Risk of hypoglycemia following intensification of metformin treatment with insulin versus sulfonylurea

Background:

Hypoglycemia remains a common life-threatening event associated with diabetes treatment. We compared the risk of first or recurrent hypoglycemia event among metformin initiators who intensified treatment with insulin versus sulfonylurea.

Methods:

We assembled a retrospective cohort using databases of the Veterans Health Administration, Medicare and the National Death Index. Metformin initiators who intensified treatment with insulin or sulfonylurea were followed to either their first or recurrent hypoglycemia event using Cox proportional hazard models. Hypoglycemia was defined as hospital admission or an emergency department visit for hypoglycemia, or an outpatient blood glucose value of less than 3.3 mmol/L. We conducted additional analyses for risk of first hypoglycemia event, with death as the competing risk.

Results:

Among 178 341 metformin initiators, 2948 added insulin and 39 990 added sulfonylurea. Propensity score matching yielded 2436 patients taking metformin plus insulin and 12 180 taking metformin plus sulfonylurea. Patients took metformin for a median of 14 (interquartile range [IQR] 5–30) months, and the median glycated hemoglobin level was 8.1% (IQR 7.2%–9.9%) at intensification. In the group who added insulin, 121 first hypoglycemia events occurred, and 466 first events occurred in the group who added sulfonylurea (30.9 v. 24.6 events per 1000 person-years; adjusted hazard ratio [HR] 1.30, 95% confidence interval [CI] 1.06–1.59). For recurrent hypoglycemia, there were 159 events in the insulin group and 585 events in the sulfonylurea group (39.1 v. 30.0 per 1000 person-years; adjusted HR 1.39, 95% CI 1.12–1.72). In separate competing risk analyses, the adjusted HR for hypoglycemia was 1.28 (95% CI 1.04–1.56).

Interpretation:

Among patients using metformin who could use either insulin or sulfonylurea, the addition of insulin was associated with a higher risk of hypoglycemia than the addition of sulfonylurea. This finding should be considered by patients and clinicians when discussing the risks and benefits of adding insulin versus a sulfonylurea.Hypoglycemia remains one of the most common medication-related adverse events among patients with diabetes and a leading cause of hospital admissions and emergency department visits.^1,2 It is a concern to patients and clinicians and a strong determinant of treatment choices.³ Hypoglycemic medications account for 25% of emergency hospital admissions for adverse drug events among patients aged 65 years and older.^2,4 Multiple factors predispose patients with diabetes to hypoglycemia, including older age, polypharmacy, poor nutrition, underlying illness, alcohol use and declining renal function.^5,6 Intensive glucose-control treatment for patients with these factors is strongly associated with hypoglycemia.^6,7Consensus statements by major diabetes associations, including the Canadian Diabetes Association, recommend lifestyle modification and metformin as first-line therapies for type 2 diabetes, with the goal of treatment being a glycated hemoglobin (HbA_1C) level of 7% or less for many patients.^8,9 Multiple options are listed as acceptable add-on treatments. Sulfonylurea is easier to initiate, but insulin dose can be modified in response to daily variation in food intake, exercise or other variables that cause fluctuations in glucose values. Within the Veterans Health Administration clinical practice guideline, both the combination of metformin plus sulfonylurea or the use of bedtime insulin combined with metformin are considered acceptable based on level I evidence.¹⁰ To make well-informed decisions about treatment regimens, patients and providers need to understand clinical benefits, such as improvement in microvascular outcomes,¹¹ and harms, such as hypoglycemia.We recently reported that intensification of metformin with insulin compared with sulfonylurea was associated with an increased risk of all-cause mortality among veterans with diabetes.¹² Evidence for a causal relation between hypoglycemia and cardiovascular disease or death is limited, because patients at risk for hypoglycemia also have factors that increase their risk for those outcomes.^7,13–15 Both sulfonylurea and insulin are associated with an elevated risk of hypoglycemia compared with metformin.^5,7,16–18 We sought to test the hypothesis that using the combination of metformin plus insulin was associated with a greater risk of serious hypoglycemia than using metformin plus sulfonylurea.