Jean-Luc Faillie

Incretin based drugs and risk of acute pancreatitis in patients with type 2 diabetes: cohort study

Objectives To determine whether the use of incretin based drugs, compared with sulfonylureas, is associated with an increased risk of acute pancreatitis. Design Population based cohort study. Setting 680 general practices in the United Kingdom contributing to the Clinical Practice Research Datalink. Participants From 1 January 2007 to 31 March 2012, 20 748 new users of incretin based drugs were compared with 51 712 users of sulfonylureas and followed up until 31 March 2013. Main outcome measures Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for acute pancreatitis in users of incretin based drugs compared with users of sulfonylureas. Models were adjusted for tenths of high dimensional propensity score (hdPS). Results The crude incidence rate for acute pancreatitis was 1.45 per 1000 patients per year (95% confidence interval 0.99 to 2.11) for incretin based drug users and 1.47 (1.23 to 1.76) for sulfonylurea users. The rate of acute pancreatitis associated with the use of incretin based drugs was not increased (hdPS adjusted hazard ratio: 1.00, 95% confidence interval 0.59 to 1.70) relative to sulfonylurea use. Conclusions Compared with use of sulfonylureas, the use of incretin based drugs is not associated with an increased risk of acute pancreatitis. While this study is reassuring, it does not preclude a modest increased risk, and thus additional studies are needed to confirm these findings.

Pioglitazone and bladder cancer.

www.thelancet.com Vol 378 October 29, 2011 1543 Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/ potential for bladder cancer with pioglitazone. In the PROactive study, published in 2005 by Dormandy and colleagues, 14 (0·5%) cases of bladder neoplasm were reported in the pioglitazone group and six (0·2%) in the placebo group. This diff erence did not reach signifi cance (p=0·069). In the overview of PROactive data published in 2009, Dormandy and colleagues anecdotally mentioned that, in the placebo group, one case in fact showed a benign histology. This information was presented in the text in brackets, but no new bladder cancer incidence was calculated. We reviewed the PROactive safety data presented in these two publications. We found that the recalculated overall incidence in the pioglitazone group was statistically greater than in the placebo group: 0·54% (14/2605) versus 0·19% (5/2633), respectively (Fisher’s exact test p=0·040). The estimated crude relative risk of bladder cancer was 2·83 (95% CI 1·02–7·85). As in the original article, this incidence did not take into account concomitant potential risk factors or treatment duration. However, this result shows a signifi cant relation between pioglita zone and bladder cancer, which has not been presented in the PROactive study reports. This fi nding, associated with the preclinical and clinical fi ndings reported on the FDA website in 2004 (PPAR agonists were claimed to be multispecies, multistrain, multisex, and multisite carcinogens), could have led to an alert 5 years sooner. With this in mind, pioglitazone prescription could have been restricted, and monitoring of patients strengthened. Given the potential loss of opportunity for patients to have been treated otherwise or at least monitored carefully since 2005, vigilance and checking of all relevant safety data reported in clinical trials are crucial.

Möbius Syndrome in a Neonate After Mifepristone and Misoprostol Elective Abortion Failure

Objective: To report a case of a child born with Möbius syndrome following exposure in utero to mifepristone and misoprostol for elective abortion. Case Summary: In the seventh week of pregnancy, a woman was administered mifepristone 600 mg and, 2 days later, misoprostol 400 μg for abortion. One month later, despite significant metrorrhagia, an ultrasound examination showed ongoing gestation. At 33 weeks and 3 days of gestation, the woman gave birth to a male with left facial palsy, microretrognathia, and axial hypotonia related to Möbius syndrome. Discussion: Möbius syndrome is characterized by unilateral or bilateral palsy of the abducens (VI) and facial (VII) cranial nerves. Other cranial nerves (eg, the hypoglossal [XII]), craniofacial or orofacial anomalies, and limb malformations are often associated. The etiology of the Möbius syndrome remains largely unknown and probably involves multiple factors. The most likely etiological hypothesis is disruption of the developing vascular system, with transient ischemia (particularly in the vertebral arteries) and fetal hypoxia. A teratogenic cause of Möbius syndrome has been suggested. The critical period for the development of Möbius syndrome following teratogen exposure appears to be 5–8 weeks of gestation. To date, mifepristone alone does not appear to have induced Möbius syndrome. In contrast, oral or vaginal misoprostol administration can lead to a significant increase in Doppler-measured uterine artery resistance and may induce uterine contractions. If these occur during the critical embryonic period, they may cause flexion in the areas of the sixth and seventh cranial nerves and decreased blood flow. Conclusions: Ineffective use of mifepristone and misoprostol in the first trimester of pregnancy may be associated with a risk of Möbius syndrome, primarily due to misoprostol activity. Women with ongoing pregnancy after failed abortion with misoprostol administration should be informed of this risk.

