not inhibit lipolysis, but leads to increased free fatty acid (FFA) concentrations and lipid oxidation(Ferrannini et al., 2014).”
BackgroundMaraka, S., Kearns, A. E., Kittah, N. E., & O'Keeffe, D. T. (2016) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2016.06.004 · Cited by 10
Qiu, R., Balis, D. A., Capuano, G. A., Xie, J., & Meininger, G. E. (2016) · Diabetes Therapy · doi:10.1007/s13300-016-0201-z · Cited by 10
Melmer, A., Kempf, P., Lunger, L., Pieber, T. R., Mader, J. K., Stettler, C., Tilg, H., Ebenbichler, C. F., & Laimer, M. W. (2018) · Diabetes Obesity and Metabolism · doi:10.1111/dom.13439 · Cited by 10
Ferrannini, G., & Rydén, L. (2018) · Clinical Science · doi:10.1042/cs20171374 · Cited by 10
Noda, T., Ebihara, E., Ueno, H., Sadohara, K., Tanaka, Y., Nagatomo, Y., Murakami, Y., Yonamine, S., Tsuchimochi, W., Sakoda, H., et al. (2019) · Diabetes Therapy · doi:10.1007/s13300-019-0666-7 · Cited by 10
Menghoum, N., Oriot, P., Hermans, M. P., & Mariage, J.-L. (2019) · La Revue de Médecine Interne · doi:10.1016/j.revmed.2019.12.006 · Cited by 10
Efficacy and safety of saxagliptin for the treatment of type 2 diabetes mellitus
Orime, K., & Terauchi, Y. (2020) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2020.1803280 · Cited by 10
Hughes, C. B., Mussman, G. M., Ray, P., Bunn, R. C., Cornea, V., Thrailkill, K. M., Fowlkes, J. L., & Popescu, I. R. (2021) · Cell and Tissue Research · doi:10.1007/s00441-020-03358-8 · Cited by 10
Baba, Y., Ishibashi, R., Takasaki, A., Ito, C., Watanabe, A., Tokita, M., Meguro, M., Harama, T., Hirayama, K., Yamamoto, T., et al. (2021) · Diabetes Therapy · doi:10.1007/s13300-021-01047-5 · Cited by 10
Lund, S. S., Sattar, N. A., Salsali, A., Neubacher, D., & Ginsberg, H. N. (2021) · Diabetes Obesity and Metabolism · doi:10.1111/dom.14534 · Cited by 9
“This suggests that the observed net changes in triglycerides with empagliflozin treatment are a function of the opposing effects of possible haemoconcentration (tending to increase triglycerides levels) and changes in other variables, such as improvements in blood glucose, body weight, and possibly insulin sensitivity…”
BackgroundEffect of Dapagliflozin on Cardiac Function and Metabolic and Hormonal Responses to Exercise
Herring, R. A., Parsons, I., Shojaee‐Moradie, F., Stevenage, M., Jackson, N., MANDERS, R. J. F., Umpleby, A. M., Fielding, B. A., Davies, M. J., & Russell-Jones, D. L. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac617 · Cited by 10
Maranghi, M., Carnovale, A., Durante, C., Tarquini, G., Tiseo, G., & Filetti, S. (2014) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.2015.986457 · Cited by 10
Management of diabetic ketoacidosis and hyperglycemic hyperosmolar state in adults
Anzola, I., Gomez, P., & Umpierrez, G. E. (2016) · Expert Review of Endocrinology & Metabolism · doi:10.1586/17446651.2016.1145049 · Cited by 10
Suzuki, R., Tamura, Y., Takeno, K., Kakehi, S., Funayama, T., Furukawa, Y., Kaga, H., Sugimoto, D., Kadowaki, S., Someya, Y., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-40498-6 · Cited by 10
Vadasz, B., Arazi, M., Shukha, Y., Koren, O., & Taher, R. (2021) · Journal of Medical Case Reports · doi:10.1186/s13256-020-02607-2 · Cited by 10
Lucidi, P., Perriello, G., Porcellati, F., Pampanelli, S., Fano, M. D., Tura, A., Bolli, G. B., & Fanelli, C. G. (2023) · Diabetes · doi:10.2337/db22-0721 · Cited by 12
“M . was associated with increased glucagon and lower I/Glg molar ratio, a key factor in the regulation of EGP (30,42).”
