The Peripheral Neuropathy Prevalence and Characteristics Are Comparable in People with Obesity and Long-Duration Type 1 Diabetes.

INTRODUCTION: Peripheral neuropathy is reported in obesity even in the absence of hyperglycaemia. OBJECTIVE: To compare the prevalence and characterise the phenotype of peripheral neuropathy in people living with obesity (OB) and long-duration type 1 diabetes (T1D). PATIENTS AND METHODS: We performed a prospective cross-sectional study of 130 participants including healthy volunteers (HV) (n = 28), people with T1D (n = 51), and OB (BMI 30-50 kg/m2) (n = 51). Participants underwent assessment of neuropathic symptoms (Neuropathy Symptom Profile, NSP), neurological deficits (Neuropathy Disability Score, NDS), vibration perception threshold (VPT) and evaluation of sural nerve conduction velocity and amplitude. RESULTS: Peripheral neuropathy was present in 43.1% of people with T1D (age 49.9 ± 12.9 years; duration of diabetes 23.4 ± 13.5 years) and 33.3% of OB (age 48.2 ± 10.8 years). VPT for high risk of neuropathic foot ulceration (VPT ≥ 25 V) was present in 31.4% of T1D and 19.6% of OB. Participants living with OB were heavier (BMI 42.9 ± 3.5 kg/m2) and had greater centripetal adiposity with an increased body fat percentage (FM%) (P < 0.001) and waist circumference (WC) (P < 0.001) compared to T1D. The OB group had a higher NDS (P < 0.001), VAS for pain (P < 0.001), NSP (P < 0.001), VPT (P < 0.001) and reduced sural nerve conduction velocity (P < 0.001) and amplitude (P < 0.001) compared to HV, but these parameters were comparable in T1D. VPT was positively associated with increased WC (P = 0.011), FM% (P = 0.001) and HbA1c (P < 0.001) after adjusting for age (R2 = 0.547). Subgroup analysis of respiratory quotient (RQ) measured in the OB group did not correlate with VPT (P = 0.788), nerve conduction velocity (P = 0.743) or amplitude (P = 0.677). CONCLUSION: The characteristics of peripheral neuropathy were comparable between normoglycaemic people living with obesity and people with long-duration T1D, suggesting that metabolic factors linked to obesity play a pivotal role in the development of peripheral neuropathy. Further studies are needed to investigate the mechanistic link between visceral adiposity and neuropathy.

Mechanisms, screening modalities and treatment options for individuals with non-alcoholic fatty liver disease and type 2 diabetes.

Non-alcoholic fatty liver disease (NAFLD) exists as a spectrum of disease ranging from excessive accumulation of fat within the liver (simple steatosis), inflammation (non-alcoholic steatohepatitis) through to fibrosis, cirrhosis and end-stage liver disease. There is also an increased risk of hepatocellular carcinoma. The principal risk factor for NAFLD is overweight or obesity, along with type 2 diabetes, and NAFLD itself is also a risk factor for incident type 2 diabetes. Overweight/obesity is synergistic with alcohol consumption in causing progressive and insidious liver damage. Recent consensus advocates a change in nomenclature from NAFLD to 'metabolic associated fatty liver disease' (MAFLD), reflective of the associated metabolic abnormalities (insulin resistance/type 2 diabetes and metabolic syndrome components). Additional extra-hepatic manifestations of NAFLD include cardiovascular disease, chronic kidney disease and certain cancers. Unlike other micro- and macrovascular complications of type 2 diabetes, systematic screening or surveillance protocols have not been widely adopted in routine diabetes care to assess for presence/severity of NAFLD. Various screening tools are available (non-invasive tests and biochemical indices) combined with imaging techniques (e.g. transient elastography) to detect steatosis and more importantly advanced fibrosis/cirrhosis to facilitate appropriate surveillance. Liver biopsy may be sometimes necessary. Treatment options for type 2 diabetes, including lifestyle interventions (dietary change and physical activity), glucose-lowering therapies and metabolic surgery, can modulate hepatic steatosis and to a lesser extent fibrosis. Awareness of the impact of liver disease on the choice of glucose-lowering medications in individuals with type 2 diabetes is also critical.