Slow-Release Oral Morphine Sulfate Abuse: Results of the Postmarketing Surveillance Systems for Psychoactive Prescription Drug Abuse in France

Background: Few data are available concerning the diversion and abuse of morphine sulfate. In France, morphine sulfate abuse is currently investigated by the health authorities. The aim of our study was to provide data on morphine sulfate abuse in France, collected during the period 1996–2011. Methods: The French monitoring system for psychoactive medication abuse collected data from several sources: spontaneous reporting of cases of abuse or dependence (NotS; ‘Notifications Spontanées’), specific periodic surveys from specialized care centers (OPPIDUM; ‘Observation des Produits Psychotropes Illicites ou Détournés de leur Utilisation Médicamenteuse’), and community pharmacists (OSIAP; ‘Ordonnances Suspectes Indicateur d’Abus Possible’). Results: A total of 649 cases (75% men, median age: 34 years) were spontaneously reported: 578 cases of abuse and 71 cases of use as opiate maintenance treatment. The medication formulation was Skenan® (614 cases), and Moscontin® (35 cases). All surveys (NotS, OPPIDUM, and OSIAP) showed an overrepresentation of Skenan® (87.9–94.6% of cases) that was intravenously injected in 60.4–61.2% of the cases. Data analysis showed that patients abusing morphine sulfate have a long history of drug abuse and a history of polydrug use. Conclusion: All the data presented in this study highlight the level of morphine sulfate abuse, specify the modalities of use (intravenous route), and show the risks associated with abuse (infectious diseases). This study outlines the usefulness of our epidemiological tools, and provides evidence supporting intensive surveillance.

Pioglitazone and the risk of bladder cancer

Risks seem to outweigh benefits as yet more evidence emerges

Association of Bile Duct and Gallbladder Diseases With the Use of Incretin-Based Drugs in Patients With Type 2 Diabetes Mellitus

Importance The use of dipeptidyl-peptidase-4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) analogues-a group of drugs used in the management of type 2 diabetes mellitus-may be associated with an increased risk of bile duct and gallbladder disease. To date, no observational study has assessed this possible association. Objective To determine whether the use of DPP-4 inhibitors and GLP-1 analogues is associated with an increased risk of incident bile duct and gallbladder disease in patients with type 2 diabetes. Design, Setting, and Participants A population-based cohort study linked the United Kingdom Clinical Practice Research Datalink with the Hospital Episodes Statistics database, yielding a cohort of 71 369 patients, 18 years or older, initiating an antidiabetic drug (including oral and injectable agents) between January 1, 2007, and March 31, 2014. Exposures Current use of DPP-4 inhibitors and GLP-1 analogues (alone or in combination therapy) compared with current use of at least 2 oral antidiabetic drugs. Main Outcomes and Measures Time-dependent Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% CIs of incident bile duct or gallbladder events (cholelithiasis, cholecystitis, cholangitis) causing hospitalization, comparing current use of DPP-4 inhibitors and GLP-1 analogues with current use of at least 2 oral antidiabetic drugs. Results During 227 994 person-years of follow-up, 853 of the 71 369 patients were hospitalized for bile duct and gallbladder disease (incidence rate per 1000 person-years, 3.7; 95% CI, 3.5-4.0). Current use of DPP-4 inhibitors was not associated with an increased risk of bile duct and gallbladder disease compared with current use of at least 2 oral antidiabetic drugs (3.6 vs 3.3 per 1000 person-years; adjusted HR, 0.99; 95% CI, 0.75-1.32). In contrast, the use of GLP-1 analogues was associated with an increased risk of bile duct and gallbladder disease compared with current use of at least 2 oral antidiabetic drugs (6.1 vs 3.3 per 1000 person-years; adjusted HR, 1.79; 95% CI, 1.21-2.67). In a secondary analysis, GLP-1 analogues were also associated with an increased risk of cholecystectomy (adjusted HR, 2.08; 95% CI, 1.08-4.02). Conclusions and Relevance The use of GLP-1 analogues was associated with an increased risk of bile duct and gallbladder disease. Physicians should be aware of this potential adverse event when prescribing these drugs.

