3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial

Background: Liraglutide 3·0 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In the 3-year assessment of the SCALE Obesity and Prediabetes trial we aimed to evaluate the proportion of individuals with prediabetes who were diagnosed with type 2 diabetes. Methods: In this randomised, double-blind, placebo-controlled trial, adults with prediabetes and a body-mass index of at least 30 kg/m2, or at least 27 kg/m2 with comorbidities, were randomised 2:1, using a telephone or web-based system, to once-daily subcutaneous liraglutide 3·0 mg or matched placebo, as an adjunct to a reduced-calorie diet and increased physical activity. Time to diabetes onset by 160 weeks was the primary outcome, evaluated in all randomised treated individuals with at least one post-baseline assessment. The trial was conducted at 191 clinical research sites in 27 countries and is registered with ClinicalTrials.gov, number NCT01272219. Findings: The study ran between June 1, 2011, and March 2, 2015. We randomly assigned 2254 patients to receive liraglutide (n=1505) or placebo (n=749). 1128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2·7 times longer with liraglutide than with placebo (95% CI 1·9 to 3·9, p<0·0001), corresponding with a hazard ratio of 0·21 (95% CI 0·13–0·34). Liraglutide induced greater weight loss than placebo at week 160 (–6·1 [SD 7·3] vs −1·9% [6·3]; estimated treatment difference −4·3%, 95% CI −4·9 to −3·7, p<0·0001). Serious adverse events were reported by 227 (15%) of 1501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group. Interpretation: In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation. Liraglutide 3·0 mg might provide health benefits in terms of reduced risk of diabetes in individuals with obesity and prediabetes. Funding: Novo Nordisk, Denmark

Cigarette Smoking Interferes With Treatment of Hypertension

• We retrospectively analyzed two studies to determine whether smoking affected the treatment of hypertension. In a study of the effects of propranolol hydrochloride (a hepatically metabolized β-blocker) vs hydrochlorothiazide, 108 smokers and 232 nonsmokers were randomized to the propranolol treatment group. The propranolol-treated smokers tended to be younger, taller, thinner, and were more likely to be black. This group also had an initial blood pressure reduction (± SD) of -7.9 ± 12.9/ -8.7 ± 8.4 mm Hg compared with -10.7 ± 13.0/ -10.9 ± 7.1 mm Hg for the nonsmokers. Blood pressure increased less during the one-year maintenance period for the nonsmokers. However, when analyzed by race, this effect was seen in blacks, but not in whites. Diastolic blood pressure tended to be reduced more in nonsmokers (vs smokers) receiving hydrochlorothiazide (-12.1 ± 6.7 vs -10.7 ± 6.7 mm Hg, respectively). The second study compared the effects of nadolol (a renally excreted β-blocker) with bendroflumethiazide. There were no significant effects on blood pressure for either of these drugs. In both studies, there was a greater tendency for smokers to be terminated from the study irrespective of drug group. We conclude that cigarette smoking does interfere with the treatment of hypertension in general, and especially with reduction of blood pressure by propranolol in black patients.(Arch Intern Med 1988;148:2116-2119

Centronuclear (myotubular) myopathy

<p>Abstract</p> <p>Centronuclear myopathy (CNM) is an inherited neuromuscular disorder characterised by clinical features of a congenital myopathy and centrally placed nuclei on muscle biopsy.</p> <p>The incidence of X-linked myotubular myopathy is estimated at 2/100000 male births but epidemiological data for other forms are not currently available.</p> <p>The clinical picture is highly variable. The X-linked form usually gives rise to a severe phenotype in males presenting at birth with marked weakness and hypotonia, external ophthalmoplegia and respiratory failure. Signs of antenatal onset comprise reduced foetal movements, polyhydramnios and thinning of the ribs on chest radiographs; birth asphyxia may be the present. Affected infants are often macrosomic, with length above the 90^thcentile and large head circumference. Testes are frequently undescended. Both autosomal-recessive (AR) and autosomal-dominant (AD) forms differ from the X-linked form regarding age at onset, severity, clinical characteristics and prognosis. In general, AD forms have a later onset and milder course than the X-linked form, and the AR form is intermediate in both respects.</p> <p>Mutations in the myotubularin <it>(MTM1) </it>gene on chromosome Xq28 have been identified in the majority of patients with the X-linked recessive form, whilst AD and AR forms have been associated with mutations in the dynamin 2 <it>(DNM2) </it>gene on chromosome 19p13.2 and the amphiphysin 2 <it>(BIN1) </it>gene on chromosome 2q14, respectively. Single cases with features of CNM have been associated with mutations in the skeletal muscle ryanodine receptor <it>(RYR1) </it>and the hJUMPY <it>(MTMR14) </it>genes.</p> <p>Diagnosis is based on typical histopathological findings on muscle biopsy in combination with suggestive clinical features; muscle magnetic resonance imaging may complement clinical assessment and inform genetic testing in cases with equivocal features. Genetic counselling should be offered to all patients and families in whom a diagnosis of CNM has been made.</p> <p>The main differential diagnoses include congenital myotonic dystrophy and other conditions with severe neonatal hypotonia.</p> <p>Management of CNM is mainly supportive, based on a multidisciplinary approach. Whereas the X-linked form due to <it>MTM1 </it>mutations is often fatal in infancy, dominant forms due to <it>DNM2 </it>mutations and some cases of the recessive <it>BIN1</it>-related form appear to be associated with an overall more favourable prognosis.</p