BackgroundMoon, J. S., Park, I. R., Kim, H. J., Chung, C. H., Won, K. C., Han, K. A., Park, C., Won, J. C., Kim, D. J., Koh, G. P., et al. (2023) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2022.0387 · Cited by 9
“However, some studies have shown that SGLT2 inhibitors paradoxically increase endogenous glucose production with glucagon secretion [11,12].”
Lee, S. W., Park, H., Lee, M. Y., Lee, H., & Kang, E. S. (2025) · Endocrinology and Metabolism · doi:10.3803/enm.2024.2223 · Cited by 9
“SGLT2 inhibitors also enhance hepatic glucose production, which is often associated with elevated plasma glucagon levels [13].”
Sodium–glucose cotransporter 2 inhibitors and diabetic ketoacidosis
Bloomgarden, Z. T. (2015) · Journal of Diabetes · doi:10.1111/1753-0407.12353 · Cited by 9
Lucidi, P., Porcellati, F., Cioli, P., Candeloro, P., Andreoli, A. M., Bolli, G. B., & Fanelli, C. G. (2019) · Diabetes Technology & Therapeutics · doi:10.1089/dia.2019.0231 · Cited by 9
“In fact, it is the relative concentration of the two islet hormones that perfuse the liver through the portal route, to determine the fine physiological tuning of Endogenous Glucose Production, more than isolated individual concentrations of serum insulin and glucagon.(10) The greater suppression of glucagon and lipid…”
InfluentialGamil, N. M., Fattah, M. A. A. E., Ahmed, M. A. E., Maklad, Y. A., el Din, A. A. G., & Eid, N. I. (2020) · Journal of Biochemical and Molecular Toxicology · doi:10.1002/jbt.22451 · Cited by 9
Urine Metabolic Fingerprints Encode Subtypes of Kidney Diseases
Yang, J., Wang, R., Huang, L., Zhang, M., Niu, J., Bao, C., Shen, N., Dai, M., Guo, Q., Wang, Q., et al. (2019) · Angewandte Chemie · doi:10.1002/ange.201913065 · Cited by 9
SGLT2 inhibitors and autophagy in diabetes
Yaribeygi, H., Maleki, M., Atkin, S. L., Jamialahmadi, T., & Sahebkar, A. (2023) · Cell Biochemistry and Function · doi:10.1002/cbf.3792 · Cited by 9
Sodium–glucose cotransporter 2 inhibitors in horses—Magic bullet or latest fad?
Sundra, T., Lester, G. D., Rossi, G., & Rendle, D. I. (2023) · Equine Veterinary Journal · doi:10.1111/evj.13944 · Cited by 9
Empagliflozin improves cardiac function in rats with chronic heart failure
Wang, Z.-Z., Liu, Q., Wang, X., Wang, P.-P., Wang, Z.-W., & Zhang, F.-L. (2023) · Naunyn-Schmiedeberg's Archives of Pharmacology · doi:10.1007/s00210-023-02655-7 · Cited by 10
Genetic and clinical characterization of familial renal glucosuria
Xu, L., Zhao, R., Zhao, Y., Tang, X., Si, N., Guo, X., Yue, C., Nie, M., & Chen, L. (2023) · Clinical Kidney Journal · doi:10.1093/ckj/sfad265 · Cited by 9
“Increased glucagon level after SGLT2 inhibition has been re-ported in clinical studies [11 , 12 ], and it may play a role in the development of euglycemia diabetic ketoacidosis [13 ].”
BackgroundKugathasan, L., Sridhar, V. S., Lovblom, L. E., Matta, S., Saliba, A., Debnath, S., Alakwaa, F., Nair, V., Bjornstad, P., Kretzler, M., et al. (2023) · Diabetes · doi:10.2337/db23-0694 · Cited by 10
Lyu, Y. S., Hong, S., Lee, S. E., Cho, B. Y., & Park, C. (2024) · Cardiovascular Diabetology · doi:10.1186/s12933-024-02155-9 · Cited by 9
“The non-insulin-dependent mechanism of SGLT-2 increases endogenous glucose production by increasing the glucagon levels in the body, which is a potential confounder when assessing the relationship between UGE and the blood glucose-lowering effect [20].”