Correction to: Adipokines and the insulin resistance syndrome in familial partial lipodystrophy caused by a mutation in lamin A/C.

The authors regret that Alexandra Bargiota's name was spelt incorrectly in the author list. The details given in this correction are correct.

Beyond lifestyle interventions: exploring the potential of anti-obesity medications in the UK.

In the UK, over one-quarter of the adult population have obesity (body mass index ≥30 kg m-2 ). This has major implications for patients' health and the National Health Service. Despite published studies showing that significant weight loss can be achieved and maintained in primary care, and guidance from the National Institute for Health and Care Excellence, weight management services are inconsistently implemented. This may be due primarily to workload and financial constraints. There is also a lack of belief that specialist weight management services and anti-obesity medications (AOMs) are a viable alternative to bariatric surgery for long-term maintenance of weight loss. This article discusses the challenges facing obesity management and explores the reasons for the lack of investment in AOMs in the UK to date. The aim of this article is to identify whether the newer AOMs, such as naltrexone/bupropion and liraglutide 3.0 mg, are likely to perform better in a real-world setting than current or withdrawn AOMs. In addition, it considers whether the equitable provision of specialist weight management services and future clinical trial design could be improved to help identify those individuals most likely to benefit from AOMs and, thus, improve outcomes for people with obesity in the UK.

Evaluation of Aintree LOSS, a community-based, multidisciplinary weight management service: outcomes and predictors of engagement.

Aintree LOSS is a community-based, multidisciplinary weight management programme for patients with severe and complex obesity, focusing on a flexible and individualized service with follow-up for up to 2 years. We evaluated all 2472 patients referred to the service between October 2009 and 2013. Demographic data were recorded at baseline, with the Index of Multiple Deprivation (IMD) used to measure socioeconomic deprivation. Weight was recorded at each visit. Mean body mass index at baseline was 45.6 (standard deviation 6.8), and 58.9% of patients lived in areas in the most deprived decile nationally. Of 2315 appropriate referrals, 1249 (55.1%) attended >2 visits; mean final weight loss was 3.50 ± 8.55 kg, and 24.1% achieved ≥5% weight loss. Of the patients, 754 (33.3%) attended for over 6 months; mean final weight loss was 4.94 ± 10 kg, and 34% achieved 5% weight loss. Multivariate logistic regression analysis showed increasing age, residence in a less deprived area and sleep apnoea to be independently associated with attendance for >6 months, and there was a linear relationship between 6-month attendance and deprivation quintile. Year-on-year analyses showed improvement in engagement over time, coinciding with efforts to improve access to the service. This work shows a multidisciplinary, community-based weight loss programme prioritizing a fully flexible and individualized approach functioning effectively in real-world practice. Maintaining engagement remains a challenge in weight loss programmes, and our results suggest younger patients living in areas with greater deprivation should be a target for efforts to improve engagement.

Arrhythmogenic gene remodelling in elderly patients with type 2 diabetes with aortic stenosis and normal left ventricular ejection fraction.

NEW FINDINGS: What is the central question of this study? Type 2 diabetes is associated with a higher rate of ventricular arrhythmias compared with the non-diabetic population, but the associated myocardial gene expression changes are unknown; furthermore, it is also unknown whether any changes are attributable to chronic hyperglycaemia or are a consequence of structural changes. What is the main finding and its importance? We found downregulation of left ventricular ERG gene expression and increased NCX1 gene expression in humans with type 2 diabetes compared with control patients with comparable left ventricular hypertrophy and possible myocardial fibrosis. This was associated with QT interval prolongation. Diabetes and associated chronic hyperglycaemia may therefore promote ventricular arrhythmogenesis independently of structural changes. Type 2 diabetes is associated with a higher rate of ventricular arrhythmias, and this is hypothesized to be independent of coronary artery disease or hypertension. To investigate further, we compared changes in left ventricular myocardial gene expression in type 2 diabetes patients with patients in a control group with left ventricular hypertrophy. Nine control patients and seven patients with type 2 diabetes with aortic stenosis undergoing aortic valve replacement had standard ECGs, signal-averaged ECGs and echocardiograms before surgery. During surgery, a left ventricular biopsy was taken, and mRNA expressions for genes relevant to the cardiac action potential were estimated by RT-PCR. Mathematical modelling of the action potential and calcium transient was undertaken using the O'Hara-Rudy model using scaled changes in gene expression. Echocardiography revealed similar values for left ventricular size, filling pressures and ejection fraction between groups. No difference was seen in positive signal-averaged ECGs between groups, but the standard ECG demonstrated a prolonged QT interval in the diabetes group. Gene expression of KCNH2 and KCNJ3 were lower in the diabetes group, whereas KCNJ2, KCNJ5 and SLC8A1 expression were higher. Modelling suggested that these changes would lead to prolongation of the action potential duration with generation of early after-depolarizations secondary to a reduction in density of the rapid delayed rectifier K+ current and increased Na+ -Ca2+ exchange current. These data suggest that diabetes leads to pro-arrythmogenic changes in myocardial gene expression independently of left ventricular hypertrophy or fibrosis in an elderly population.

