Showing papers in "Diabetes, Obesity and Metabolism in 2013"

Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes.

Abstract: Aims Sodium–glucose co-transporter 2 (SGLT2) reabsorbs glucose and sodium in the renal proximal tubule. Dapagliflozin, an SGLT2 inhibitor, targets hyperglycaemia in type 2 diabetes by increasing renal glucose excretion. To investigate whether the parallel occurring sodium loss would have diuretic-like physiologic effects, we compared dapagliflozin and hydrochlorothiazide (HCTZ) effects on 24-h blood pressure (BP), body weight, plasma volume and glomerular filtration rate (GFR). Methods In this randomized, placebo-controlled, double-blind trial, 75 subjects with type 2 diabetes were assigned placebo, dapagliflozin 10 mg/day, or HCTZ 25 mg/day. Changes from baseline BP, body weight, plasma volume and GFR were assessed after 12 weeks of treatment. Results Subjects' mean age was 56 years, type 2 diabetes mellitus (T2DM) duration 6.3 years, and haemoglobin A1c (HbA1c) 7.5%. Treatment with placebo, dapagliflozin or HCTZ resulted in changes from baseline in 24-h ambulatory mean systolic blood pressure (SBP) of −0.9 (95%CI −4.2, +2.4), −3.3 (95%CI −6.8, +0.2), and −6.6 (95%CI −9.9, −3.2) mmHg, respectively at week 12, adjusted for baseline SBP. Body weight decreased with dapagliflozin and HCTZ. In a sub-study plasma volume appeared to decrease with dapagliflozin but did not change with placebo or HCTZ treatment. Dapagliflozin induced a greater reduction in GFR (−10.8%; 95%CI −14.6, −6.7) relative to placebo (−2.9%; 95% CI −6.9, +1.2) or HCTZ (−3.4%; 95%CI −7.3, +0.6). Conclusions Dapagliflozin-induced SGLT2 inhibition for 12 weeks is associated with reductions in 24-h BP, body weight, GFR and possibly plasma volume. Cumulatively, these effects suggest that dapagliflozin may have a diuretic-like capacity to lower BP in addition to beneficial effects on glycaemic control.

Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise

Abstract: Aims Canagliflozin is a sodium glucose co-transporter 2 inhibitor in development for type 2 diabetes mellitus (T2DM). The efficacy and safety of canagliflozin were evaluated in subjects with T2DM inadequately controlled with diet and exercise. Methods In this 26-week, randomized, double-blind, placebo-controlled, phase 3 trial, subjects (N = 584) received canagliflozin 100 or 300 mg or placebo once daily. Primary endpoint was the change from baseline in haemoglobin A1c (HbA1c) at week 26. Secondary endpoints included the proportion of subjects achieving HbA1c < 7.0%; change from baseline in fasting plasma glucose (FPG), 2-h postprandial glucose (PPG) and systolic blood pressure (BP); and percent change in body weight, high-density lipoprotein cholesterol (HDL-C) and triglycerides. Adverse events (AEs) were recorded throughout the study. Results At week 26, HbA1c was significantly reduced from baseline with canagliflozin 100 and 300 mg compared with placebo (−0.77, −1.03 and 0.14%, respectively; p < 0.001 for both). Both canagliflozin doses significantly decreased FPG, 2-h PPG, body weight and systolic BP (p < 0.001 for all), and increased HDL-C compared with placebo (p < 0.01 for both). Overall incidences of AEs were modestly higher with canagliflozin versus placebo; rates of serious AEs and AE-related discontinuations were low and similar across groups. Incidences of genital mycotic infections, urinary tract infections and osmotic diuresis-related AEs were higher with canagliflozin; these led to few discontinuations. The incidence of hypoglycaemia was low across groups. Conclusion Canagliflozin treatment improved glycaemic control, reduced body weight and was generally well tolerated in subjects with T2DM inadequately controlled with diet and exercise.

Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease

Abstract: Aims Canagliflozin is a sodium glucose co-transporter 2 inhibitor in development for treatment of type 2 diabetes mellitus (T2DM). This study evaluated the efficacy and safety of canagliflozin in subjects with T2DM and stage 3 chronic kidney disease [CKD; estimated glomerular filtration rate (eGFR) ≥30 and <50 ml/min/1.73 m2]. Methods In this randomized, double-blind, placebo-controlled, phase 3 trial, subjects (N = 269) received canagliflozin 100 or 300 mg or placebo daily. The primary efficacy endpoint was change from baseline in HbA1c at week 26. Prespecified secondary endpoints were change in fasting plasma glucose (FPG) and proportion of subjects reaching HbA1c <7.0%. Safety was assessed based on adverse event (AE) reports; renal safety parameters (e.g. eGFR, blood urea nitrogen and albumin/creatinine ratio) were also evaluated. Results Both canagliflozin 100 and 300 mg reduced HbA1c from baseline compared with placebo at week 26 (–0.33, –0.44 and –0.03%; p < 0.05). Numerical reductions in FPG and higher proportions of subjects reaching HbA1c < 7.0% were observed with canagliflozin 100 and 300 mg versus placebo (27.3, 32.6 and 17.2%). Overall AE rates were similar for canagliflozin 100 and 300 mg and placebo (78.9, 74.2 and 74.4%). Slightly higher rates of urinary tract infections and AEs related to osmotic diuresis and reduced intravascular volume were observed with canagliflozin 300 mg compared with other groups. Transient changes in renal function parameters that trended towards baseline over 26 weeks were observed with canagliflozin. Conclusion Canagliflozin improved glycaemic control and was generally well tolerated in subjects with T2DM and Stage 3 CKD.