BackgroundNUEVOS FÁRMACOS EN DIABETES MELLITUS
Aylwin, C. G. (2016) · Revista Médica Clínica Las Condes · doi:10.1016/j.rmclc.2016.04.013 · Cited by 9
“Si bien estos fármacos no afectan directamente la secreción de insulina ni la captación de glucosa en los tejidos, tienen un impacto beneficioso en ambas condiciones al corregir la hiperglicemia y por ende, la glucotoxicidad (102, 112).”
BackgroundMiyauchi, M., Toyoda, M., & Fukagawa, M. (2017) · Internal medicine · doi:10.2169/internalmedicine.56.7945 · Cited by 5
“More importantly the renal glucose clearance in euDKA is twice as high that in DKA (18, 19); this also results in a milder increase in the blood glucose level.”
BackgroundRizos, C. V., Filippatos, T. D., & Elisaf, M. (2017) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2018.1418325 · Cited by 10
“Of interest, this effect has also been observed with empagliflozin, a highly selective SGLT2i, albeit with milder intensity [72].”
BackgroundJürgens, M., Schou, M., Hasbak, P., Kjær, A., Wolsk, E., Zerahn, B., Wiberg, M., Brandt, N., Gæde, P., Rossing, P. R., et al. (2019) · BMJ Open · doi:10.1136/bmjopen-2019-029098 · Cited by 9
Pollock, C. A., & Neuen, B. L. (2021) · Advances in Chronic Kidney Disease · doi:10.1053/j.ackd.2021.02.006 · Cited by 10
New insights into cellular links between sodium–glucose cotransporter‐2 inhibitors and ketogenesis
Yaribeygi, H., Maleki, M., Butler, A. E., Jamialahmadi, T., & Sahebkar, A. (2022) · Journal of Cellular Biochemistry · doi:10.1002/jcb.30327 · Cited by 9
“Ferrannini et al.36 also reported that glucagon secretion increased in response to empagliflozin in patients with T2DM.”
BackgroundCorreale, M., Tricarico, L., Croella, F., Alfieri, S., Fioretti, F., Brunetti, N. D., Inciardi, R. M., & Nodari, S. (2023) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2023.1157472 · Cited by 9
Kanazawa, K., Uchino, H., Shigiyama, F., Igarashi, H., Ikehara, K., Yoshikawa, F., Usui, S., Miyagi, M., Yoshino, H., Ando, Y., et al. (2018) · Journal of Diabetes Investigation · doi:10.1111/jdi.12994 · Cited by 9
Strategies for implementing effective mealtime insulin therapy in type 2 diabetes
Peyrot, M. F., Bailey, T. S., Childs, B. P., & Reach, G. (2018) · Current Medical Research and Opinion · doi:10.1080/03007995.2018.1440200 · Cited by 9
Paredes, S., Matta-Coelho, C., Monteiro, A. M., Brás, A., Marques, O., Alves, M., & Ribeiro, L. V. P. T. (2016) · HORMONES · doi:10.14310/horm.2002.1671 · Cited by 9
Sato, M., Tamura, Y., Kaga, H., Yamasaki, N., Kiya, M., Kadowaki, S., Sugimoto, D., Funayama, T., Someya, Y., Kakehi, S., et al. (2021) · Biomedicines · doi:10.3390/biomedicines9091154 · Cited by 8
Ji, L., Mishra, M., & Geest, B. D. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15041092 · Cited by 8
“In other words, SGLT2 inhibitors improve insulin sensitivity and enhance β-cell function [48,49].”
BackgroundSiddiqui, F., Mishra, P., Khanam, S., Ranjan, S., Alam, P., Albalawi, T., Khan, S., & Mir, S. S. (2025) · European Journal of Neuroscience · doi:10.1111/ejn.70142 · Cited by 8
Tsur, A., Leibowitz, G., Cohen, M. J., Cahn, A., & Pollack, R. M. (2025) · Diabetes Obesity and Metabolism · doi:10.1111/dom.16545 · Cited by 8
Chaudhry, A., Thompson, D. M., & Chanoine, J. (2025) · Diabetes Obesity and Metabolism · doi:10.1111/dom.70240 · Cited by 8
“83,84 In T1D, SGLT2 inhibitors can reduce HbA1c, insulin requirements and body weight modestly, albeit with a higher risk of diabetic ketoacidosis (DKA).”