Pharmacological aspects of the safety of gliflozins

Graphical abstract Main effects and suspected adverse reactions secondary to inhibition of sodium‐glucose transporter 2 (SGLT2) by gliflozins. Figure. No caption available. &NA; Sodium‐glucose transporter 2 (SGLT2) inhibitors, also known as gliflozins, are a new class of orally active drugs used in the management of type 2 diabetes. By inhibiting the SGLT responsible for the reabsorption of glucose from the kidney, their use aims primarily to induce glycosuria and, as a consequence, lower glycemic levels. However, their specific mechanism of action involves other pharmacodynamic consequences including potentially harmful adverse reactions. This manuscript reviews the physiological and pharmacological background behind inhibition of SGLTs, and discusses the pharmacological aspects of the safety of gliflozins.

Stay vigilant: a glitazone (pioglitazone) can hide a glitazar!

Between 1995 and 2000, many peroxisome proliferatoractivated receptor (PPAR) agonists were developed for the treatment of type 2 diabetes mellitus. Whereas PPARα agonists (fibrates) improve lipid metabolism, PPARγ agonists (thiazolidinediones) sensitize insulin action and improve glycemic control. The search for a wider pharmacodynamic effect with synergism on lipid and glucose homeostasis in patients with metabolic syndrome or type 2 diabetes led to the concept of dual-acting PPARα and PPARγ agonists [1, 2]. These dual agonists, named glitazars, were all stopped during preclinical or clinical development, mainly because of carcinogenic effects in animals, especially bladder tumors in male rats [3]. In September 2010, the U.S. Food and Drug Administration issued an alert in connection with a potential relationship between the occurrence of bladder cancers in patients and the prescription of pioglitazone at high doses and for long periods [4]. Reviewing the PROactive study safety data, we reported that the incidence of bladder cancers was significantly higher in the pioglitazone-treated group than in the placebo group, with an estimated crude relative risk of 2.83 (95 % CI 1.02–7.85) [5]. This result is supported by a recent study from Neumann et al. [6], showing a dose-dependent increase in the incidence of bladder cancer in pioglitazone-exposed diabetic patients. Analysis of the pharmacological data published so far gives evidence that pioglitazone has a pharmacodynamic profile comparable to that of the glitazar compounds (Table 1); specifically, it has a dual pharmacological effect on both PPARα and PPARγ that can be obtained in humans at the concentrations clinically used. In order to explain hyperplasia and bladder cancers in male rats during the preclinical development of pioglitazone, the Takeda group favored the hypothesis of urolithiasis [4, 7]. This hypothesis is supported by the presence of crystals causing continuous irritation, particularly in ventral bladder. Recently, Sato and colleagues reported data from a 24-month mechanistic study showing decreased formation of urinary microcrystals when using an acidifying diet [7]; under these conditions, the elevated incidence of advanced proliferative changes in pioglitazone-treated animals was significantly decreased. However, the incidence of hyperplasia was not reduced, and the incidence of D. Hillaire-Buys Department of Medical Pharmacology and Toxicology, CHRU Montpellier and INSERM U1058, Montpellier, France

Dipeptidyl peptidase‐4 inhibitors and the risk of community‐acquired pneumonia in patients with type 2 diabetes

To determine whether the use of dipeptidyl peptidase‐4 (DPP‐4) inhibitors is associated with an increased risk of community‐acquired pneumonia.

Acute Hepatitis and Renal Failure Related to Intranasal Buprenorphine Misuse Case Report and Analysis of Cases Reported to the French Network for Drug Monitoring

Background: Rare cases of acute hepatitis have been reported following injection, overdose, and even during the use of buprenorphine (BPN) at therapeutic doses, especially in carriers of hepatitis C virus (HCV). Objectives: To report a case of acute hepatitis and renal failure related to intranasal BPN misuse in a HCV-negative patient and to analyze cases reported to the French postmarketing surveillance system (PMSS) of drugs and in the literature. Methods: All cases of hepatitis related to BPN reported to PMSS between January 1996 and December 2012 were analyzed. Results: A 42-year-old man with a history of intranasal BPN misuse (8 mg/d) for at least 10 years was admitted for flu-like symptoms and abdominal pain. At admission, the patient consumed alcohol, cannabis, and tobacco. Acute hepatitis and acute renal failure were diagnosed . Clinical signs and biological parameters resolved within 26 days. An objective causality assessment revealed that an adverse drug reaction (ADR) was possible. In the French PMSS database, 41 cases of suspected BPN-induced hepatitis are reported. In 36.6% of cases, BPN was misused by the intravenous route. In the literature, 16 cases of acute hepatitis related to BPN with or without renal failure are reported. In all cases, patients were HCV carriers. The primary mechanism of BPN-induced hepatitis is a mitochondrial dysfunction, exacerbated by cofactors (HCV, alcohol, and medications). Conclusion: Intranasal misuse of BPN is increasingly frequent. We report here the first documented case of acute hepatitis and renal failure related to intranasal BPN misuse in a patient negative for HCV infection.