Obesity: a chronic relapsing progressive disease process. A position statement of the World Obesity Federation.

This paper considers the argument for obesity as a chronic relapsing disease process. Obesity is viewed from an epidemiological model, with an agent affecting the host and producing disease. Food is the primary agent, particularly foods that are high in energy density such as fat, or in sugar-sweetened beverages. An abundance of food, low physical activity and several other environmental factors interact with the genetic susceptibility of the host to produce positive energy balance. The majority of this excess energy is stored as fat in enlarged, and often more numerous fat cells, but some lipid may infiltrate other organs such as the liver (ectopic fat). The enlarged fat cells and ectopic fat produce and secrete a variety of metabolic, hormonal and inflammatory products that produce damage in organs such as the arteries, heart, liver, muscle and pancreas. The magnitude of the obesity and its adverse effects in individuals may relate to the virulence or toxicity of the environment and its interaction with the host. Thus, obesity fits the epidemiological model of a disease process except that the toxic or pathological agent is food rather than a microbe. Reversing obesity will prevent most of its detrimental effects.

Screening methods for obstructive sleep apnoea in severely obese pregnant women.

Obstructive sleep apnoea (OSA) is an often-overlooked diagnosis, more prevalent in the obese population. Screening method accuracy, uptake and hence diagnosis is variable. There is limited data available regarding the obese pregnant population; however, many studies highlight potential risks of apnoeic episodes to mother and foetus, including hypertension, diabetes and preeclampsia. A total of 162 women with a body mass index (BMI) ≥ 35 were recruited from a tertiary referral hospital in the northwest of England. They were invited to attend three research antenatal clinics, completing an Epworth Sleepiness Scale (ESS) questionnaire at each visit. A monitor measuring the apnoea hypopnoea index (AHI) was offered at the second visit. Data taken from consent forms, hospital notes and hospital computer records were collated and anonymized prior to statistical analysis. A total of 12.1% of women had an ESS score of >10, suggesting possible OSA. Rates increased throughout pregnancy, although unfortunately, the attrition rate was high; 29.0% of women used the RUSleeping (RUS) meter, and only one (2.1%) met pre-specified criteria for OSA (AHI ≥ 15). This individual had OSA categorized as severe and underwent investigations for preeclampsia, eventually delivering by emergency caesarean section due to foetal distress. The accuracy of the ESS questionnaire, particularly the RUS monitor, to screen for OSA in the pregnant population remains unclear. Further research on a larger sample size using more user-friendly technology to confidently measure AHI would be beneficial. There are currently no guidelines regarding screening for OSA in the obese pregnant population, yet risks to both mother and foetus are well researched.

Exposure-response analyses of liraglutide 3.0 mg for weight management.