2025 iCatCare consensus guidelines on the diagnosis and management of diabetes mellitus in cats
Taylor, S. S., Cannon, M., Church, D. B., Fleeman, L. M., Fracassi, F., Gilor, C., Mott, J., & Niessen, S. (2025) · Journal of Feline Medicine and Surgery · doi:10.1177/1098612x251399103 · Cited by 9
Bell, K. F., Katz, A., & Sheehan, J. (2016) · Risk Management and Healthcare Policy · doi:10.2147/rmhp.s108586 · Cited by 8
“The use of SGLT-2 inhibitor has been found to be associated with an increase in plasma glucagon concentration and endogenous glucose production (EGP), which may diminish the glucose-lowering effects of these agents.(47,48) This increase in EGP was shown to be potentially related to inhibition of SGLT-2 expressed in pa…”
Hepatic benefits of sodium-glucose cotransporter 2 inhibitors in liver disorders
Yaribeygi, H., Maleki, M., Jamialahmadi, T., Moallem, S. A., & Sahebkar, A. (2023) · EXCLI journal · doi:10.17179/excli2023-6022 · Cited by 10
“Moreover, they are involved in gluconeogenesis, improvement of peripheral insulin sensitivity, glucagon release, and insulin secretion (Han et al., 2008; Ferrannini et al., 2014; Wilding et al., 2014; Kern et al., 2016).”
Voigt, J. H., Lauritsen, K. M., Pedersen, S. B., Hansen, T. K., Møller, N., Jessen, N., LAURENTI, M. C., Man, C. D., Vella, A. V., Gormsen, L. C., et al. (2024) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.13991 · Cited by 8
“3,5 This altered insulin/glucagon ratio results in increased lipolysis, circulating free fatty acid (FFA) levels and keto-genesis.”
BackgroundResultInfluentialSingh, A. K., Misra, A., Das, A. K., Behl, A., Srivastava, A., Paneerselvam, A., Chidambaram, B., Saboo, B., Sethi, B. K., Makkar, B. M., et al. (2023) · Journal of the Association of Physicians of India · doi:10.59556/japi.71.0422 · Cited by 9
“In 2013, Ferrannini et al. 6 reported that empagliflozin (−1.87 to −2.08) showed a better reduction in body weight when compared to metformin (−0.89) during a 90-week trial.”
InfluentialMari, A., Rosenstock, J., Ma, X., Li, Y. G., & Jackson, J. A. (2015) · Endocrine Practice · doi:10.4158/ep15898.or · Cited by 8
Self-citationSkelin, M., Javor, E., Lucijanić, M., Lucijanić, T., Jakupović, L., & Rahelić, D. (2018) · International Journal of Clinical Practice · doi:10.1111/ijcp.13274 · Cited by 8
Moon, J. S., Kim, N. H., Na, J. O., Cho, J., Jeong, I., Lee, S. H., Mok, J., Kim, N. H., Chung, D. J., Cho, J., et al. (2022) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2021.0356 · Cited by 8
Thirumathyam, R., Richter, E. A., Goetze, J. P., Fenger, M., van Hall, G., Dixen, U., Holst, J. J., Madsbad, S., Vejlstrup, N. G., Madsen, P. L., et al. (2022) · BMJ Open · doi:10.1136/bmjopen-2021-054100 · Cited by 9
Sun, W., Xing, Y., Kong, D., Zhang, Z., Ma, H., & Yang, L. (2022) · Medicine · doi:10.1097/md.0000000000030553 · Cited by 8
Zaina, A., Prencipe, N., Golden, E., Berton, A. M., Arad, E., Ali, A., Shehadeh, J., Kassem, S., & Ghigo, E. (2023) · Endocrine · doi:10.1007/s12020-023-03352-4 · Cited by 8
“enhanced by a lower alpha cell glucose uptake due to SGLT2 inhibition [19, 20].”