Hypoglycaemia risk with insulin degludec compared with insulin glargine in type 2 and type 1 diabetes: a pre-planned meta-analysis of phase 3 trials

Abstract: Aim Hypoglycaemia and the fear of hypoglycaemia are barriers to achieving normoglycaemia with insulin. Insulin degludec (IDeg) has an ultra-long and stable glucose-lowering effect, with low day-to-day variability. This pre-planned meta-analysis aimed to demonstrate the superiority of IDeg over insulin glargine (IGlar) in terms of fewer hypoglycaemic episodes at equivalent HbA1c in type 2 and type 1 diabetes mellitus (T2DM/T1DM). Methods Pooled patient-level data for self-reported hypoglycaemia from all seven (five in T2DM and two in T1DM) randomized, controlled, phase 3a, treat-to-target trials in the IDeg clinical development programme comparing IDeg once-daily (OD) vs. IGlar OD were analysed. Results Four thousand three hundred and thirty subjects (2899 IDeg OD vs. 1431 IGlar OD) were analysed. Among insulin-naive T2DM subjects, significantly lower rates of overall confirmed, nocturnal confirmed and severe hypoglycaemic episodes were reported with IDeg vs. IGlar: estimated rate ratio (RR):0.83[0.70;0.98]95%CI, RR:0.64[0.48;0.86]95%CI and RR:0.14[0.03;0.70]95%CI. In the overall T2DM population, significantly lower rates of overall confirmed and nocturnal confirmed episodes were reported with IDeg vs. IGlar [RR:0.83[0.74;0.94]95%CI and RR:0.68[0.57;0.82]95%CI). In the T1DM population, the rate of nocturnal confirmed episodes was significantly lower with IDeg vs. IGlar during maintenance treatment (RR:0.75[0.60;0.94]95%CI). Reduction in hypoglycaemia with IDeg vs. IGlar was more pronounced during maintenance treatment in all populations. Conclusions The limitations of this study include the open-label design and exclusion of subjects with recurrent severe hypoglycaemia. This meta-analysis confirms that similar improvements in HbA1c can be achieved with fewer hypoglycaemic episodes, particularly nocturnal episodes, with IDeg vs. IGlar across a broad spectrum of patients with diabetes.

GLP-1 receptor activated insulin secretion from pancreatic β-cells: mechanism and glucose dependence

Abstract: The major goal in the treatment of type 2 diabetes mellitus is to control the hyperglycaemia characteristic of the disease. However, treatment with common therapies such as insulin or insulinotrophic sulphonylureas (SU), while effective in reducing hyperglycaemia, may impose a greater risk of hypoglycaemia, as neither therapy is self-regulated by ambient blood glucose concentrations. Hypoglycaemia has been associated with adverse physical and psychological outcomes and may contribute to negative cardiovascular events; hence minimization of hypoglycaemia risk is clinically advantageous. Stimulation of insulin secretion from pancreatic β-cells by glucagon-like peptide 1 receptor (GLP-1R) agonists is known to be glucose-dependent. GLP-1R agonists potentiate glucose-stimulated insulin secretion and have little or no activity on insulin secretion in the absence of elevated blood glucose concentrations. This ‘glucose-regulated’ activity of GLP-1R agonists makes them useful and potentially safer therapeutics for overall glucose control compared to non-regulated therapies; hyperglycaemia can be reduced with minimal hypoglycaemia. While the inherent mechanism of action of GLP-1R agonists mediates their glucose dependence, studies in rats suggest that SUs may uncouple this dependence. This hypothesis is supported by clinical studies showing that the majority of events of hypoglycaemia in patients treated with GLP-1R agonists occur in patients treated with a concomitant SU. This review aims to discuss the current understanding of the mechanisms by which GLP-1R signalling promotes insulin secretion from pancreatic β-cells via a glucose-dependent process.

The immune cells in adipose tissue.

Abstract: Although the pathological role of the immune system in several metabolic disorders, including type 1 diabetes mellitus (T1DM) and Addison's disease, has long been recognized and studied, only in the last decade has it become apparent that the immune system plays a broad and more subtle role in local and systemic metabolism. It is now apparent that the immune system monitors and responds to specific metabolic cues in both pathologic and non-pathologic settings through a set of processes dubbed immunometabolism. Expansion of adipose tissue mass, activation of lipolysis, eating a high fat diet and even non-shivering thermogenesis all lead to the recruitment and activation of immune cells in key metabolic tissues. The responses are complex and not completely defined, and indeed, as is typical of rapidly evolving research areas, there are some conflicting reports, especially related to the metabolic consequences of manipulation of immune function. However, what is clear is the consensus that metabolic processes, especially obesity and obesity-related complications, activate both the innate and adaptive arms of the immune system. Canonical immune processes consist of discrete steps: surveillance, recognition, effector action and resolution. Over the last decade evidence for each part of the immune response has been found at the intersection of the immune system with metabolism. Although evidence for immune surveillance and modulation of metabolism has been found in the liver, muscle, hypothalamus and pancreas, immune cell function has been most intensively studied and best understood in adipose tissue where studies continue to provide insights into the intersection of the metabolic and immune systems. Here we review the modulation of immune cell populations in adipose tissue and discuss regulatory processes implicated in controlling the interface between metabolism and immunologic function.

Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical trials

Abstract: Aims Preliminary data from randomized trials with metabolic outcomes have shown that treatment with dipeptidyl peptidase-4 inhibitors (DPP4i) could be associated with a reduced incidence of major cardiovascular events (MACE). The present meta-analysis is aimed at verifying this protective effect, collecting all available data from randomized trials. Methods A comprehensive search for published and unpublished trials with a duration =24 weeks comparing DPP4i with placebo or other drugs was performed, retrieving all MACE reported as serious adverse events together with death from any cause. MantelHaenzel odds ratio (MHOR) was calculated with random effect models for MACE, myocardial infarction, stroke and mortality. When available, effects on glycated haemoglobin, lipid profile and blood pressure were also assessed and used for the estimation of the modification of risk for myocardial infarction using the UKPDS risk engine. Results A total of 70 trials, enrolling 41?959 patients with a mean follow-up of 44.1 weeks, was collected and included in the analysis. The MHOR (95% Confidence Interval) was 0.71[0.59;0.86], 0.64[0.44;0.94], 0.77[0.48;1.24] and 0.60[0.41;0.88] for MACE, myocardial infarction, stroke and mortality, respectively. Conclusions Treatment with DPP4i reduces the risk of cardiovascular events (particularly myocardial infarction) and all-cause mortality in patients with type 2 diabetes. The reduction in the incidence of myocardial infarction is greater than what predicted on the basis of conventional risk factors, suggesting a role for other mechanisms. (Less)

Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks' treatment with empagliflozin once daily in patients with type 2 diabetes.

Abstract: Aim To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of empagliflozin in patients with type 2 diabetes following oral administration of 10, 25 or 100 mg doses once daily over 28 days. Methods A total of 78 patients were assigned to empagliflozin 10 mg (n = 16), 25 mg (n = 16) or 100 mg (n = 30) or placebo (n = 16) for 28 days. Assessments included adverse events (AEs) and pharmacokinetic and pharmacodynamic endpoints. Results Empagliflozin exposure increased dose-proportionally over the dose range 10–100 mg and showed linear pharmacokinetics with respect to time. Urinary glucose excretion (UGE) increased from baseline to day 1 by 74, 90 and 81 g with empagliflozin 10, 25 and 100 mg, respectively. The increases in UGE were maintained over 28 days with multiple dosing. Virtually no change in UGE was observed in the placebo group. Significant reductions from baseline in mean daily plasma glucose and fasting plasma glucose were observed with empagliflozin compared with placebo. The incidence of AEs was similar in the empagliflozin and placebo groups (50.0, 56.3 and 66.7% with empagliflozin rising doses and 62.5% with placebo). The most frequently reported AEs were pollakiuria (10.3%), nasopharyngitis (9.0%), constipation (9.0%) and headache (7.7%). Conclusions Oral administration of empagliflozin at doses of 10, 25 or 100 mg once daily over 28 days resulted in significant increases in UGE and reductions in blood glucose compared with placebo, and were well tolerated in patients with type 2 diabetes.

Cardiovascular safety of sulfonylureas: a meta-analysis of randomized clinical trials.

Abstract: Aim Cardiovascular safety of sulfonylurea has been questioned by some authors. This article aims at collecting all available data on this issue from randomized trials. Methods A meta-analysis was performed including all trials with a duration of at least 6 months, comparing a sulfonylurea with a non-sulfonylurea agent in type 2 diabetes. Major cardiovascular events (MACE) and mortality were retrieved and combined to calculate Mantel-Haenzel odds ratio (MH-OR). Results Of the 115 selected trials, 62 reported information on MACE, and 30 reported at least one event. MH-OR for sulfonylurea was 1.08 [0.86–1.36], p = 0.52 (1.85 [1.20–2.87], p = 0.005, in the five trials vs. DPP4 inhibitors, no significant differences vs. other comparators). The MH-OR for myocardial infarction and stroke was 0.88 [0.75–1.04], p = 0.13 and 1.28 [1.03–1.60], p = 0.026, respectively. Mortality was significantly increased with sulfonylureas (MH-OR: 1.22 [1.01–1.49], p = 0.047). Conclusions In type 2 diabetes, the use of sulfonylureas is associated with increased mortality and a higher risk of stroke, whereas the overall incidence of MACE appears to be unaffected. Significant differences in cardiovascular risk could be present in direct comparisons with specific classes of glucose-lowering agents, such as DPP4 inhibitors, but this hypothesis needs to be confirmed in long-term cardiovascular outcomes trials. The results of this meta-analysis need to be interpreted with caution, mainly because of limitations in trial quality and under-reporting of information on cardiovascular events and mortality. However, the cardiovascular safety of sulfonylureas cannot be considered established unless it is evaluated in long-term cardiovascular outcomes trials.

The effect of physical activity on mediators of inflammation

Abstract: Being physically active and undertaking exercise on a regular basis are critical lifestyle behaviours which protect against the development of numerous chronic metabolic conditions. One of the key mechanisms by which physical activity exerts favourable health effects appears to be due to its capacity to reduce chronic low-grade inflammation. Single bouts of exercise have a potent anti-inflammatory influence with recent advances describing important effects of acute exercise on inflammatory mediators produced within skeletal muscle (myokines), adipose tissue (adipokines) and leucocytes. The accumulated effects of physical activity or exercise training on systemic inflammation have been studied widely within epidemiological research; however, information from intervention trials is still emerging. Current data suggest that the most marked improvements in the inflammatory profile are conferred with exercise performed at higher intensities, with combined aerobic and resistance exercise training potentially providing the greatest benefit. The purpose of this review is to describe recent advances in our understanding surrounding the acute and chronic effects of physical activity on key mediators of inflammation. Within this, particular attention is given to the interleukin-6 system owing to its apparent centrality in mediating the anti-inflammatory effects of exercise.

Efficacy and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, as add-on to metformin in type 2 diabetes with mild hyperglycaemia.

