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 Interpretation In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation.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

Epidemiological and family studies imply that genetic factors are important in the etiology of diabetic nephropathy in subjects with IDDM (1,2). Vascular disease is characteristic of nephropathy, and lipoproteins are important determinants of atherosclerosis. Apolipoprotein E (apoE) is a major protein constituent of lipoproteins, mediating hepatic lipoprotein uptake and reverse cholesterol transport. ApoE occurs as three isoproteins: E3 with normal function, E2 with reduced affinity, and E4 with increased affinity for the apoE receptor. These are encoded by three codominant alleles e2, E3, and e4. This polymorphism has an influence on lipid levels, the E2 isoform being associated with lower cholesterol but higher triglyceride levels compared with the E3 isoform, and the E4 isoform being associated with higher cholesterol but lower triglyceride levels (3). There is also an association with vascular disease in diabetic and nondiabetic populations (3,4). Preliminary data suggest that this triallelic polymorphism may be associated with genetic susceptibility to diabetic nephropathy (5). The aim of this study was thus to determine the role of the apoE gene polymorphism in a large cohort of IDDM patients with and without diabetic nephropathy.Four patient cohorts were examined: IDDM patients with diabetic nephropathy (nephropathy group, n = 252), IDDM patients with long duration of disease and no nephropathy (long-duration non-nephropathy group [LDNN], n = 197), a Received for publication 7 April 1997 and accepted in revised form 22 October 1997. apoE, apolipoprotein E; LDNN, long-duration non-nephropathy; UA/UC, urinary albumin/creatinine. background population of recently diagnosed patients with IDDM (sporadic diabetic group, n = 270), and nondiabetic control patients (nondiabetic group, n = 346). The criteria used to classify patients has been described previously in detail (6). Presence of hypertension, and retinopathy were inclusion criteria in the nephropathy cohort. DNA was extracted from peripheral blood leukocytes by the Nucleon method (Scotlab, Paisley, Scotland, U.K.). ApoE genotyping was performed by the method of Crook et al. (7).The distribution of alleles and genotypes were compared between the groups by x 2 analysis. A probability of <1 in 20 (P < 0.05) was taken to be significant. Odds ratios were determined by the logit method (Woolfs analysis). Statistical analysis was performed using the statistical package SPSS.No significant difference was seen between the nephropathy and LDNN groups in age at diagnosis of diabetes, duration of diabetes, mean HbA lc , and serum cholesterol at time of venesection. The nephropathy group had a significantly higher proportion of men (P < 0.01), systolic and diastolic blood pressure (P < 0.001), proportion on antihypertensive therapy (P < 0.01), and serum creatinine (P < 0.001). Allele frequencies between the nondiabetic group and the sporadic group (Table 1) were almost identical (x 2 = 0.886, P = 0.642). There was, however, significant heterogeneity in allele frequen...

Premature cardiovascular disease is common in insulin-dependent diabetic (IDDM) patients who develop diabetic nephropathy. Genetic polymorphism within the renin-angiotensin system has been implicated in the aetiology of a number of cardiovascular disorders; these loci are therefore candidate genes for susceptibility to diabetic renal disease. We have examined the angiotensin converting enzyme insertion/deletion polymorphism and angiotensinogen methionine 235 threonine polymorphism in a large cohort of Caucasian patients with IDDM and diabetic nephropathy. Patients were classified as having nephropathy by the presence of persistent dipstick positive proteinuria (in the absence of other causes), retinopathy and hypertension (n = 242). Three groups were examined for comparison: ethnically matched non-diabetic subjects (n = 187); a geographically defined cohort of newly diagnosed diabetic patients (n = 341); and IDDM patients with long duration of disease (> 15 years) and no evidence of overt nephropathy (n = 166). No significant difference was seen in distribution of angiotensin converting enzyme or angiotensinogen genotypes between IDDM patients with nephropathy and recently diagnosed diabetic subjects (p = 0.282 and 0.584, respectively), nor the long-duration non-nephropathy diabetic subjects (p = 0.701 and 0.190, respectively). We conclude that these genetic loci are unlikely to influence susceptibility to diabetic nephropathy in IDDM in the United Kingdom.

Recent evidence suggests that a mutation of the glucagon receptor (GCG-R) gene is involved in the development of type 2 diabetes in French patients. We have examined patients from three geographically distinct regions in the UK and found the GGT40 (Gly) to AGT40 (Ser) mutation to be present in 15/691 (2.2%) of patients with type 2 (non-insulin dependent) diabetes and 1/425 (0.2%) of geographically matched controls and have therefore replicated association of the GCG-R mutation with classical type 2 diabetes (Fisher's exact test p = 0.008). An increased frequency of the mutation of the GCG-R gene was also found in probands of type 1 (insulin dependent) diabetic multiplex (affected sib pair) families, (10/404, 2.5%). However, a lack of preferential transmission from parents heterozygous for the mutation, to affected type 1 diabetic sibs may suggest population stratification. This in turn cannot be excluded as an alternative explanation for the difference in frequency of the GCG-R gene mutation between subjects with type 2 diabetes and normal controls.