Journal of Diabetes and Related Disorders

Could Initial Glucosuria Suggest Sodium Glucose Co-Transporters Type 2 Inhibitors Failure?

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Could Initial Glucosuria Suggest Sodium Glucose Co-Transporters Type 2 Inhibitors Failure?

Tamez-Pérez HE 1,2*, De la Cruz GG1, Garza LA1, Tamez Peña AL1, Cedillo Huerta HE1

1Research Division, School of Medicine, Universidad Autónoma de Nuevo León, Mexico

2Clínica NOVA de Monterrey, Av. del Bosque #139, Cuauhtémoc, 66450 San Nicolas de los Garza, N.L., Mexico

*Corresponding author: Tamez Pérez HE, Research Division, School of Medicine, Universidad Autónoma de Nuevo León, Ave. Madero y Gonzalitos s/n, Colonia Mitras Centro, Monterrey, Nuevo León 64460, México. E-mail:

Citation: Tamez-Pérez HE, De la Cruz GG, Garza LA, Tamez Peña AL, Cedillo Huerta HE (2015) Could Initial Glucosuria Suggest Sodium Glucose Co-Transporters Type 2 Inhibitors Failure? J Diab Rel Dis 1(1): 103.




Sodium glucose co-transporters type 2 (SGLT-2) inhibitors are a novel and effective treatment for type 2 diabetes mellitus (DM2). However, a fraction of the treated patients are not responsive to these drugs and the mechanisms and predictive factors underlying this phenomenon are unknown. We carried out a retrospective analysis of 42 patients with DM2 and SGLT-2 inhibitors treatment. Nonresponsive cases were analyzed to look for common characteristics. Seven cases were not responsive, and when reviewed, all had a basal glucosuria of at least 100 mg/dL. Even though their glucosuria increased to > 1000mg/dL, weight, HbA1c and fasting glucose remained unchanged. This could suggest that patients with a baseline significant glucosuria might be less responsive to SGLT-2 inhibitors.

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The treatment of type 2 diabetes mellitus (DM2) requires a multifactorial approach of the diverse defects of glucose homeostasis. An increase in the expression and activity of sodium-glucose co-transporter 2 (SGLT2) in the kidney has recently been found. Pharmacological inhibition of SGLT2 limits the absorption of glucose by the kidney and increases glucosuria, which decreases glycemia and, therefore, glucotoxicity. SGLT2 inhibitors are currently considered a new and effective group of drugs in DM2 treatment that contribute with several beneficial effects since not only they allow glycemic control, but also promote weight loss and decrease arterial pressure. Since SGLT2 inhibition is completely independent of insulin secretion there is no increased risk of hypoglycemia [1,2].

The aim of this paper is to report a series of patients with failure in the use of SGLT2 inhibitors and initial glucosuria as a predictive factor.

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A retrospective analysis of 42 cases where the use of SGLT2 inhibitors was indicated was carried out in our DM clinic during 2014. We followed current international guidelines that suggest their indication in DM2, secondary failure with the use of two or more oral hypoglycemics, and a glycosylated hemoglobin ? 7% y < 10% [1,2].  We collected demographic variables such as weight, age, time of evolution of DM, adherence to treatment, and drug safety by carrying out evaluations that included adverse events and alterations in lab tests.



Seven patients, five women and two men between the ages of 39 and 54 years with an evolution of DM of 5-11 years were evaluated. After three months, significant changes were not observed in their weight (P = 0.74), fasting blood glucose (P = 0.28) or glycosylated hemoglobin (P = 0.4150). The initial level of glycosuria increased in all cases from 100 mg/dL to more than 1000 mg/dL (P < 0 .0001). Adverse effects or data of a urinary tract and/or mycotic infection were not reported.

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Discussion and Conclusion


Our cases had accepted indications for a good glycemic response with SGLT2 inhibitors [3]; however, a good response was not achieved. We have several hypotheses; for example, the finding of glucosuria in basal data could explain baseline SGLT2 inhibition or saturation in patients with chronic hyperglycemia – hyperinsulinemia and over expression of SGLT2; therefore, despite increased urinary glucose, only a partial inhibition of the SGLT2 receptors was achieved. The caloric loss was not sufficiently important as a mechanism for weight loss and the decrease in glucose, also, a variation of the response to SGLT2 has been observed, even, with the age [4].

