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.

What have human experimental overfeeding studies taught us about adipose tissue expansion and susceptibility to obesity and metabolic complications?

Overfeeding experiments, in which we impose short-term positive energy balance, help unravel the cellular, physiological and behavioural adaptations to nutrient excess. These studies mimic longer-term mismatched energy expenditure and intake. There is considerable inter-individual heterogeneity in the magnitude of weight gain when exposed to similar relative caloric excess reflecting variable activation of compensatory adaptive mechanisms. Significantly, given similar relative weight gain, individuals may be protected from/predisposed to metabolic complications (insulin resistance, dyslipidaemia, hypertension), non-alcoholic fatty liver disease and cardiovascular disease. Similar mechanistic considerations underpinning the heterogeneity of overfeeding responses are pertinent in understanding emerging metabolic phenotypes, for example, metabolically unhealthy normal weight and metabolically healthy obesity. Intrinsic and extrinsic factors modulate individuals' overfeeding response: intrinsic factors include gender/hormonal status, genetic/ethnic background, baseline metabolic health and cardiorespiratory fitness; extrinsic factors include macronutrient (fat vs carbohydrate) content, fat/carbohydrate composition and overfeeding pattern. Subcutaneous adipose tissue (SAT) analysis, coupled with metabolic assessment, with overfeeding have revealed how SAT remodels to accommodate excess nutrients. SAT remodelling occurs either by hyperplasia (increased adipocyte number) or by hypertrophy (increased adipocyte size). Biological responses of SAT also govern the extent of ectopic (visceral/liver) triglyceride deposition. Body composition analysis by DEXA/MRI (dual energy X-ray absorptiometry/magnetic resonance imaging) have determined the relative expansion of SAT (including abdominal/gluteofemoral SAT) vs ectopic fat with overfeeding. Such studies have contributed to the adipose expandability hypothesis whereby SAT has a finite capacity to expand (governed by intrinsic biological characteristics), and once capacity is exceeded ectopic triglyceride deposition occurs. The potential for SAT expandability confers protection from/predisposes to the adverse metabolic responses to overfeeding. The concept of a personal fat threshold suggests a large inter-individual variation in SAT capacity with ectopic depot expansion/metabolic decompensation once one's own threshold is exceeded. This review summarises insight gained from overfeeding studies regarding susceptibility to obesity and related complications with nutrient excess.

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.

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.

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.

Cerebral activations during viewing of food stimuli in adult patients with acquired structural hypothalamic damage: a functional neuroimaging study.

BACKGROUND/OBJECTIVES: Obesity is common following hypothalamic damage due to tumours. Homeostatic and non-homeostatic brain centres control appetite and energy balance but their interaction in the presence of hypothalamic damage remains unknown. We hypothesized that abnormal appetite in obese patients with hypothalamic damage results from aberrant brain processing of food stimuli. We sought to establish differences in activation of brain food motivation and reward neurocircuitry in patients with hypothalamic obesity (HO) compared with patients with hypothalamic damage whose weight had remained stable. SUBJECTS/METHODS: In a cross-sectional study at a University Clinical Research Centre, we studied 9 patients with HO, 10 age-matched obese controls, 7 patients who remained weight-stable following hypothalamic insult (HWS) and 10 non-obese controls. Functional magnetic resonance imaging was performed in the fasted state, 1 h and 3 h after a test meal, while subjects were presented with images of high-calorie foods, low-calorie foods and non-food objects. Insulin, glucagon-like peptide-1, Peptide YY and ghrelin were measured throughout the experiment, and appetite ratings were recorded. RESULTS: Mean neural activation in the posterior insula and lingual gyrus (brain areas linked to food motivation and reward value of food) in HWS were significantly lower than in the other three groups (P=0.001). A significant negative correlation was found between insulin levels and posterior insula activation (P=0.002). CONCLUSIONS: Neural pathways associated with food motivation and reward-related behaviour, and the influence of insulin on their activation may be involved in the pathophysiology of HO.

Dapagliflozin in type 2 diabetes: effectiveness across the spectrum of disease and over time.