BackgroundTahara, A., Takasu, T., Yokono, M., Imamura, M., & Kurosaki, E. (2015) · Archives of Pharmacal Research · doi:10.1007/s12272-015-0621-8 · Cited by 8
“In contrast, SGLT2 inhibitors, dapagliflozin and empagliflozin, have been reported to increase endogenous glucose production with a concomitant increase in plasma glucagon levels in type 2 diabetic patients (Merovci et al. 2014; Ferrannini et al. 2014).”
BackgroundSingh‐Franco, D. (2015) · Expert Review of Endocrinology & Metabolism · doi:10.1586/17446651.2015.1004311 · Cited by 8
“These increases appeared to be attenuated after 4 weeks compared with the single dose [24].”
BackgroundCoppenrath, V. A., & Hydery, T. (2017) · Annals of Pharmacotherapy · doi:10.1177/1060028017731111 · Cited by 8
“Clinical data suggest that SGLT-2 inhibitors are also associated with a paradoxical increase in EGP accompanied by increased plasma glucagon levels.(18,19) Therefore, addition of a DPP-4 inhibitor, which inhibits glucagon, could theoretically block the increase in EGP and further improve the antihyperglycemic effect o…”
BackgroundSodium–Glucose Cotransporter-2 Inhibitors: Lack of a Complete History Delays Diagnosis
Leslie, B. R., Gerwin, L. E., & Taylor, S. I. (2019) · Annals of Internal Medicine · doi:10.7326/m19-1463 · Cited by 8
Sodium-glucose cotransporter 2 inhibitors and cardiorenal outcomes in kidney transplantation
Mahalwar, G., Mathew, R. O., & Rangaswami, J. (2023) · Current Opinion in Nephrology & Hypertension · doi:10.1097/mnh.0000000000000948 · Cited by 8
Sundra, T., Kelty, E. A., Rossi, G., Lester, G. D., & Rendle, D. I. (2024) · Equine Veterinary Education · doi:10.1111/eve.13975 · Cited by 7
The effect of PPARγ agonist on SGLT2 and glucagon expressions in alpha cells under hyperglycemia
Kim, M.-K., Lee, E. J., Shin, H., Jung, H. S., Kim, T. K., Kim, T. N., Kwon, M. J., Lee, S. H., Rhee, B. D., & Park, J. H. (2017) · Journal of Endocrinological Investigation · doi:10.1007/s40618-017-0659-1 · Cited by 7
Nakamura, Y., Horie, I., Kitamura, T., Kusunoki, Y., Nishida, K., Yamamoto, A., Hirota, Y., Fukui, T., Maeda, Y., Minami, M., et al. (2024) · Diabetes Obesity and Metabolism · doi:10.1111/dom.15458 · Cited by 7
“18,19 It is widely known that people with T1D have an impaired counter-regulatory response of glucagon to hypoglycaemia.”
BackgroundClinical Implications of Canagliflozin Treatment in Patients With Type 2 Diabetes
Valentine, V., & Hinnen, D. A. (2015) · Clinical Diabetes · doi:10.2337/diaclin.33.1.5 · Cited by 8
“Recently, SGLT2 inhibition has been shown to be associated with an increase in endogenous glucose production via increased ratio of circulating glucagon to insulin levels (26,27); in the event of hypoglycemia, this increased endogenous glucose production could provide a source for glycemic “rescue” (9).”
BackgroundCanagliflozin, a Sodium Glucose Co-transporter 2 Inhibitor, for the Management of Type 2 Diabetes
Brunton, S., & Reid, T. (2014) · Hospital Practice · doi:10.3810/hp.2014.08.1122 · Cited by 7
Monteiro, P. F., Aguíar, C., Matos, P., Silva‐Nunes, J., Birne, R., Branco, P. Q., Calado, J., Melo, M., & Polónia, J. J. (2019) · Revista Portuguesa de Cardiologia · doi:10.1016/j.repc.2019.02.008 · Cited by 9
Alsahli, M., Shrayyef, M. Z., & Gerich, J. E. (2017) · Springer eBooks · doi:10.1007/978-3-319-18741-9_2 · Cited by 7
Azman, S. S. W., Sukor, N., Shamsi, M. Y. A., Ismail, I., & Kamaruddin, N. A. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.867647 · Cited by 7
“org 3 conducted a study on the metabolic response to SGLT2 inhibitor in type 2 diabetic patients where they observed a reduction in insulin secretory response and an augmentation of the glucagon response, such that the prehepatic insulin-to-glucagon concentration ratio decreased by 25% with empagliflozin in response t…”
BackgroundSGLT-2 Inhibitor-Associated Euglycemic Diabetic Ketoacidosis: A Case Report and a Literature Review
Mahfooz, R. S., Khan, M. K., Hennawi, H. A., & Khedr, A. (2022) · Cureus · doi:10.7759/cureus.26267 · Cited by 7
“Although SGLT-2 inhibitors increase glucose excretion in urine, this effect may be counterbalanced by its effect of increasing endogenous glucose production and glucagon release, which can eventually lead to ketosis [10,11].”
