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In this secondary analysis of data from ADVANCE, severe hypoglycemia in patients with type 2 diabetes was associated with increased risks of macrovascular events, microvascular events, and death. Hypoglycemia may contribute directly or may be a marker of vulnerability. In patients with diabetes treated with insulin or insulin secretagogues, severe hypoglycemia is more common when glucose control is intensified. 1 – 4 Although most episodes of severe hypoglycemia resolve without apparent permanent injury, there are anecdotal reports of acute coronary syndromes coinciding with hypoglycemia in people with type 2 diabetes. 5 , 6 In addition, observational studies have suggested that hypoglycemia and reduced levels of glycated hemoglobin are associated with an increased risk of death in patients with diabetes or hyperglycemia who have been hospitalized for myocardial infarction. 7 – 11 Recently completed trials investigating the effect of intensive glucose control on macrovascular outcomes in . . .

Abstract Context Low-dose sulfonylureas (SUs) have been found to augment the classical incretin effect, increase glucose sensitivity and late phase incretin potentiation. Objective To evaluate potential synergy between low-dose SU plus a dipeptidyl peptidase 4 (DPP4) inhibitor. Methods Unblinded randomized crossover study at the Clinical Research Centre, University of Dundee. Thirty participants with T2DM (HbA1c < 64 mmol/mol) were treated with diet or metformin. Participants completed 4, 14-day blocks in a random order: control, gliclazide 20 mg (SU), sitagliptin 100 mg (DPP4 inhibitor [DPP4i]), or combination (SUDPP4i). A mixed meal test was conducted after each intervention. The primary outcome was the effect of treatment on beta-cell glucose sensitivity. Secondary outcomes included frequency of glucose <3 mmol/L on continuous glucose monitoring, subanalyses by genotype (KNCJ11 E23K), gender, and body mass index. Results SU combination with DPP4i showed additive effect on glucose lowering: mean glucose area under the curve (mean 95% CI) (mmol/L) was control 11.5 (10.7-12.3), DPP4i 10.2 (9.4-11.1), SU 9.7 (8.9-10.5), SUDPP4i 8.7 (7.9-9.5) (P < .001). Glucose sensitivity mirrored the additive effect (pmol min−1 m−2 mM−1): control 71.5 (51.1-91.9), DPP4i 75.9 (55.7-96.0), SU 86.3 (66.1-106.4), SUDPP4i 94.1 (73.9-114.3) (P = .04). The additive effect was seen in men but not women. Glucose time in range <3 mmol/L on continuous glucose monitoring (%) was unaffected: control 1 (2-4), DPP4i 2 (3-6), SU 1 (0-4), SUDPP4i 3 (2-7) (P = .65). Conclusion Low-dose sulfonylurea plus DPP4i has a potent glucose-lowering effect through augmentation of beta-cell function. A double-blind randomized controlled trial would formalize efficacy and safety of this combination, which may avoid negative aspects of SU.

To assess the magnitude and independence of the effects of routine blood pressure lowering and intensive glucose control on clinical outcomes in patients with long-standing type 2 diabetes. This was a multicenter, factorial randomized trial of perindopril-indapamide versus placebo (double-blind comparison) and intensive glucose control with a gliclazide MR-based regimen (target A1C 0.1): the separate effects of the two interventions for the renal outcomes and death appeared to be additive on the log scale. Compared with neither intervention, combination treatment reduced the risk of new or worsening nephropathy by 33% (95% CI 12-50%, P = 0.005), new onset of macroalbuminuria by 54% (35-68%, P < 0.0001), and new onset of microalbuminuria by 26% (17-34%). Combination treatment was associated with an 18% reduction in the risk of all-cause death (1-32%, P = 0.04). The effects of routine blood pressure lowering and intensive glucose control were independent of one another. When combined, they produced additional reductions in clinically relevant outcomes.

Aims/Introduction To compare the effects of gliclazide, liraglutide and metformin on body composition in patients with type 2 diabetes mellitus with non‐alcoholic fatty liver disease. Materials and Methods A total of 85 patients were randomly allocated to receive gliclazide (n = 27), liraglutide (n = 29) or metformin (n = 29) monotherapy for 24 weeks. Body composition was measured using dual‐energy X‐ray absorptiometry. Results Liraglutide and metformin reduced total, trunk, limb, android and gynoid fat mass; this also led to weight reduction. However, gliclazide treatment produced no significant changes in weight or fat mass, likely because reductions in fat mass were concomitant with increases in lean tissue mass. Blood glucose concentrations and glycated hemoglobin levels improved in all treatment arms; levels of the latter were lower in patients treated with liraglutide and metformin. Serum alanine aminotransferase concentrations decreased in all treatment arms, whereas serum aspartate aminotransferase concentrations were reduced only by liraglutide and metformin. In all patients, weight loss and total, trunk, limb, and android fat mass reductions were positively correlated with decreases in serum alanine aminotransferase and aspartate aminotransferase levels, whereas reductions in waist circumference were positively correlated with lower serum alanine aminotransferase levels. Conclusions Compared with gliclazide, liraglutide and metformin monotherapies result in greater weight loss, reductions in body fat mass, and better blood glucose control among type 2 diabetes mellitus patients with non‐alcoholic fatty liver disease. Reductions in weight, fat mass and waist circumference favorably affect hepatic function. This single‐center, open‐label, prospective, randomized clinical trial examined the effect of liraglutide, metformin, and gliclazide on body composition in patients with type 2 diabetes and concomitant non‐alcoholic fatty liver disease. The results show that liraglutide and metformin are superior to gliclazide in terms of reducing body weight, body mass index, and body fat mass, and in terms of improving liver function and glycosylated hemoglobin levels. In addition, liraglutide and metformin were shown to reduce fat mass rather than lean tissue mass, which is helpful in improving the body weight and glycemic control. Weight remained stable in the gliclazide group; this resulted from identical reductions in fat mass and increases in lean tissue mass.