Abstract: Aims To evaluate the effects of the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin added to metformin for 12 weeks in patients with type 2 diabetes. Methods This dose-ranging, double-blind, placebo-controlled trial randomized 495 participants with type 2 diabetes inadequately controlled on metformin [haemoglobin A1c (HbA1c) >7 to ≤10%] to receive 1, 5, 10, 25, or 50 mg empagliflozin once daily (QD), or placebo, or open-label sitagliptin (100 mg QD), added to metformin for 12 weeks. The primary endpoint was change in HbA1c from baseline to week 12 (empagliflozin groups versus placebo). Results Reductions in HbA1c of −0.09 to −0.56% were observed with empagliflozin after 12 weeks, versus an increase of 0.15% with placebo (baseline: 7.8–8.1%). Compared with placebo, empagliflozin doses from 5 to 50 mg resulted in reductions in fasting plasma glucose (−2 to −28 mg/dl vs. 5 mg/dl with placebo; p < 0.0001) and body weight (−2.3 to −2.9 kg vs. −1.2 kg; p < 0.01). Frequency of adverse events was generally similar with empagliflozin (29.6–48.6%), placebo (36.6%) and sitagliptin (35.2%). Hypoglycaemia rates were very low and balanced among groups. Most frequent adverse events with empagliflozin were urinary tract infections (4.0% vs. 2.8% with placebo) and pollakiuria (2.5% vs. 1.4% with placebo). Genital infections were reported only with empagliflozin (4.0%). Conclusions Once daily empagliflozin as add-on therapy to metformin was well tolerated except for increased genital infections and resulted in reductions in HbA1c, fasting plasma glucose and body weight in patients with type 2 diabetes inadequately controlled on metformin monotherapy.

Pharmacodynamic characteristics of lixisenatide once daily versus liraglutide once daily in patients with type 2 diabetes insufficiently controlled on metformin

Abstract: Aim Assess the pharmacodynamics of lixisenatide once daily (QD) versus liraglutide QD in type 2 diabetes insufficiently controlled on metformin.

Blood pressure-lowering effects of GLP-1 receptor agonists exenatide and liraglutide: a meta-analysis of clinical trials.

Abstract: Aims Aside from lowering blood glucose, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) attract much attention because of their cardioprotective effects. The aim of this study was to assess the blood pressure-lowering effects of the GLP-1 RAs exenatide and liraglutide compared with other common drugs used to treat type 2 diabetes (T2DM) based on randomized controlled trials (RCTs) including data describing complete blood pressure (BP) changes from baseline. Methods We searched the major databases for published or unpublished RCTs that had been performed in patients with T2DM and compared the effects of exenatide and liraglutide to those of other common drugs used to treat T2DM. The RCTs that included data describing BP changes between the baseline and the end of the study were selected for further analysis. Results A total of 16 RCTs that enrolled 3443 patients in the GLP-1 RA treatment group and 2417 subjects in the control group were included in this meta-analysis. The GLP-1 RA exenatide reduced systolic blood pressure (SBP) when compared with both placebo and insulin glargine, with mean differences of −5.24 and −3.46 mmHg, respectively, and with 95% confidence intervals (CI) of −6.88 to −3.59, p < 0.00001 and −3.63 to −3.29, p < 0.00001, respectively. Meanwhile, in the exenatide-treated group, diastolic blood pressure (DBP) was reduced by −5.91 mmHg, with a 95% CI of −7.53 to −4.28, p < 0.00001 compared with the placebo group, and −0.99 mmHg with a 95% CI of −1.12 to −0.87, p < 0.00001 compared with the sitagliptin group. SBP changes in this meta-analysis were assessed in the groups treated with 1.2 or 1.8 mg liraglutide per day. In the 1.2 mg-treated group, liraglutide treatment reduced SBP compared with placebo and glimepiride treatment, with mean differences of −5.60 and −2.38 mmHg, and 95% CIs of −5.84 to −5.36, p < 0.00001 and −4.75 to −0.01, p = 0.05, respectively. In the 1.8-mg-treated group, liraglutide also reduced SBP compared with placebo and glimepiride treatment with mean differences of −4.49 and −2.62 mmHg, and a 95% CI of −4.73 to −4.26, p < 0.00001, and −2.91 to −2.33, p < 0.00001, respectively. Conclusion Treatment with the GLP-1 RAs exenatide and liraglutide reduced SBP and DBP by 1 to 5 mmHg compared with some other anti-diabetic drugs including insulin, glimepiride and placebo for patients with T2DM. GLP-1 RAs may offer an alternative therapy for these patients and will help provide extra cardiovascular benefits.

The importance of NAMPT/NAD/SIRT1 in the systemic regulation of metabolism and ageing.

Abstract: Ageing is associated with a variety of pathophysiological changes, including development of insulin resistance, progressive decline in β-cell function and chronic inflammation, all of which affect metabolic homeostasis in response to nutritional and environmental stimuli. SIRT1, the mammalian nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase, and nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting NAD biosynthetic enzyme, together comprise a novel systemic regulatory network, named the 'NAD World', that orchestrates physiological responses to internal and external perturbations and maintains the robustness of the physiological system in mammals. In the past decade, an accumulating body of evidence has demonstrated that SIRT1 and NAMPT, two essential components in the NAD World, play a critical role in regulating insulin sensitivity and insulin secretion throughout the body. In this article, we will summarize the physiological significance of SIRT1 and NAMPT-mediated NAD biosynthesis in metabolic regulation and discuss the ideas of functional hierarchy and frailty in determining the robustness of the system. We will also discuss the potential of key NAD intermediates as effective nutriceuticals for the prevention and the treatment of age-associated metabolic complications, such as type 2 diabetes.

