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Risk of hypoglycaemia in users of sulphonylureas compared with metformin in relation to renal function and sulphonylurea metabolite group: population based cohort study

BMJ 2016; 354 doi: (Published 13 July 2016) Cite this as: BMJ 2016;354:i3625
  1. Judith van Dalem, PhD candidate and hospital pharmacist in training1 2 3,
  2. Martijn C G J Brouwers, medical specialist internal medicine4,
  3. Coen D A Stehouwer, professor of internal medicine5,
  4. André Krings, hospital pharmacist2,
  5. Hubert G M Leufkens, professor of pharmacoepidemiology6,
  6. Johanna H M Driessen, PhD candidate1 3 6,
  7. Frank de Vries, associate professor1 6,
  8. Andrea M Burden, postdoctoral researcher1 3 6
  1. 1Department of Clinical Pharmacy, Maastricht University Medical Centre, Maastricht, Netherlands
  2. 2Department of Clinical Pharmacy, Zuyderland MC, Heerlen, Netherlands
  3. 3Care and Public Health Research Institute (CAPHRI), Maastricht, Netherlands
  4. 4Department of Internal Medicine, Division of Endocrinology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands
  5. 5Department of Internal Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands
  6. 6Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences Utrecht University, PO Box 80082, 3508 TB Utrecht, Netherlands
  1. Correspondence to: F de Vries f.devries{at}
  • Accepted 26 June 2016


Objective To determine the association between use of sulphonylureas and risk of hypoglycaemia in relation to renal function and sulphonylurea metabolic group compared with use of metformin.

Design Population based cohort study using routinely collected data from general practices in England.

Setting Clinical Practice Research Datalink (CPRD) database, 2004-12.

Participants 120 803 new users of a non-insulin antidiabetic agent with at least one prescription and aged 18 years or more. The first prescription defined start of follow-up. Patients were followed until the end of data collection, a record for hypoglycaemia, or a blood glucose level of less than 3.0 mmol/L.

Main outcome measures Associations between sulphonylurea dose, renal impairment, type of sulphonylurea used, and risk of hypoglycaemia, were determined using Cox proportional hazard models. Adjustments were made for age, sex, lifestyle, comorbidity, and drug use.

Results The risk of hypoglycaemia in current users of sulphonylureas only was significantly increased compared with current users of metformin only (adjusted hazard ratio 2.50, 95% confidence interval 2.23 to 2.82). The higher risk in current users of sulphonylureas only was further increased in patients with an estimated glomerular filtration rate of less than 30 mL/min/1.73 m2 (4.96, 3.76 to 6.55). The risk of hypoglycaemia was also significantly higher in patients with a high sulphonylurea dose (3.12, 2.68 to 3.62) and in current users of glibenclamide (7.48, 4.89 to 11.44). Gliclazide, the sulphonylurea of first choice, showed a similar risk of hypoglycaemia compared with other sulphonylureas.

Conclusions Sulphonylurea treatment in patients with a renal function of less than 30 mL/min/1.73 m2 should be considered with caution. Moreover, an increased risk of hypoglycaemic events was observed among all users of sulphonylureas. This contrasts with several guidelines that recommend gliclazide as first choice sulphonylurea, and therefore requires further investigation.


  • Contributors: JvD initiated the study, did the literature review, and wrote the first draft of the paper. AMB led the statistical analysis. JvD, MCGJB, FdV, and AMB were responsible for the study concept and design and participated in the interpretation of data. All authors critically revised the paper for important intellectual content and approved the final version to be published. All authors, external and internal, had full access to all of the data (including statistical reports and tables) in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis. FdV and AMB supervised the study and are the guarantors.

  • Funding: AMB is supported by a Canadian Institutes for Health Research fellowship.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: HGML receives no direct funding or donations from private parties, including the pharmaceutical industry. Research funding from public-private partnerships, ie, IMI and TI Pharma (, has been accepted under the condition that no company specific product or company related study is conducted. He has received unrestricted research funding from the public sources, ie, the Netherlands Organisation of Health Research and Development (ZonMW), the EU 7th Framework Program (FP7), the Dutch Medicines Evaluation Board (MEB), the National Health Care Institute (ZIN), and the Dutch Ministry of Health. Other authors declare no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work

  • Ethical approval: This study was reviewed and approved by the independent scientific committee of the Clinical Research Practice Datalink (reference 16_016R), which is responsible for reviewing protocols for scientific quality.

  • Data sharing: No additional data available.

  • Transparency: The lead author (FdV) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. The study hypothesis originated before inspection of the data.

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