BACKGROUND: Despite many available therapies, patients with type 2 diabetes mellitus (T2DM) frequently do not achieve/maintain glycaemic control. Furthermore, side effects such as hypoglycaemia and weight gain may limit therapy choices. Dapagliflozin, a selective sodium-glucose cotransporter-2 inhibitor, reduces hyperglycaemia by increasing glucosuria independently of insulin, representing a novel approach in T2DM. Dapagliflozin efficacy, safety and tolerability were evaluated across a wide range of clinical trials. METHODS: Dapagliflozin 10-mg efficacy data from (i) two short-term, active-comparator studies (vs. metformin-XR over 24 weeks and vs. glipizide over 52 weeks), (ii) pooled 24-week analyses of five placebo-controlled trials (as monotherapy or add-on therapy), and (iii) long-term studies over 2 years; dapagliflozin 5- and 10-mg pooled safety data from 12 placebo-controlled trials; and cardiovascular safety and malignancy data from 19 dapagliflozin studies were evaluated. RESULTS: In treatment-naïve patients (baseline HbA1c 9%), dapagliflozin reduced HbA1c (-1.45%) similarly to metformin-XR (-1.44%). In metformin-treated patients (baseline HbA1c 7.7%), dapagliflozin achieved a clinically significant reduction (-0.52%) similar to glipizide (-0.52%). In pooled 24-week analyses, dapagliflozin vs. placebo differences in HbA1c, weight and systolic blood pressure (SBP) were -0.60%, -1.61 kg and -3.6 mmHg, respectively. At 2 years, dapagliflozin vs. placebo differences in HbA1c and weight were -0.44 to -0.80% and -2.41 to -3.19 kg, respectively, and vs. glipizide, differences in HbA1c, weight, and SBP were -0.18%, -5.06 kg, and -3.89 mmHg, respectively. Major hypoglycaemia with dapagliflozin was rare (< 0.1%). Urinary tract and genital infections were more common with dapagliflozin, but responded to standard care and rarely led to study discontinuation. Events of renal failure/impairment and malignancies were rare and balanced across treatment groups. Pooled analyses did not indicate that dapagliflozin increased cardiovascular event risk. CONCLUSIONS: Dapagliflozin improved glycaemic control, decreased body weight, and lowered blood pressure across the spectrum of T2DM disease, with maintenance of these benefits over time.

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.

Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin.

AIMS: Dapagliflozin, a highly selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), reduces hyperglycaemia and weight in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion. Long-term glycaemic control, body composition and bone safety were evaluated in patients with T2DM after 102 weeks of dapagliflozin treatment. METHODS: This randomized, double-blind, placebo-controlled study (NCT00855166) enrolled patients with T2DM [mean: age 60.7 years; HbA1c 7.2%; body mass index (BMI) 31.9 kg/m(2) ; body weight 91.5 kg] inadequately controlled on metformin. Patients (N = 182) were randomly assigned 1 : 1 to receive dapagliflozin 10 mg/day or placebo added to open-label metformin for a 24-week double-blind treatment period followed by a 78-week site- and patient-blinded extension period. At week 102, changes from baseline in HbA1c, weight, waist circumference, total body fat mass as measured by dual-energy X-ray absorptiometry (DXA), serum markers of bone turnover, bone mineral density (BMD) as measured by DXA, and adverse events were evaluated. RESULTS: A total of 140 patients (76.9%) completed the study. Over 102 weeks, dapagliflozin-treated patients showed reductions in HbA1c by -0.3%, weight by -4.54 kg, waist circumference by -5.0 cm and fat mass by -2.80 kg without increase in rate of hypoglycaemia. Compared with placebo, no meaningful changes from baseline in markers of bone turnover or BMD were identified over 102 weeks. One fracture occurred in each treatment group. The frequency of urinary tract infection (UTI) and genital infection was similar in both treatment groups. CONCLUSIONS: Over 102 weeks, dapagliflozin improved glycaemic control, and reduced weight and fat mass, without affecting markers of bone turnover or BMD in patients with T2DM inadequately controlled on metformin.

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.

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.

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.

Effects of chronic treatment with metformin on dipeptidyl peptidase-4 activity, glucagon-like peptide 1 and ghrelin in obese patients with Type 2 diabetes mellitus.

AIMS: Studies investigating the acute effects of metformin have demonstrated actions on the incretin system and appetite regulatory hormones. There are limited data to support that these effects are sustained in the long term. We therefore studied the effects of chronic treatment with metformin on endogenous glucagon-like peptide 1, dipeptidyl peptidase-4 activity and active ghrelin (an orexigenic hormone) in obese patients with Type 2 diabetes mellitus. METHODS: Eight subjects [six male, age 58.7 ± 2.6 years, BMI 41.1 ± 2.9 kg/m(2) , HbA(1c) 69 ± 6 mmol/mol (8.5 ± 0.5%), mean ± sem] with drug-naïve Type 2 diabetes were studied for 6 h following a standard mixed meal, before and after at least 3 months of metformin monotherapy (mean dose 1.75 g daily). RESULTS: The area under the curve (AUC(0-6 h) ) for active glucagon-like peptide 1 was significantly higher on metformin (pre-metformin 1750.8 ± 640 pmol l(-1) min(-1) vs. post-metformin 2718.8 ± 1182.3 pmol l(-1) min(-1) ; P=0.01). The areas under the curves for dipeptidyl peptidase-4 activity and ghrelin were not significantly different pre- and post-treatment with metformin. CONCLUSION: Three months or more of metformin monotherapy in obese patients with Type 2 diabetes was associated with increased postprandial active glucagon-like peptide 1 levels. The effects of metformin on the enteroinsular axis may represent yet another important mechanism underlying its glucose-lowering effects.