A Phase IIb, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes

Abstract: Aim This Phase IIb, randomized, double-blind, placebo-controlled trial evaluated the efficacy, safety, tolerability and pharmacokinetics of empagliflozin in patients with type 2 diabetes. Methods Four hundred and eight patients (treatment-naive or after a 4-week wash-out period) were randomized to receive empagliflozin 5, 10 or 25 mg once daily, placebo or open-label metformin for 12 weeks. The primary endpoint was change in haemoglobin A1c (HbA1c) after 12 weeks. Results After 12 weeks' treatment, empagliflozin showed dose-dependent reductions in HbA1c from baseline [5 mg: −0.4%, 10 mg: −0.5%, 25 mg: −0.6%; all doses p < 0.0001 vs. placebo (+0.09%)]. Fasting plasma glucose (FPG) decreased with empagliflozin [5 mg: −1.29 mmol/l, 10 mg: −1.61 mmol/l, 25 mg: −1.72 mmol/l; all doses p < 0.0001 vs. placebo (+0.04 mmol/l)]. Body weight decreased in all empagliflozin groups (all doses p < 0.001 vs. placebo). The incidence of adverse events (AEs) was similar in the placebo (32.9%) and empagliflozin (29.1%) groups. The most frequently reported AEs on empagliflozin were pollakiuria (3.3% vs. 0% for placebo), thirst (3.3% vs. 0% for placebo) and nasopharyngitis (2.0% vs. 1.2% for placebo). AEs consistent with urinary tract infections (UTIs) were reported in four (1.6%) patients on empagliflozin vs. one (1.2%) on placebo. Genital infections were reported in five (2%) patients on empagliflozin vs. 0% on placebo. No UTIs or genital infections led to premature discontinuation. Conclusions In patients with type 2 diabetes, empagliflozin resulted in dose-dependent, clinically meaningful reductions in HbA1c and FPG, and reductions in body weight compared with placebo. Empagliflozin was well-tolerated with a favourable safety profile.

Anti‐inflammatory cytokines and risk of type 2 diabetes

Abstract: Proinflammatory processes have been investigated extensively in the development of type 2 diabetes, but our knowledge on anti-inflammatory proteins is rather limited. This article summarizes studies that investigated associations between circulating levels of anti-inflammatory cytokines and incident type 2 diabetes preferably in prospective epidemiological studies. Adiponectin is the only known anti-inflammatory protein whose circulating levels are decreased before type 2 diabetes. In contrast, concentrations of interleukin-1 receptor antagonist (IL-1RA), transforming growth factor-β1 (TGF-β1) and growth differentiation factor-15 (GDF-15) are increased and indicate the presence of a compensatory, but eventually futile, counter-regulation of proinflammatory stimuli. Importantly, a proof-of-principle study using recombinant IL-1RA to improve metabolic control in patients with type 2 diabetes demonstrated that a more pronounced upregulation of this protein than that found in the natural course of diabetes development may have clinical relevance. Other interesting candidates like omentin (which shows similar associations with metabolic parameters as adiponectin), interleukin-10 (IL-10) and secreted frizzled-related protein-5 (Sfrp5) are currently less well studied with sometimes conflicting results regarding their association with type 2 diabetes. Thus, further research is required to better understand the causal role of proinflammatory cytokines, hypoadiponectinaemia and the upregulation of anti-inflammatory proteins before the onset of type 2 diabetes.

Efficacy and safety of lixisenatide once daily versus placebo in type 2 diabetes insufficiently controlled on pioglitazone (GetGoal-P)

Abstract: Aims To compare the efficacy and safety of once-daily prandial lixisenatide with placebo in type 2 diabetes mellitus (T2DM) insufficiently controlled by pioglitazone ± metformin. Methods This randomized, double-blind study included a 24-week main treatment period and a ≥52-week variable extension period. Patients were randomized 2 : 1 to receive lixisenatide 20 µg once daily or placebo. The primary endpoint was change in glycated haemoglobin (HbA1c) at week 24. Results In total, 484 patients were randomized: 323 to lixisenatide; 161 to placebo. After 24 weeks, lixisenatide once daily significantly improved HbA1c (−0.56% vs. placebo; p < 0.0001) and increased the proportion of patients achieving HbA1c <7% compared with placebo (52.3% vs. 26.4%, respectively; p < 0.0001) and significantly improved fasting plasma glucose (−0.84 mmol/l vs. placebo; p < 0.0001). There was a small decrease in body weight with lixisenatide once daily and a small increase with placebo, with no statistically significant difference between the two groups. Overall, lixisenatide once daily was well tolerated, with a similar proportion of treatment-emergent adverse events (TEAEs) and serious TEAEs between groups (lixisenatide: 72.4% and 2.5%; placebo: 72.7% and 1.9%). Symptomatic hypoglycaemia rates were also relatively low in both groups (lixisenatide 3.4% and placebo 1.2%), with no severe episodes. Lixisenatide continued to be efficacious and well tolerated during the variable extension period. Conclusions Lixisenatide once daily significantly improved glycaemic control with a low risk of hypoglycaemia, and was well tolerated over 24 weeks and during the long-term, double-blind extension period in patients with T2DM insufficiently controlled on pioglitazone ± metformin.

