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Sulfonylureas as second line treatment for type 2 diabetes

BMJ 2018; 362 doi: https://doi.org/10.1136/bmj.k3041 (Published 18 July 2018) Cite this as: BMJ 2018;362:k3041

Re: Sulfonylureas as second line treatment for type 2 diabetes: different approaches used for mortality analysis in observation studies of T2D patients can present discrepant results.

Diabetes Mellitus was described by Greek medicine in II century B.C., and during the times of Byzantine Empire was already a common illness [1]. It is surprising that the need for drug treatment of asymptomatic type 2 diabetes (T2D) - its most common category is still a matter of discussion. Recommendations of some experts that call to completely abandon the use of oral glucose-lowering drugs (OGLDs) with a single exception, made for metformin [2], or others that are skeptical concerning sulfonylureas (SUs) [3] – still the largest category of OGLDs, prove the seriousness of distrust in the current model of T2D treatment used for the last decade.

Retrospective evaluations of mortality risks in cohorts of T2D patients, receiving OGLDs gave conclusions about association between certain OGLDs and mortality that do not exactly agree with each other. Different approaches were used: 1) recording the outcomes depending on the first prescription, later changes were ignored or 2) receiving one of OGLDs according to data of last documented visit before the end of observation period; 3) without change of OGLD during the whole observation; 4) treatment intervals - period from onset of treatment to onset of the next drug treatment, or until outcome.

Danish patient registry-based observational study used the “treatment intervals” approach and showed an increase of all-cause and cardiovascular mortality risks in T2D patients, receiving glibenclamide, glimepiride, and glipizide versus metformin, whereas gliclazide had no such risks [4].

Douros et al. [5] like authors of other studies Pantalone et al. [6] did not perform the verification of treatment unchangeableness during the observation period, so they did not identify an increased total mortality risk among individual SUs probably due to the treatment changes during the observation period.

We conducted comparative analysis to evaluate impact of each study approach using the database of Ukrainian Diabetes Register. Gliclazide or metformin-treated patients demonstrated lesser mortality risk than glibenclamide-treated ones in all four evaluation models, but age and duration stratification can influence this phenomenon in case of “first prescription model”. In case of “without change OGLD” model the increase of mortality risk in glibenclamide-treated group is the most evident when comparing to gliclazide-treated, rather than to metformin-treated one. When comparing gliclazide vs metformin mortality risk for this model, gliclazide-treated patients demonstrated lesser mortality risk than metformin treated ones [7].
In addition, our later analysis of diabetic registry database data (unpublished data) partly supports the findings of Douros et al. [5] that the use of a combination of metformin + glibenclamide is associated with a lower overall mortality than monotherapy with glibenclamide. Nevertheless, we believe that this phenomenon is rather the result of the selection due to the knowledge that metformin is not tolerated in patients with impaired renal function.

Conclusion: Different approaches used for mortality analysis in observation studies of T2D patients can present discrepant results.

Competing interests: M. Kh. has been a principle investigator on projects to create Diabetes register in Ukraine. Diabetes register lunched by Komisarenko Institute of Endocrinology and Metabolism in 1998 and updated in most regions till 2008 in the framework of government grants. This letter was not funded by any grants.

1. Christopoulou-Aletra H., Papavramidou N. 'Diabetes' as described by Byzantine writers from the fourth to the ninth century AD: the Graeco-Roman influence. Diabetologia, 2008. 51: 892-896.
2. Havas S. The ACCORD Trial and control of blood glucose level in type 2 diabetes mellitus: time to challenge conventional wisdom. Arch Intern Med. 2009 Jan 26;169 (2):150-4.
3. Sola, Daniele, et al. "Sulfonylureas and their use in clinical practice." Archives of medical science: AMS 11.4 (2015): 840.
4. Schramm TK, Gislason GH, Vaag A, et al. Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study. Eur Heart J 2011; 32: 1900-1908
5. Douros, Antonios, et al. "Sulfonylureas as second line drugs in type 2 diabetes and the risk of cardiovascular and hypoglycaemic events: population based cohort study." bmj362 (2018): k2693.
6. Pantalone, K. M., et al. "Increase in overall mortality risk in patients with type 2 diabetes receiving glipizide, glyburide or glimepiride monotherapy versus metformin: a retrospective analysis." Diabetes, Obesity and Metabolism 14.9 (2012): 803-809.
7. Khalangot, Mykolay, and Volodymir Kovtun. "Evaluation approach can significantly influence oral glucose-lowering drugs total mortality risks in retrospective cohorts of type 2 diabetes mellitus patients." Current diabetes reviews 10.5 (2014): 336-342.

Competing interests: M. Kh. has been a principle investigator on projects to create Diabetes register in Ukraine. Diabetes register launched by Komisarenko Institute of Endocrinology and Metabolism in 1998 and updated in most regions till 2008 in the framework of government grants. This letter was not funded by any grants.

28 August 2018
Mykola Khalangot
MD (Endocrinology)
ASSOCIATE PROFESSOR SHUPYK NATIONAL MEDICAL ACADEMY OF POSTGRADUATE EDUCATION
Dorohozhytska 9 Kyiv 04112 Ukraine