AIMS: Liraglutide 3.0 mg, an acylated GLP-1 analogue approved for weight management, lowers body weight through decreased energy intake. We conducted exposure-response analyses to provide important information on individual responses to given drug doses, reflecting inter-individual variations in drug metabolism, absorption and excretion. METHODS: We report efficacy and safety responses across a wide range of exposure levels, using data from one phase II (liraglutide doses 1.2, 1.8, 2.4 and 3.0 mg), and two phase IIIa [SCALE Obesity and Prediabetes (3.0 mg); SCALE Diabetes (1.8; 3.0 mg)] randomized, placebo-controlled trials (n = 4372). RESULTS: There was a clear exposure-weight loss response. Weight loss increased with greater exposure and appeared to level off at the highest exposures associated with liraglutide 3.0 mg in most individuals, but did not fully plateau in men. In individuals with overweight/obesity and comorbid type 2 diabetes, there was a clear exposure-glycated haemoglobin (HbA1c) relationship. HbA1c reduction increased with higher plasma liraglutide concentration (plateauing at ∼21 nM); however, for individuals with baseline HbA1c >8.5%, HbA1c reduction did not fully plateau. No exposure-response relationship was identified for any safety outcome, with the exception of gastrointestinal adverse events (AEs). Individuals with gallbladder AEs, acute pancreatitis or malignant/breast/benign colorectal neoplasms did not have higher liraglutide exposure compared with the overall population. CONCLUSIONS: These analyses support the use of liraglutide 3.0 mg for weight management in all subgroups investigated; weight loss increased with higher drug exposure, with no concomitant deterioration in safety/tolerability besides previously known gastrointestinal side effects.

Fit for Birth - the effect of weight changes in obese pregnant women on maternal and neonatal outcomes: a pilot prospective cohort study.

UNLABELLED: The 'Fit for Birth' study aimed to explore patterns of gestational weight gain and their relationship with pregnancy outcomes. The study had three aims: 1. To explore the feasibility of conducting a large cohort study in this setting. 2. To describe patterns of weight gain through pregnancy in obese women. 3. To explore associations of weight change during pregnancy with outcomes. STUDY POPULATION: Pregnant women with a BMI ≥ 30 kg m(-2) at first antenatal clinic visit. METHODS: This was a single centre pilot observational study based at the Liverpool Women's Hospital, a large UK maternity hospital.Women were recruited into the study at their antenatal booking visit and had weights measured throughout pregnancy. Patterns of weight gain were described and related to maternal and neonatal outcomes. MAIN OUTCOME MEASURE: The primary outcome was a composite measure consisting of any of 12 adverse maternal and foetal outcomes. This was compared by categorized pregnancy weight gain (<0 kg, 0-5 kg, 5.1-9 kg and >9 kg). RESULTS: Eight hundred and twenty four women consented to participation between June 2009 and June 2010. Weight data were collected on 756 women. Only 385 women had weights measured in all three study assessment periods (6-20 weeks, 20 + 1 to 32 weeks and >32 weeks gestation) while 427 women had weights measured in period 3. Individual patterns of weight gain varied widely and missing data were common and non-random. There was a significant association between increased weight gain during pregnancy and poor maternal and foetal outcome. CONCLUSIONS: Weight gain in obese women during pregnancy can be highly variable. Our study supports an association between increased weight gain in pregnancy and adverse perinatal outcomes.

Role of incretin-based therapies and sodium-glucose co-transporter-2 inhibitors as adjuncts to insulin therapy in Type 2 diabetes, with special reference to IDegLira.

The progressive nature of Type 2 diabetes necessitates treatment intensification over time in order to maintain glycaemic control, with many patients ultimately requiring insulin therapy. While insulin has unlimited potential efficacy, its initiation is often delayed and improvements in glycaemic control are typically accompanied by weight gain and an increased risk of hypoglycaemia, particularly as HbA1c approaches and falls below target levels. This may account for the sub-optimal control often achieved after insulin initiation. Combining insulin with antihyperglycaemic therapies that have a low risk of hypoglycaemia and are weight-neutral or result in weight loss is a therapeutic strategy with the potential to improve Type 2 diabetes management. Although the effects differ with each individual class of therapy, clinical trials have shown that adding a glucagon-like peptide-1 receptor agonist, dipeptidyl peptidase-4 inhibitor or sodium-glucose co-transporter-2 inhibitor to insulin regimens can offer a significant reduction in HbA1c without substantially increasing hypoglycaemia risk, or weight. The evidence and merit of each approach are reviewed in this paper. Once-daily co-formulations of a basal insulin and a glucagon-like peptide-1 receptor agonist have been developed (insulin degludec/liraglutide) or are under development (lixisenatide/insulin glargine). Insulin degludec/liraglutide phase III trials and a lixisenatide/insulin glargine phase II trial have shown robust HbA1c reductions, with weight loss and a low risk of hypoglycaemia. With insulin degludec/liraglutide now approved in Europe, an important consideration will be the types of patients who may benefit most from a fixed-ratio combination; this is discussed in the present review, and we also take a look toward future developments in the field.