Long-term efficacy and safety comparison of liraglutide, glimepiride and placebo, all in combination with metformin in type 2 diabetes: 2-year results from the LEAD-2 study

Abstract: Aims To investigate efficacy and safety of dual therapy with liraglutide and metformin in comparison to glimepiride and metformin, and metformin monotherapy over 2?years in patients with type 2 diabetes. Methods In the 26-week the Liraglutide Effect and Action in Diabetes (LEAD)-2 core trial, patients (n?=?1091) were randomized (2?:?2?:?2?:?1:?2) to liraglutide (0.6, 1.2 or 1.8?mg once-daily), placebo or glimepiride; all with metformin. Patients were enrolled if they were 1880?years old with HbA1c 7.011.0% (previous monotherapy =3?months), or 7.010.0% (previous combination therapy =3?months), and body mass index =40?kg/m2. Patients completing the 26-week double-blinded phase could enter an 18-month open-label extension. Results HbA1c decreased significantly with liraglutide (0.4% with 0.6?mg, 0.6% with 1.2 and 1.8?mg) versus 0.3% increase with metformin monotherapy (p?

Combination therapy with GLP-1 receptor agonists and basal insulin: a systematic review of the literature

Abstract: Treatment algorithms for type 2 diabetes call for intensification of therapy over time as the disease progresses and glycaemic control worsens. If diet, exercise and oral antihyperglycaemic medications (OAMs) fail to maintain glycaemic control then basal insulin is added and ultimately prandial insulin may be required. However, such an intensification strategy carries risk of increased hypoglycaemia and weight gain, both of which are associated with worse long-term outcomes. An alternative strategy is to intensify therapy by the addition of a short-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA) rather than prandial insulin. Short-acting GLP-1 RAs such as exenatide twice daily are particularly effective at reducing postprandial glucose while basal insulin has a greater effect on fasting glucose, providing a physiological rationale for this complementary approach. This review analyzes the latest randomized controlled clinical trials of insulin/GLP-1 RA combination therapy and examines results from ‘real-world’ use of the combinations as reported through observational and clinical practice studies. The most common finding across all types of studies was that combination therapy improved glycaemic control without weight gain or an increased risk of hypoglycaemia. Many studies reported weight loss and a reduction in insulin use when a GLP-1 RA was added to existing insulin therapy. Overall, the relative degree of benefit to glycaemic control and weight was influenced by the insulin titration employed in conjunction with the GLP-1 RA. The greatest glycaemic benefits were observed in studies with structured titration of insulin to glycaemic targets while the greatest weight benefits were observed in studies with a protocol-specified focus on insulin sparing. The adverse event profile of GLP-1 RAs in the reviewed trials was similar to that reported with GLP-1 RAs as monotherapy or in combination with OAMs with gastrointestinal events being the most commonly reported.

Metformin vs. insulin in gestational diabetes. A randomized study characterizing metformin patients needing additional insulin.

Abstract: Aims We compared metformin with insulin as treatment of gestational diabetes mellitus (GDM). Furthermore, we aimed to characterize metformin-treated patients needing additional insulin to achieve prespecified glucose targets. Methods We conducted a single centre randomized controlled study with non-inferiority design comparing metformin and insulin in the treatment of 217 GDM patients having birth weight as primary outcome variable. Results There were no significant differences in mean birth weight expressed in grams [+15 (90% confidence interval (CI): −121 to 89)] or SD units [+0.04 (90% CI: −0.27 to 0.18)] between the metformin and insulin groups. There were no significant differences in neonatal or maternal data between the groups. Only 23 (20.9%) of the 110 patients in the metformin group needed additional insulin. Compared with the patients on metformin only, those needing additional insulin were older (p = 0.04), their oral glucose tolerance test had been performed earlier and diabetes therapy started earlier in gestation (p = 0.01 and p = 0.004, respectively). The risk for additional insulin was 4.6-fold in women with baseline serum fructosamine concentration above median compared with those below median. Conclusions Metformin is an effective alternative to insulin in the treatment of GDM patients. Serum fructosamine may help in predicting the adequacy of metformin treatment alone.

Candidate genes for type 1 diabetes modulate pancreatic islet inflammation and β‐cell apoptosis

Abstract: Genome-wide association studies (GWAS) have identified more than 50 loci associated with genetic risk of type 1 diabetes (T1D). Several T1D candidate genes have been suggested or identified within these regions, but the molecular mechanisms by which they contribute to insulitis and β-cell destruction remain to be clarified. More than 60% of the T1D candidate genes are expressed in human pancreatic islets, suggesting that they contribute to T1D by regulating at least in part pathogenic mechanisms at the β-cell level. Recent studies by our group indicate that important genetically regulated pathways in β-cells include innate immunity and antiviral activity, involving RIG-like receptors (particularly MDA5) and regulators of type I IFNs (i.e. PTPN2 and USP18), and genes related to β-cell phenotype and susceptibility to pro-apoptotic stimuli (i.e. GLIS3). These observations reinforce the concept that the early pathogenesis of T1D is characterized by a dialogue between the immune system and pancreatic β-cells. This dialogue is probably influenced by polymorphisms in genes expressed at the β-cell and/or immune system level, leading to inadequate responses to environmental cues such as viral infections. Further studies are needed to clarify how these disease-associated variants affect pancreatic β-cell responses to inflammation and the subsequent triggering of autoimmune responses and progressive β-cell loss.

Efficacy and safety of dapagliflozin as a monotherapy for type 2 diabetes mellitus in Japanese patients with inadequate glycaemic control: a phase II multicentre, randomized, double-blind, placebo-controlled trial.

