Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes.

BACKGROUND: The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown. METHODS: In this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes. RESULTS: A total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P=0.007). The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P=0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group. CONCLUSIONS: In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048.).

LEADER 3--lipase and amylase activity in subjects with type 2 diabetes: baseline data from over 9000 subjects in the LEADER Trial.

OBJECTIVES: This report from the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial describes baseline lipase and amylase activity in type 2 diabetic subjects without acute pancreatitis symptoms before randomization to the glucagonlike peptide analog liraglutide or placebo. METHODS: The LEADER is an international randomized placebo-controlled trial evaluating the cardiovascular safety of liraglutide in 9340 type 2 diabetic patients at high cardiovascular risk. Fasting lipase and amylase activity was assessed at baseline, before receiving liraglutide or placebo, using a commercial assay (Roche) with upper limit of normal values of 63 U/L for lipase and 100 U/L for amylase. RESULTS: Either or both enzymes were above the upper limit of normal in 22.7% of subjects; 16.6% (n = 1540) had an elevated lipase level (including 1.2% >3-fold elevated), and 11.8% (n = 1094) had an elevated amylase level (including 0.2% >3-fold elevated). In multivariable regression models, severely reduced kidney function was associated with the largest effect on increasing activity of both. However, even among subjects with normal kidney function, 12.2% and 7.7% had elevated lipase and amylase levels. CONCLUSIONS: In this large study of type 2 diabetic patients, nearly 25% had elevated lipase or amylase levels without symptoms of acute pancreatitis. The clinician must take these data into account when evaluating abdominal symptoms in type 2 diabetic patients.

Desmopressin 30 years in clinical use: a safety review.

Desmopressin acetate is the synthetic analogue of the antidiuretic hormone arginine vasopressin. It has been employed clinically for >30 years in a range of formulations: intranasal solution (since 1972), injectable solution (since 1981), tablets (since 1987), and most recently, an oral lyophilisate (since 2005). The antidiuretic properties of desmopressin have led to its use in polyuric conditions including primary nocturnal enuresis, nocturia, and diabetes insipidus. While a large body of clinical data is available for desmopressin, and despite its widespread use, comprehensive reviews of the safety of desmopressin are lacking (although some case series have attempted to correlate patient and/or dosing characteristics with the occurrence of adverse reactions). The purpose of this paper is to review the safety of desmopressin, based on analyses of both published data (MedLine) and of adverse reactions reported to Ferring Pharmaceuticals, the major manufacturer of desmopressin. Based on the findings, suggested strategies to reduce the risk of adverse reactions are proposed. Treatment with intranasal and oral formulations of desmopressin is generally well tolerated, and side effects are usually minor. The risk of hyponatraemia, although small, can be reduced by adhering to the indications, dosing recommendations and precautions when prescribing desmopressin.