Energy balance and metabolic changes with sodium-glucose co-transporter 2 inhibition.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are the latest addition to the class of oral glucose-lowering drugs. They have been rapidly adopted into clinical practice because of therapeutic advantages, including weight loss and reduction in blood pressure, in addition to glycaemic benefits and a low intrinsic risk of hypoglycaemia. Although there are extensive data on the clinical effects of SGLT2 inhibition, the metabolic effects of inhibiting renal glucose reabsorption have not been fully described. Recent studies have identified compensatory metabolic effects, such as an increase in endogenous glucose production, and have also shown an increase in glucagon secretion during SGLT2 inhibition. In addition, there is a discrepancy between the expected and observed weight loss found in clinical studies on SGLT2 inhibitors, probably as a result of changes in energy balance with this treatment approach. SGLT2 inhibition is likely to have intriguing effects on whole body metabolism which have not been fully elucidated, and which, if explained, might help optimize the use of this new class of medicines.

Impact of bariatric surgery on physical functioning in obese adults.

Obesity is associated with a profound impairment in the ability to perform the basic physical activities required for everyday function. This impacts on quality of life and contributes to disability. Bariatric surgery leads to weight loss and metabolic improvements in severe obesity; however, less is known about its effect on physical functioning. This narrative review summarizes current evidence on the effect of bariatric surgery on this outcome with a consideration of the mechanisms involved. Nine longitudinal observational studies reporting objective measures of physical functioning were identified. Inclusion criteria, follow-up time and outcomes reported varied considerably between studies and sample sizes were small. They all showed a significant improvement in performance following surgery despite variations in baseline patient characteristics. Additionally, six studies were found in which subjects were subjected to exercise testing protocols. Performance of the test protocol improved in all. Where reported, peak oxygen uptake related to body weight improved; however, absolute values were either unchanged or decreased. In conclusion, observational evidence suggests that patients' physical functioning improves following bariatric surgery. More evidence is required regarding mechanisms involved; however, it may be due to improved efficiency in performing activities as opposed to absolute improvements in cardiorespiratory or muscle function.

Characteristics and perspectives of night-eating behaviour in a severely obese population.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Night-eating syndrome (NES) can be a feature of severe obesity. NES is a dysfunction of circadian rhythm and is associated with impaired sleep. WHAT THIS STUDY ADDS: Night eaters with severe obesity are more likely to be low in mood and unemployed compared with non-night eaters. Night eaters with severe obesity describe compulsive and uncontrolled eating. Research interest in night-eating syndrome (NES) has grown in recent years in line with increased rates of obesity. This study used a mixed-methods approach to investigate its characteristics in severe obesity. Eighty-one individuals (mean [standard deviation] age 44.6 [11.6] years, [body mass index] 50.0 [10.7] kg m(-2) ; 43% men) from a hospital-based UK obesity clinic were interviewed for NES based on 2003 criteria. Full and partial NES were combined into one night-eating behaviour (NEB) group (n = 31). Demographic and clinical characteristics were compared with those of non-NEB individuals (n = 50). NEB characteristics were also identified through exploratory thematic analysis of interview data. NEB individuals had lower mood (P = 0.01) and were less likely to be employed (P = 0.03). Differences in mean age and reported sleep duration were not significant. Thematic analysis of patient perceptions of NEB highlighted the potential heterogeneity of NEB development: NEB developed in childhood, adolescence and adulthood. Individuals reported long-standing and current sleep difficulties, negative affect and conflictful relationships. Night eating was solitary, compulsive and uncontrolled, and daytime eating patterns were chaotic. Accounts of awareness of night eating were conflicting. Severely obese night eaters are characterized by low mood and lack of employment. Further studies are required to explore behavioural and cognitive influences on night eating in severe obesity.