PPAR agonists for the treatment of cardiovascular disease in patients with diabetes.

Diabetes is a complex disease defined by hyperglycaemia; however, strong associations with abdominal obesity, hypertension and dyslipidaemia contribute to the high risk of cardiovascular disease. Although aggressive glycaemic control reduces microvascular complications, the evidence for macrovascular complications is less certain. The theoretical benefits of the mode of action of peroxisome proliferator-activated receptor (PPAR) agonists are clear. In clinical practice, PPAR-α agonists such as fibrates improve dyslipidaemia, while PPAR-γ agonists such as thiazolidinediones improve insulin resistance and diabetes control. However, although these agents are traditionally classed according to their target, they have different and sometimes conflicting clinical benefit and adverse event profiles. It is speculated that this is because of differing properties and specificities for the PPAR receptors (each of which targets specific genes). This is most obvious in the impact on cardiovascular outcomes--in clinical trials pioglitazone appeared to reduce cardiovascular events, whereas rosiglitazone potentially increased the risk of myocardial infarction. The development of a dual PPAR-α/γ agonist may prove beneficial in effectively managing glycaemic control and improving dyslipidaemia in patients with type 2 diabetes. Yet, development of agents such as muraglitazar and tesaglitazar has been hindered by various serious adverse events. Aleglitazar, a balanced dual PPAR-α/γ agonist, is currently the most advanced in clinical development and has shown promising results in phase II clinical trials with beneficial effects on glucose and lipid variables. A phase III study, ALECARDIO, is ongoing and will establish whether improvements in laboratory test profiles translate into an improvement in cardiovascular outcomes.

Dapagliflozin has no effect on markers of bone formation and resorption or bone mineral density in patients with inadequately controlled type 2 diabetes mellitus on metformin.

AIMS: Dapagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, reduces hyperglycaemia in patients with type 2 diabetes (T2DM) by increasing urinary glucose excretion. Owing to its mechanism of action, dapagliflozin could potentially affect the renal tubular transportation of bone minerals. Therefore, markers of bone formation and resorption and bone mineral density (BMD) were evaluated in patients with T2DM after 50 weeks of dapagliflozin treatment. METHODS: This international, multi-centre, randomized, parallel-group, double-blind, placebo-controlled study (ClinicalTrials.gov NCT00855166) enrolled patients with T2DM (women 55-75 years and men 30-75 years; HbA1c 6.5-8.5%; BMI ≥ 25 kg/m(2) ; body weight ≤ 120 kg) whose T2DM was inadequately controlled on metformin. One hundred and eighty-two patients were randomly assigned 1:1 to receive dapagliflozin 10 mg/day or placebo added to open-label metformin for a 24-week double-blind treatment period followed by a 78-week site- and patient-blinded extension period. At week 50, serum markers of bone formation (procollagen type 1 N-terminal propeptide; P1NP) and resorption (C-terminal cross-linking telopeptides of type I collagen; CTX), bone mineral density (BMD) as assessed by standardized Dual-Energy X-ray Absorptiometry (DXA) measurements and adverse events of fracture were evaluated as safety objectives. RESULTS: One hundred and sixty-five patients (90.7%) completed the first 50 weeks. Compared with placebo, no significant changes from baseline in P1NP, CTX or BMD were identified over 50 weeks of dapagliflozin treatment, with no significant treatment-by-gender interactions. No fractures were reported. CONCLUSIONS: Dapagliflozin had no effect on markers of bone formation and resorption or BMD after 50 weeks of treatment in both male and post-menopausal female patients whose T2DM was inadequately controlled on metformin.

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.

The four-variable modification of diet in renal disease formula underestimates glomerular filtration rate in obese type 2 diabetic individuals with chronic kidney disease.

AIMS/HYPOTHESIS: GFR is commonly estimated using the four-variable Modification of Diet in Renal Disease (MDRD) formula and this forms the basis for classification of chronic kidney disease (CKD). We investigated the effect of obesity on the estimation of glomerular filtration rate in type 2 diabetic participants with CKD. METHODS: We enrolled 111 patients with type 2 diabetes mellitus in different stages of CKD. GFR was measured using (51)Cr-labelled EDTA plasma clearance and was estimated using the four-variable MDRD formula. RESULTS: The bias between estimated and measured GFR was -22.4 (-33.8 to -11.0) p < 0.001 in the obese group compared with -6.04 (-17.6 to -5.5) p = 0.299 in the non-obese group. When GFR was indexed to body surface area of 1.73 m(2), the bias remained significant at -9.4 (-13.4 to -5.4) p < 0.001 in the obese participants. CONCLUSIONS/INTERPRETATION: This study suggests that the four-variable MDRD formula significantly underestimates GFR in obese type 2 diabetic participants with CKD.