Abstract: Aim Dapagliflozin is a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor under development as a treatment for type 2 diabetes mellitus (T2DM). This study assessed the efficacy and safety of dapagliflozin monotherapy in Japanese T2DM patients with inadequate glycaemic control. Methods Patients (n = 279) were randomized to receive dapagliflozin (1, 2.5, 5 or 10 mg/day) or placebo once daily for 12 weeks. The primary endpoint was change from baseline in haemoglobin A1c (HbA1c) at week 12. Secondary endpoints included change from baseline in fasting plasma glucose (FPG) and proportion of patients achieving HbA1c <7.0% at week 12. Results Significant reductions in HbA1c were seen with all dapagliflozin doses (−0.11 to −0.44%) versus placebo (+0.37%). Reductions were also observed in FPG with dapagliflozin (−0.87 to −1.77 mmol/l [−15.61 to −31.94 mg/dl]) versus placebo (+0.62 mmol/l [+11.17 mg/dl]). No significant difference in the proportion of patients achieving HbA1c levels <7.0% was noted with dapagliflozin versus placebo. Adverse events (AEs) were more frequent with dapagliflozin (40.7–53.8%) versus placebo (38.9%) and were mostly mild/moderate in intensity. Three hypoglycaemic events were reported (1 each with placebo, dapagliflozin 2.5 mg and 10 mg). The frequency of signs and symptoms suggestive of urinary tract or genital infections was 0–3.8 and 0–1.8% respectively with dapagliflozin and 1.9 and 0% with placebo. No AEs of pyelonephritis were observed. Conclusions Compared with placebo, dapagliflozin significantly reduced hyperglycaemia over 12 weeks with a low risk of hypoglycaemia in Japanese T2DM patients with inadequate glycaemic control.

Efficacy and safety of canagliflozin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, 12-week study

Abstract: Aims We examined the efficacy, safety and tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in Japanese patients with type 2 diabetes (T2DM) undergoing diet and exercise therapy. Methods Patients aged 20–80 years with T2DM diagnosed ≥3 months previously, and HbA1c of 6.9–9.9% were randomized to 50, 100, 200 or 300 mg canagliflozin or placebo once daily for 12 weeks. The primary and secondary endpoints were changes in HbA1c, fasting plasma glucose (FPG), urinary glucose/creatinine and postprandial glycaemic parameters following a meal test. The safety assessments included adverse events (AEs) and clinical laboratory tests. Results Overall, 383 patients were randomized to receive either placebo (n = 75), or 50 mg (n = 82), 100 mg (n = 74), 200 mg (n = 77) or 300 mg canagliflozin (n = 75). At week 12, significant reductions in HbA1c were observed in all canagliflozin groups relative to placebo (−0.61, –0.80, –0.79 and −0.88% for 50, 100, 200 and 300 mg, respectively, versus +0.11% for placebo; all, p < 0.01). FPG and postprandial glycaemic parameters improved significantly in the canagliflozin groups. Body weight was significantly decreased by canagliflozin. No deaths or drug-related serious AEs were reported. There was no dose-dependent increase in the incidence of AEs in the canagliflozin groups. The incidence of hypoglycaemia was low; episodes were not severe or dose dependent. Canagliflozin did not affect serum creatinine levels or the urinary albumin/creatinine ratio. Conclusions Treatment with canagliflozin for 12 weeks significantly improved glycaemic control and reduced body weight in Japanese patients with T2DM. Canagliflozin was well tolerated.

Cardiovascular safety of the dipetidyl peptidase‐4 inhibitor alogliptin in type 2 diabetes mellitus

Abstract: Aim As there have been concerns that some classes or agents for the treatment of type 2 diabetes may increase CV risk, we evaluated the cardiovascular profile of the dipeptidyl peptidase-4 inhibitor alogliptin. Methods We evaluated the incidence of CV events in patients treated with alogliptin, placebo or comparator antihyperglycaemic drugs in the clinical trial database for alogliptin using the composite major adverse cardiovascular event (MACE) endpoints of CV death, non-fatal myocardial infarction and non-fatal stroke. Results The pooled analysis included 4168 patients exposed to alogliptin 12.5 and 25 mg daily for 2023 patient-years compared to 691 patients treated with placebo for 263 patient-years and 1169 patients treated with other antidiabetic agents (metformin, sulfonylureas and thiazolidinediones) for 703 patient-years. CV events were adjudicated by an expert endpoint committee blinded to treatment allocation. The incidence rates of the combined MACE were not significantly different between patients treated with alogliptin and comparator therapies (hazard ratio=0.635, 95% confidence interval, 0.0, 1.41). Additionally, other types of serious CV events were not significantly different between patients treated with alogliptin and comparator therapies. Conclusion These analyses have not shown a signal of increased CV risk with alogliptin in patients with type 2 diabetes. Future results from the adequately powered EXAMINE trial will definitively assess the CV safety profile of aloglipin in patients with type 2 diabetes mellitus.

Liraglutide suppresses postprandial triglyceride and apolipoprotein B48 elevations after a fat‐rich meal in patients with type 2 diabetes: a randomized, double‐blind, placebo‐controlled, cross‐over trial

Abstract: Aims Postprandial triglyceridaemia is a risk factor for cardiovascular disease (CVD). This study investigated the effects of steady-state liraglutide 1.8 mg versus placebo on postprandial plasma lipid concentrations after 3 weeks of treatment in patients with type 2 diabetes mellitus (T2DM). Methods In a cross-over trial, patients with T2DM (n = 20, 18–75 years, BMI 18.5–40 kg/m2) were randomized to once-daily subcutaneous liraglutide (weekly dose escalation from 0.6 to 1.8 mg) and placebo. After each 3-week period, a standardized fat-rich meal was provided, and the effects of liraglutide on triglyceride (primary endpoint AUC0–8h), apolipoprotein B48, non-esterified fatty acids, glycaemic responses and gastric emptying were assessed. ClinicalTrials.gov ID: NCT00993304. Funding: Novo Nordisk A/S. Results After 3 weeks, mean postprandial triglyceride (AUC0–8h liraglutide/placebo treatment-ratio 0.72, 95% CI [0.62–0.83], p = 0.0004) and apolipoprotein B48 (AUC0–8h ratio 0.65 [0.58–0.73], p < 0.0001) significantly decreased with liraglutide 1.8 mg versus placebo, as did iAUC0–8h and Cmax (p < 0.001). No significant treatment differences were observed for non-esterified fatty acids. Mean postprandial glucose and glucagon AUC0–8h and Cmax were significantly reduced with liraglutide versus placebo. Postprandial gastric emptying rate [assessed by paracetamol absorption (liquid phase) and the 13C-octanoate breath test (solid phase)] displayed no treatment differences. Mean low-density lipoprotein and total cholesterol decreased significantly with liraglutide versus placebo. Conclusions Liraglutide treatment in patients with T2DM significantly reduced postprandial excursions of triglyceride and apolipoprotein B48 after a fat-rich meal, independently of gastric emptying. Results indicate liraglutide's potential to reduce CVD risk via improvement of postprandial lipaemia.