The importance of weight management in type 2 diabetes mellitus.

BACKGROUND: The obesity epidemic is driving the increased prevalence of type 2 diabetes mellitus (T2DM), and the vast majority of patients with T2DM are overweight or obese. Excess body weight is associated with the risk of cardiometabolic complications, which are major causes of morbidity and mortality in T2DM. AIMS: To review evidence about effects of weight loss in pre-diabetes and established T2DM. RESULTS: In prediabetes, weight loss has been shown to delay the onset or decrease the risk of T2DM, while in established T2DM weight loss has been shown to improve glycaemic control, with severe calorie restriction even reversing the progression of T2DM. Observational studies support the reduction in cardiovascular risk factors following weight loss in patients with T2DM. However, data from the randomised Look AHEAD trial revealed intensive weight loss interventions did not reduce the rate of cardiovascular events in overweight or obese adults with T2DM, and secondary analyses of other large cardiovascular outcomes trials have also been inconclusive. However, besides cardiovascular risk, other documented benefits of weight loss in T2DM include improvements in quality of life, mobility, and physical and sexual function. CONCLUSIONS: Physicians should encourage weight loss in all overweight patients with or at risk of T2DM, and should consider the impact on weight when choosing the most appropriate glucose-lowering therapies for these patients.

Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: efficacy and safety over 2 years.

AIMS: Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), has been shown to improve glycaemic control, stabilize insulin dosing and mitigate insulin-associated weight gain over 48 weeks in patients whose type 2 diabetes mellitus (T2DM) was inadequately controlled despite high doses of insulin. Here the efficacy and safety of dapagliflozin therapy after a total of 104 weeks are evaluated in this population. METHODS: This was a 24-week, randomized, placebo-controlled, double-blinded, multicentre trial followed by two site- and patient-blinded extension periods of 24 and 56 weeks (NCT00673231), respectively. A total of 808 patients, whose T2DM was inadequately controlled on insulin ≥30 IU/day, with or without up to two oral antidiabetic drugs, were randomly assigned to receive placebo or 2.5, 5 or 10 mg/day of dapagliflozin for 104 weeks. At 48 weeks, patients on dapagliflozin 5 mg were switched to 10 mg. Outcomes over 104 weeks included change from baseline in HbA1c, insulin dose and body weight; analyses used observed cases and included data after insulin up-titration. Adverse events (AEs) were evaluated throughout 104 weeks. RESULTS: Five hundred and thirteen patients (63.6%) completed the study. Mean HbA1c changes from baseline at 104 weeks were -0.4% in the placebo group and -0.6 to -0.8% in the dapagliflozin groups. In the placebo group, mean insulin dose increased by 18.3 IU/day and weight increased by 1.8 kg at 104 weeks, whereas in the dapagliflozin groups, insulin dose was stable and weight decreased by 0.9-1.4 kg. AEs, including hypoglycaemia, were balanced across groups. Proportions of patients with events suggestive of genital infection and of urinary tract infection (UTI) were higher with dapagliflozin versus placebo (genital infection 7.4-14.3% vs. 3.0%; UTI 8.4-13.8% vs. 5.6%) but most occurred in the first 24 weeks and most were single episodes that responded to routine management. CONCLUSIONS: Dapagliflozin improved glycaemic control, stabilized insulin dosing and reduced weight without increasing major hypoglycaemic episodes over 104 weeks in patients whose T2DM was inadequately controlled on insulin. However, rates of genital infection and of UTI were elevated with dapagliflozin therapy.

Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial.