BackgroundMartinelli, S., Amore, F., Mello, T., Mannelli, M., Maggi, M., & Rapizzi, E. (2022) · Cancers · doi:10.3390/cancers14143471 · Cited by 7
Cognitive Benefits of Sodium-Glucose Co-Transporters-2 Inhibitors in the Diabetic Milieu
Yaribeygi, H., Maleki, M., Sathyapalan, T., Rizzo, M., & Sahebkar, A. (2023) · Current Medicinal Chemistry · doi:10.2174/0929867330666230202163513 · Cited by 8
Deciding oral drugs after metformin in type 2 diabetes: An evidence-based approach
Singh, A. K. (2014) · Indian Journal of Endocrinology and Metabolism · doi:10.4103/2230-8210.139214 · Cited by 7
Pafili, K., Maltezos, E. S., & Παπάνας, Ν. (2016) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2016.1229302 · Cited by 7
“Furthermore, enhanced UGE also induces glucagon secretion, depending on the condition of individual patients [42,108], which may account for the diversity of efficacy among SGLT2 inhibitors.”
BackgroundEMPA-REG OUTCOME: The Endocrinologist's Point of View
Perreault, L. (2017) · The American Journal of Medicine · doi:10.1016/j.amjmed.2017.04.005 · Cited by 8
SGLT-2 Inhibition: Novel Therapeutics for Reno-and Cardioprotection in Diabetes Mellitus
Gill, A., Gray, S. P., Jandeleit-Dahm, K. A. M., & Watson, A. M. D. (2018) · Current Diabetes Reviews · doi:10.2174/1573399814666180417121246 · Cited by 8
Usui, M., Tanaka, M., & Takahashi, H. (2020) · Journal of Clinical & Translational Endocrinology · doi:10.1016/j.jcte.2020.100233 · Cited by 7
“SGLT2 inhibitors reduce the workload of glucose metabolism by promoting the excretion of glucose in the urine, restoring the incretinresponsive insulin secretion [6],[7], and improve insulin sensitivity [8,9].”
BackgroundShepard, B. D., & ECELBARGER, C. A. (2021) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2021.06.005 · Cited by 7
da Rocha, A. F., Junior, P. S. P., Calefi, G. S., Marquezine, G. F., Morimoto, H. K., Mazzuco, T. L., de Faria, E. C., Urbano, M. R., & Carrilho, A. J. F. (2021) · Endocrine · doi:10.1007/s12020-021-02730-0 · Cited by 7
“and FFA levels in parallel with the lower glucose concentrations and better diabetes control are explained by the improvement in insulin sensitivity and β cell function [13].”
BackgroundTalha, K. M., Green, J., Filippatos, G. S., Pocock, S., Zannad, F. M., Brueckmann, M., Schueler, E., Ofstad, A. P., Ferreira, J. P., Anker, S. D., et al. (2024) · Diabetes Obesity and Metabolism · doi:10.1111/dom.15572 · Cited by 6
“23 The event rate for the CV endpoints was significantly higher in patients with diabetes on insulin at baseline, even after adjustment for risk factors that differed between the insulin and non-insulin users (Table S2).”
BackgroundWang, Y., Qin, Y., Zhang, J., Wu, A., Qin, X., Du, L., Zhang, H., Guo, X., & Zhang, S. (2025) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.3615 · Cited by 7
“SGLT2i might indirectly increase the levels of ketone bodies by enhancing hepatic gluconeogenesis, ketogenesis 22,23 and renal reabsorption of ketones.”
