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

van Dalem J, Brouwers MC, Stehouwer CD et al.,
BMJ. 2016 Jul 13;354:i3625. doi: 10.1136/bmj.i3625

Background

Sulphonylureas play an important role in achieving strict glycaemic control in diabetes, since they stimulate insulin secretion, thereby suppressing glucose production and stimulating the use of glucose [1]. The mechanism of action brings an inherent risk of hypoglycaemia. This risk may be even more increased in patients with renal impairment, which is a common comorbidity of type 2 diabetes. Tolbutamide, glipizide and gliclazide on the other hand, are for a large part excreted as unchanged drug or inactive metabolites with minimal hypoglycaemic effect [2].

In patients without renal impairment, incidence rates of hypoglycaemia have been reported to range from 0.2 to 1.8 per 100 person-years [3-6]. Data on patients with renal impairment is sparse and conflicting. One study with glibenclamide use did not find an association, while three others suggested an increased risk of hypoglycaemia in users of suphonylurea users with renal impairment.

Risk of hypoglycaemia in patients with renal impairment has not been compared between sulphonylureas with active metabolites (glimepiride, glibenclamide) and those with inactive metabolites (glipizide, tolbutamide, gliclazide). This study therefore evaluated the association between current use of sulphonylurea and risk of hypoglycaemia, according to renal function and sulphonylurea metabolite group, in comparison with current use of metformin. Data of the Clinical Practice Research Datalink (CPRD), which holds medical records for over 11 million patients in the United Kingdom (currently 7% of the UK population). 120 803 Patients aged 18 years or more (mean age: 67.4 years) with at least one prescription of a non-insulin antidiabetic agent were included between April 2004 and August 2012. Mean duration of follow-up was 3.7 years.

Main results

• Sulphonylurea users less often had BMI>30 (26.8%, n=3544) than metformin users (57.1%, n=52496), but more had lower renal function, as compared with users of metformin or other non-insulin antidiabetic agents. CV disease was more prevalent in sulphonylurea users.
• Risk of hypoglycaemia was 2.5-fold higher in current users of sulphonylureas, as compared with current metformin use (adj HR: 2.50, 95%CI: 2.23-2.82). Patients prescribed the highest daily dose showed an even higher risk of hypoglycaemia as compared with metformin only (adj HR: 3.12, 95%CI: 2.68-3.62).
• Patients on current concomitant sulphonylureas and metformin therapy showed a higher risk than patients on metformin only (HR: 3.06, 95%CI: 2.79-3.37).
• Risk of hypoglycaemic events increased with reduced renal function. In patients with eGFR <30 mL/min/1.73m2 on sulphonylureas only, showed a fivefold higher risk than those only using metformin (adj HR: 4.96, 95%CI: 3.76-6.55), while in those with eGFR of 30-59 mL/min/1.73 risk was less increased (adjHR: 2.69, 95%CI: 2.25-3.20), like in those with eGFR>60 mL/min/1.73 m2 (adjHR: 2.04, 95%CI: 1.73-2.41).
• HRs indicating a two- to threefold risk of hypoglycaemia were seen in sulphonylureas with active metabolites, as well as inactive metabolites.
• Stratifying to individual sulphonylureas suggested that use of glibenclamide was associated with the highest risk of hypoglycaemic events (adjHR: 7.48, 95%CI: 4.89-11.44), with metformin use as reference. Gliclazide, often considered the first choice sulphonylurea, appeared to convey a similar risk as glimepiride, glipizide and tolbutamide.

Conclusion

In contemporary UK diabetic patients, current use of sulphonylureas only was associated with an increased risk of hypoglycaemic events, as compared with current use of metformin. The risk was particularly elevated in patients prescribed the highest daily dose, and those with stage 4 or 5 chronic kidney disease. The increased risk did not appear to depend on the type of sulphonylureas, with active or inactive metabolites. The data do not support gliclazide being the sulphonylurea of choice in many countries due to a lower rate of hypoglycaemia, as the current data showed similar rates as compared with glimepiride, glipizide and tolbutamide.

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