AIMS: Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed for the treatment of type 2 diabetes mellitus (T2DM). This randomised, double-blind, placebo-controlled, Phase 3 study evaluated the efficacy and safety of canagliflozin as an add-on to metformin plus sulphonylurea in patients with T2DM. METHODS: Patients (N = 469) received canagliflozin 100 or 300 mg or placebo once daily during a 26-week core period and a 26-week extension. Prespecified primary end-point was change in HbA1c at 26 weeks. Secondary end-points included change in HbA1c at week 52 as well as proportion of patients achieving HbA1c < 7.0%, change in fasting plasma glucose (FPG) and systolic blood pressure, and per cent change in body weight, high-density lipoprotein cholesterol, and triglycerides (weeks 26 and 52). RESULTS: HbA1c was significantly reduced with canagliflozin 100 and 300 mg vs. placebo at week 26 (-0.85%, -1.06%, and -0.13%; p < 0.001); these reductions were maintained at week 52 (-0.74%, -0.96%, and 0.01%). Both canagliflozin doses reduced FPG and body weight vs. placebo at week 26 (p < 0.001) and week 52. Overall adverse event (AE) rates were similar across groups over 52 weeks, with higher rates of genital mycotic infections and osmotic diuresis-related AEs seen with canagliflozin vs. placebo; these led to few discontinuations. Increased incidence of documented, but not severe, hypoglycaemia episodes was seen with canagliflozin vs. placebo. CONCLUSIONS: Canagliflozin improved glycaemic control, reduced body weight, and was generally well tolerated in T2DM patients on metformin plus sulphonylurea over 52 weeks.

[Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin]. / Langzeitwirkung von Dapagliflozin bei Typ-2-Diabetikern unter hoch dosierter Insulintherapie.

BACKGROUND: Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2, may improve glycemic control with a lower dose of insulin and attenuate the associated weight gain in patients with inadequate control despite high doses of insulin. OBJECTIVE: To evaluate the efficacy and safety of adding dapagliflozin therapy in patients whose type 2 diabetes mellitus is inadequately controlled with insulin with or without oral antidiabetic drugs. DESIGN: A 24-week, randomized, placebo-controlled, multicenter trial followed by a 24-week extension period. An additional 56-week extension period is ongoing. (ClinicalTrials.gov registration number: NCT00673231). SETTING: 126 centers in Europe and North America from 30 April 2008 to 19 November 2009. PATIENTS: 808 patients with inadequately controlled type 2 diabetes mellitus receiving at least 30 U of insulin daily, with or without up to 2 oral antidiabetic drugs. INTERVENTION: Patients were randomly assigned in a 1:1:1:1 ratio and allocated with a computer-generated scheme to receive placebo or 2.5, 5, or 10 mg of dapagliflozin, once daily, for 48 weeks. MEASUREMENTS: The primary outcome was change in hemoglobin A1c from baseline to 24 weeks. Secondary outcomes included changes in body weight, insulin dose, and fasting plasma glucose level at 24 weeks and during the 24-week extension period. Adverse events were evaluated throughout both 24-week periods. RESULTS: 800 patients were analyzed. After 24 weeks, mean hemoglobin A1c decreased by 0.79 % to 0.96 % with dapagliflozin compared with 0.39 % with placebo (mean difference, -0.40 % [95 % CI, -0.54 % to -0.25 %] in the 2.5-mg group, -0.49 % [CI, -0.65 % to -0.34 %] in the 5-mg group, and -0.57 % [CI, -0.72 % to -0.42 %] in the 10-mg group). Daily insulin dose decreased by 0.63 to 1.95 U with dapagliflozin and increased by 5.65 U with placebo (mean difference, -7.60 U [CI, -10.32 to -4.87 U] in the 2.5-mg group, -6.28 U [CI, -8.99 to -3.58 U] in the 5-mg group, and -6.82 U [CI, -9.56 to -4.09 U] in the 10-mg group). Body weight decreased by 0.92 to 1.61 kg with dapagliflozin and increased by 0.43 kg with placebo (mean differences, -1.35 kg [CI, -1.90 to -0.80 kg] in the 2.5-mg group, -1.42 kg [CI, -1.97 to -0.88 kg] in the 5-mg group, and -2.04 kg [CI, -2.59 to -1.48 kg] in the 10-mg group). These effects were maintained at 48 weeks. Compared with the placebo group, patients in the pooled dapagliflozin groups had a higher rate of hypoglycemic episodes (56.6 % vs. 51.8 %), events suggesting genital infection (9.0 % vs. 2.5 %), and events suggesting urinary tract infection (9.7 % vs. 5.1 %). LIMITATION: Insulin doses were not titrated to target, and the study was not designed to evaluate long-term safety. CONCLUSION: Dapagliflozin improves glycemic control, stabilizes insulin dosing, and reduces weight without increasing major hypoglycemic episodes in patients with inadequately controlled type 2 diabetes mellitus.