On the other hand, Abdul-Ghani et al., recently published other hypotheses to explain why SGLT2 inhibitors only inhibit 30%-50% of glomerular filtration in patients with type 2 DM. They mentioned the importance of initial activity of sub-maximum transport of SGLT1, which could decrease the expected response with SGLT2 inhibitors [5].

Ferrannini documented other types of acute and chronic adaptation mechanisms to the glycemic response with the use of SGLT2 inhibitors with modifications in the carbohydrate to lipids substrate and the disposition of glucose, since a single dose of a SGLT2 inhibitor reduced insulin secretion with modifications in tissue glucose disposition and the endogenous production of glucose. Nevertheless, after meals there was an increase in the response of glucagon attributing this hyperglucagonemia to multiple factors where GLP1 plays an important role [6].

However, we know that the effectiveness of multiple drugs in DM is heterogenous and that genetic, environmental, and other factors could be involved in the lack of a good response to SGLT2 inhibitors [7].

This may help us in the day to day clinical practice to select better the patients for these drugs and to anticipate who is going to need a different treatment, before we give it to them. Also, the diabetes mellitus is an excellent example of the need of a precise/personalized medicine because the risk of different treatments could induce extra morbidity (i.e. risk of vision loss, kidney failure, and limb loss) [8,9].

The use of SGLT2 inhibitors will depend on continued clinicians’ real-world experience, and this information will ultimately prove important to considerations of long-term management of T2DM in individual patients for whom SGLT2 inhibitors offer advantages over other therapies [10].

This study is neither a clinical trial nor a cohort or case-control study. This case series has several limitations that require further consistency and research with an adequate sample to determine if these findings are really an important factor in the decision to use SGLT2 inhibitors.

In conclusion, the initial glycosuria over 100 mg/dl could be a useful screening parameter to detect those patients that may not response effectively to the SGLT2 inhibitors. There is needed more experimental and prospective studies where the effect of the SGLT2 inhibitors will be measured in patients with initial glycosuria. Patient demographic data are shown in Table 1.


Table 1:  Patient demographic data (* M, metformin; S, sulfonylurea; DPP4, dipeptidyl peptidase-4 inhibitor, A: Initial, B :Final)

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We thank Dr. Sergio Lozano Rodriguez MD, for his help in translating the manuscript. No federal or industry support was received in the making of this research or redaction of this manuscript.



  1. Nauck MA. Update on developments with SGLT2 inhibitors in the management of type 2 diabetes. Drug Des Devel Ther. 2014;8:1335-80. doi: 10.2147/DDDT.S50773.
  2. Jung CH, Jang JE, Park JY. A Novel Therapeutic Agent for Type 2 Diabetes Mellitus: SGLT2 Inhibitor. Diabetes Metab J. 2014;38(4):261-73. doi: 10.4093/dmj.2014.38.4.261.
  3. Cefalu WT. Paradoxical insights into whole body metabolic adaptations following SGLT2 inhibition. J Clin Invest. 2014;124(2):485-7. doi: 10.1172/JCI74297.
  4. Nakamura Y, Nagai Y, Terashima Y, Nishine A, Ishii S, Kato H, et al. Better response to the SGLT2 inhibitor dapagliflozin in young adults with type 2 diabetes. Expert Opin Pharmacother. 2015:1-7.
  5. Abdul-Ghani MA, DeFronzo RA, Norton L. Novel hypothesis to explain why SGLT2 inhibitors inhibit only 30-50% of filtered glucose load in humans. Diabetes. 2013;62(10):3324-8. doi: 10.2337/db13-0604.
  6. Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124(2):499-508. doi: 10.1172/JCI72227.
  7. Cnop M. Epigenetic aspects of pancreatic beta cell function in type 2 diabetes. Arch Public Health. 2014; 72(Suppl 1): K1. doi:  10.1186/2049-3258-72-S1-K1.
  8. Kleinberger JW, Pollin TI. Personalized medicine in diabetes mellitus: current opportunities and future prospects. Ann N Y Acad Sci. 2015;1346(1):45-56. doi: 10.1111/nyas.12757.
  9. Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med. 2015;372(9):793-5. doi:10.1056/NEJMp1500523.
  10. Handelsman, Y. Potential place of SGLT2 inhibitors in treatment paradigms for type 2 diabetes mellitus. Endocr Pract. 2015;21(9):1054-65. doi: 10.4158/EP15703.RA. 



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Copyright: © 2015 Tamez-Pérez HE, et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.