Diabetes and driving

Abstract: The principal safety concern for driving for people treated with insulin or insulin secretagogues is hypoglycaemia, which impairs driving performance. Other complications, such as those causing visual impairment and peripheral neuropathy, are also relevant to medical fitness to drive. Case control studies have suggested that drivers with diabetes pose a modestly increased but acceptable and measurable risk of motor vehicle accidents compared to non-diabetic drivers, but many studies are limited and of poor quality. Factors which have been shown to increase driving risk include previous episodes of severe hypoglycaemia, previous hypoglycaemia while driving, strict glycaemic control (lower HbA1c) and absence of blood glucose monitoring before driving. Impaired awareness of hypoglycaemia may be counteracted by frequent blood glucose testing. The European Union Third directive on driving (2006) has necessitated changes in statutory regulations for driving licences for people with diabetes in all European States, including the UK. Stricter criteria have been introduced for Group 1 vehicle licences while those for Group 2 licences have been relaxed. Insulin-treated drivers can now apply to drive Group 2 vehicles, but in the UK must meet very strict criteria and be assessed by an independent specialist to be issued with a 1-year licence.

The incidence of type 2 diabetes in the United Kingdom from 1991 to 2010.

Abstract: AIMS To characterize the incidence of type 2 diabetes in the UK over the previous 20 years; and determine if there has been an increase in people aged 40 years or less at diagnosis. METHODS For this retrospective cohort study, patients newly diagnosed with type 2 diabetes between 1991 and 2010 were identified from the UK Clinical Practice Research Datalink (CPRD). Patient data were grouped into 5-year intervals by year of diagnosis and age at diagnosis. A standardized incidence ratio (SIR) was determined (1991-1995 = 100). The percentage of newly diagnosed patients for each age group and aged ≤40 years was calculated for each 5-year calendar period. The incidence rate by age and 5-year calendar period was also determined. RESULTS In 2010, the crude incidence rate of type 2 diabetes was 515 per 100,000 population. The overall SIR increased to 158 (95% CI 157-160, p < 0.001), 237 (235-238, p < 0.001) and 275 (273-276, p < 0.001) for 1996-2000, 2001-2005 and 2006-2010, respectively. For those ≤40, the respective values were 217 (209-226, p < 0.001), 327 (320-335, p < 0.001) and 598 (589-608, p < 0.001). An increase in incidence occurred with increasing 5-year calendar period. The incidence of type 2 diabetes was higher for males after the age of 40 and higher for females aged ≤40. The percentage of patients aged ≤40 years at diagnosis increased with each increasing 5-year calendar period (5.9, 8.4, 8.5 and 12.4%, respectively). CONCLUSIONS There was a significant increase in the incidence of diagnosed type 2 diabetes between 1991 and 2010 and the proportion of people diagnosed at a relatively early age has increased markedly.

Metagenome and metabolism: the tissue microbiota hypothesis.

Abstract: Over the last decade, the research community has revealed the role of a new organ: the intestinal microbiota. It is considered as a symbiont that is part of our organism since, at birth, it educates the immune system and contributes to the development of the intestinal vasculature and most probably the nervous system. With the advent of new generation sequencing techniques, a catalogue of genes that belong to this microbiome has been established that lists more than 5 million non-redundant genes called the metagenome. Using germ free mice colonized with the microbiota from different origins, it has been formally demonstrated that the intestinal microbiota causes the onset of metabolic diseases. Further to the role of point mutations in our genome, the microbiota can explain the on-going worldwide pandemic of obesity and diabetes, its dissemination and family inheritance, as well as the diversity of the associated metabolic phenotypes. More recently, the discovery of bacterial DNA within host tissues, such as the liver, the adipose tissue and the blood, which establishes a tissue microbiota, introduces new opportunities to identify targets and predictive biomarkers based on the host to microbiota interaction, as well as to define new strategies for pharmacological, immunomodulatory vaccines and nutritional applications.

Macrophages and islet inflammation in type 2 diabetes.

Abstract: Type 2 diabetes (T2D) is characterized by insulin resistance and impaired insulin secretion from pancreatic β-cells. Inflammatory cytokines, including tumour necrosis factor-α (TNF-α), have been shown to promote insulin resistance, and altered expression of cytokines (adipokines) in obese adipose tissue is thought to be an important link between obesity and insulin resistance. It is also becoming clear that inflammation plays a key role in the development of β-cell dysfunction. Inflammatory changes, including accumulation of macrophages, have been documented in T2D islets. Moreover, therapeutic inhibition of interleukin-1β (IL-1β) ameliorates β-cell dysfunction in humans. This review summarizes current understanding of the molecular mechanisms underlying inflammation within islets and its relation to β-cell dysfunction in T2D. A particular focus is on the physiological and pathological functions of macrophages within islets.

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

Abstract: 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.