Dose-ranging study with the glucokinase activator AZD1656 in patients with type 2 diabetes mellitus on metformin.

AIM: To investigate the effect of glucokinase activator AZD1656 on glycated haemoglobin (HbA1c) as an add-on to metformin in patients with type 2 diabetes. METHODS: This randomized, double-blind, placebo-controlled study (NCT01020123) was conducted over 4 months with an optional 2-month extension. Patients (n = 458) with HbA1c 7.5-10% were randomized to AZD1656 20 mg (n = 40) or 40 mg (n = 52) fixed doses or 10-140 mg (n = 91) or 20-200 mg (n = 93) titrated doses, placebo (n = 88) or glipizide 5-20 mg titrated (n = 94). Patients (n = 72) with HbA1c >10 and ≤12% received open-label AZD1656 (20-200 mg titrated). Primary outcome was placebo-corrected change in HbA1c from baseline to 4 months of treatment. RESULTS: Significant reductions in HbA1c from baseline to 4 months were observed with blinded AZD1656 10-140 and 20-200 mg versus placebo [mean (95% CI) changes: -0.80 (-1.14; -0.46) and -0.81 (-1.14; -0.47) %, respectively), with similar reductions observed with glipizide. A higher percentage of patients on AZD1656 than on placebo achieved HbA1c ≤7.0 or ≤6.5 % after 4 months. Mean (s.d.) change in HbA1c for open-label AZD1656 (20-200 mg) was -2.8 (1.19) % after 4 months. AZD1656 was well tolerated, with less hypoglycaemia than glipizide. In the extension population, HbA1c was still reduced with AZD1656 versus placebo after 6 months, but the effect of AZD1656 on glucose control was not sustained over time. CONCLUSION: Addition of AZD1656 (individually titrated) to metformin gave significant improvements in glycaemic control up to 4 months, although efficacy diminished over time.

Efficacy and safety of ipragliflozin in patients with type 2 diabetes inadequately controlled on metformin: a dose-finding study.

AIMS: Ipragliflozin is a novel, selective inhibitor of sodium glucose co-transporter 2 (SGLT2 inhibitor) in clinical development for type 2 diabetes mellitus (T2DM) treatment. This study assessed the efficacy and safety of different doses of ipragliflozin. METHODS: In a 12-week, multicentre, double-blind, randomized, placebo-controlled, dose-finding study patients with inadequate glycaemic control on metformin monotherapy (≥1500 mg/day) were randomized to one of four ipragliflozin treatment groups (12.5, 50, 150 or 300 mg once daily) or placebo. Primary efficacy outcome was mean change from baseline in haemoglobin A1c (HbA1c) compared to placebo at week 12. Adverse events (AEs), vital signs and laboratory safety measurements were assessed. RESULTS: Ipragliflozin dose dependently decreased HbA1c from baseline to week 12 compared to placebo (-0.22, -0.34, -0.40 and -0.48% for ipragliflozin 12.5, 50, 150 and 300 mg, respectively). Decreases in body weight and blood pressure were observed for all ipragliflozin groups. AEs occurred in 39.7-51.4% of the ipragliflozin groups and 39.4% of placebo patients. Urinary tract infections (1.4-6.9 vs. 6.1%), genital infections (0-4.3 vs. 1.5%) and hypoglycaemia (0-5.9 vs. 3.0%) were similar in the ipragliflozin and placebo groups, respectively, without dose dependency. There were no clinically relevant effects on other safety measurements. CONCLUSIONS: Ipragliflozin treatment improved glycaemic control when added to metformin therapy and may be associated with weight loss and reductions in blood pressure compared to placebo. No safety or tolerability concerns were identified at any of the tested doses supporting the further development of ipragliflozin at ≥50 mg doses in T2DM patients.