Sinclair, A. J., Sequiera, I., & Abdelhafiz, A. H. (2025) · Metabolites · doi:10.3390/metabo15060381 · Cited by 7
Protective Mechanisms of SGLTi in Ischemic Heart Disease
Liao, L., Wang, T., Zhang, L., Yan, W., & Fan, X. (2024) · Journal of Cardiovascular Translational Research · doi:10.1007/s12265-024-10513-x · Cited by 6
“EGG was similarly increased in nondiabetic subjects [25, 26].”
Forouzanmehr, B., Hedayati, A. H., Gholami, E., Hemmati, M. A., Maleki, M., Butler, A. E., Jamialahmadi, T., Kesharwani, P., Yaribeygi, H., & Sahebkar, A. (2024) · Cellular Signalling · doi:10.1016/j.cellsig.2024.111335 · Cited by 6
Schwartz, S. S., & Katz, A. (2016) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s65588 · Cited by 7
“Dapagliflozin and other SGLT-2 inhibitors are associated with increases in endogenous glucose production and glucagon concentrations that appear to be independent of the reduction in plasma glucose by SGLT-2 inhibition and may partially blunt the glucose-lowering effects of SGLT-2 inhibitors.(47,48) SGLT-2 is expresse…”
West, K. B., Webb, L., Fenech, M. E., & Dhatariya, K. (2016) · British Journal of Diabetes · doi:10.15277/bjd.2016.079 · Cited by 6
Dapagliflozin — a key pawn on the new guidelines chessboard
Kubica, J. (2021) · Medical Research Journal · doi:10.5603/mrj.a2021.0056 · Cited by 6
“In addition, the hemodynamic effects of SGLT2 inhibition can be seen in both hyper- and euglycemic patients [1, 5].”
BackgroundKim, H. J., Kim, S. S., & Song, S. H. (2022) · The Korean Journal of Internal Medicine · doi:10.3904/kjim.2021.515 · Cited by 7
“SGLT2 inhibitors can also alleviate oxidative stress and proinflammatory and fibrotic changes by reducing lipids in the podocytes by controlling lipotoxicity [78,79].”
BackgroundKale, A., Sharma, A., Anders, H., & Gaikwad, A. B. (2022) · Current Diabetes Reviews · doi:10.2174/1573399819666220816145907 · Cited by 6
Extrarenal Benefits of SGLT2 Inhibitors in the Treatment of Cardiomyopathies
Yerra, V. G., & Connelly, K. A. (2024) · Physiology · doi:10.1152/physiol.00008.2024 · Cited by 6
Getting to goal in newly diagnosed type 2 diabetes using combination drug “subtraction therapy”
Jennings, A. S., Lovett, A. J., George, T. M., & Jennings, J. S. (2015) · Metabolism · doi:10.1016/j.metabol.2015.04.008 · Cited by 6
“[19] Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, et al.”
BackgroundYassin, S. A., & Aroda, V. R. (2017) · Drug Design Development and Therapy · doi:10.2147/dddt.s121899 · Cited by 6
Serum Betatrophin Levels and Clinical Features in Patients With Poorly Controlled Type 2 Diabetes
Takebayashi, K., Hara, K., Terasawa, T., Naruse, R., Suetsugu, M., Tsuchiya, T., & Inukai, T. (2017) · Journal of Clinical Medicine Research · doi:10.14740/jocmr3114w · Cited by 6
Evolution of Glucose-Lowering Drugs for Type 2 Diabetes
Krentz, A. J. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-812019-4.00033-7 · Cited by 7
Kishimoto, M., Yamaoki, K., & Adachi, M. (2019) · Case Reports in Endocrinology · doi:10.1155/2019/9415347 · Cited by 6
Qin, Y., Adams, J. M., Solis‐Herrera, C., Triplitt, C. L., DeFronzo, R. A., & Cersósimo, E. (2020) · Diabetes Care · doi:10.2337/dc19-1993 · Cited by 6
“Consistent with results published earlier from our laboratory (13– 15,19) and others (17), DAPA, whether administered acutely (day 1) or chronically (week 16) as monotherapy or in combination with SAXA, caused a “com-”
Result
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
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 ›
Are you an author, or do you see a problem with this page? Request a review
