Linagliptin Noninferior to Glimepiride as Add-On to Metformin in Type 2 Diabetes

Background:

Addition of a sulphonylurea to metformin improves glycaemic control in type 2 diabetes, but is associated with hypoglycaemia and weight gain. We aimed to compare a dipeptidyl peptidase-4 inhibitor (linagliptin) against a commonly used sulphonylurea (glimepiride).

Methods:

In this 2-year, parallel-group, non-inferiority double-blind trial, outpatients with type 2 diabetes and glycated haemoglobin A1c (HbA1c) 6·5—10·0% on stable metformin alone or with one additional oral antidiabetic drug (washed out during screening) were randomly assigned (1:1) by computer-generated random sequence via a voice or web response system to linagliptin (5 mg) or glimepiride (1—4 mg) orally once daily. Study investigators and participants were masked to treatment assignment. The primary endpoint was change in HbA1c from baseline to week 104. Analyses included all patients randomly assigned to treatment groups who received at least one dose of treatment, had a baseline HbA1c measurement, and had at least one on-treatment HbA1c measurement. This trial is registered at ClinicalTrials.gov, number NCT00622284.

Findings:

777 patients were randomly assigned to linagliptin and 775 to glimepiride; 764 and 755 were included in analysis of the primary endpoint. Reductions in adjusted mean HbA1c (baseline 7·69% [SE 0·03] in both groups) were similar in the linagliptin (—0·16% [SE 0·03]) and glimepiride groups (—0·36% [0·03]; difference 0·20%, 97·5% CI 0·09—0·30), meeting the predefined non-inferiority criterion of 0·35%. Fewer participants had hypoglycaemia (58 [7%] of 776 vs 280 [36%] of 775 patients, p<0·0001) or severe hypoglycaemia (1 [<1%] vs 12 [2%]) with linagliptin compared with glimepiride. Linagliptin was associated with significantly fewer cardiovascular events (12 vs 26 patients; relative risk 0·46, 95% CI 0·23—0·91, p=0·0213).

Interpretation:

The results of this long-term randomised active-controlled trial advance the clinical evidence and comparative effectiveness bases for treatment options available to patients with type 2 diabetes mellitus. The findings could improve decision making for clinical treatment when metformin alone is insufficient.

Funding:

Boehringer Ingelheim.

The Lancet, Volume 380, Issue 9840, Pages 475 - 483, 4 August 2012

Later Start of ADHD Drugs Linked to Declines in School Performance

OBJECTIVE:

We evaluated the hypothesis that later start of stimulant treatment of attention-deficit/hyperactivity disorder adversely affects academic progress in mathematics and language arts among 9- to 12-year-old children.

METHODS:

We linked nationwide data from the Icelandic Medicines Registry and the Database of National Scholastic Examinations. The study population comprised 11 872 children born in 1994–1996 who took standardized tests in both fourth and seventh grade. We estimated the probability of academic decline (drop of ≥5.0 percentile points) according to drug exposure and timing of treatment start between examinations. To limit confounding by indication, we concentrated on children who started treatment either early or later, but at some point between fourth-grade and seventh-grade standardized tests.

RESULTS:

In contrast with nonmedicated children, children starting stimulant treatment between their fourth- and seventh-grade tests were more likely to decline in test performance. The crude probability of academic decline was 72.9% in mathematics and 42.9% in language arts for children with a treatment start 25 to 36 months after the fourth-grade test. Compared with those starting treatment earlier (≤12 months after tests), the multivariable adjusted risk ratio (RR) for decline was 1.7 (95% confidence interval [CI]: 1.2–2.4) in mathematics and 1.1 (95% CI: 0.7–1.8) in language arts. The adjusted RR of mathematics decline with later treatment was higher among girls (RR, 2.7; 95% CI: 1.2–6.0) than boys (RR, 1.4; 95% CI: 0.9–2.0).

CONCLUSIONS:

Later start of stimulant drug treatment of attention-deficit/hyperactivity disorder is associated with academic decline in mathematics.

doi: 10.1542/peds.2011-3493