Abstract Context Weight loss is strongly recommended for overweight and obese adults with type 2 diabetes. Unintentional weight loss is associated with increased risk of all-cause mortality, but few studies have examined its association with cardiovascular outcomes in patients with diabetes. Objective To evaluate 2-year weight change and subsequent risk of cardiovascular events and mortality in established type 2 diabetes. Design and Setting The Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation was an international, multisite 2×2 factorial trial of intensive glucose control and blood pressure control. We examined 5 categories of 2-year weight change: >10% loss, 4% to 10% loss, stable (±<4%), 4% to 10% gain, and >10% gain. We used Cox regression with follow-up time starting at 2 years, adjusting for intervention arm, demographics, cardiovascular risk factors, and diabetes medication use from the 2-year visit. Results Among 10 081 participants with valid weight measurements, average age was 66 years. By the 2-year examination, 4.3% had >10% weight loss, 18.4% had 4% to 10% weight loss, and 5.3% had >10% weight gain. Over the following 3 years of the trial, >10% weight loss was strongly associated with major macrovascular events (hazard ratio [HR], 1.75; 95% confidence interval [CI], 1.26-2.44), cardiovascular mortality (HR, 2.76; 95% CI, 1.87-4.09), all-cause mortality (HR, 2.79; 95% CI, 2.10-3.71), but not major microvascular events (HR, 0.91; 95% CI, 0.61-1.36), compared with stable weight. There was no evidence of effect modification by baseline body mass index, age, or type of diabetes medication. Conclusions In the absence of substantial lifestyle changes, weight loss may be a warning sign of poor health meriting further workup in patients with type 2 diabetes.

Background. Hyperuricemia has a strong association with diabetes mellitus. Hyperuricemia can lead to cardiovascular and renal complications in patients with diabetes. The goal of this study was to compare the effect of sodium-glucose cotransporter-2 (SGLT-2) inhibitors dapagliflozin and empagliflozin on serum uric acid (SUA) levels in patients with type 2 diabetes against traditional oral antihyperglycemic drugs (OADs). Methods. In this double-blind randomized controlled trial, 70 patients with type 2 diabetes and elevated SUA levels were assigned to two treatment groups. Patients in group A received SGLT-2 inhibitors tablet dapagliflozin 5 mg to 10 mg and empagliflozin 10 mg to 25 mg. Group B patients received OADs such as glimepiride, metformin, sitagliptin, gliclazide, and glibenclamide as monotherapy or combination therapy. The changes in SUA level were primary end points while changes in body weight and body mass index (BMI) from baseline to end point were secondary end points. Results. After four weeks of treatment, we noted a significant reduction of mean SUA levels in the SGLT-2 inhibitor group from 7.5±2.5 to 6.3±0.8 mg/dl versus comparator group from 7.1±1.8 to 6.8±2.2 mg/dl (p=0.001). Mean body weight was significantly reduced in the SGLT-2 group from 82±10.4 to 78±12.5 kg versus comparator group from 78±13.2 to 79.2±9.7 kg (p=0.001). Similarly, the mean BMI of patients in the SGLT-2 group was significantly reduced from 25.7±3.2 to 24.2±3.2 kg/m2 versus comparator group from 27.5±4.2 to 28±3.6 kg/m2 (p=0.002). Conclusion. SGLT-2 inhibitors have a strong potential to decrease SUA levels in patients with type 2 diabetes.

Several observational studies were conducted with vildagliptin in patients with type 2 diabetes mellitus (T2DM) fasting during Ramadan, showing significantly lower incidences of hypoglycemia with vildagliptin versus sulfonylureas, including gliclazide. It was of interest to complement the existing real-life evidence with data from a randomized, double-blind, clinical trial. NCT01758380. This multiregional, double-blind study randomized 557 patients with T2DM (mean glycated hemoglobin [HbA1c], 6.9%), previously treated with metformin and any sulfonylurea to receive either vildagliptin (50 mg twice daily) or gliclazide plus metformin. The study included four office visits (three pre-Ramadan) and multiple telephone contacts, as well as Ramadan-focused advice. Hypoglycemic events were assessed during Ramadan; HbA(1c) and weight were analyzed before and after Ramadan. The proportion of patients reporting confirmed (<3.9 mmol/L and/or severe) hypoglycemic events during Ramadan was 3.0% with vildagliptin and 7.0% with gliclazide (P=0.039; one-sided test), and this was 6.0% and 8.7%, respectively, for any hypoglycemic events (P=0.173). The adjusted mean change pre- to post-Ramadan in HbA(1c) was 0.05%±0.04% with vildagliptin and -0.03%±0.04% with gliclazide, from baselines of 6.84% and 6.79%, respectively (P=0.165). In both groups, the adjusted mean decrease in weight was -1.1±0.2 kg (P=0.987). Overall safety was similar between the treatments. In line with the results from previous observational studies, vildagliptin was shown in this interventional study to be an effective, safe, and well-tolerated treatment in patients with T2DM fasting during Ramadan, with a consistently low incidence of hypoglycemia across studies, accompanied by good glycemic and weight control. In contrast, gliclazide showed a lower incidence of hypoglycemia in the present interventional than the previous observational studies. This is suggested to be linked to the specific circumstances of this study, including frequent patient-physician contacts, Ramadan-focused advice, a recent switch in treatment, and very well-controlled patients, which is different from what is often seen in real life.

Type 2 diabetes shows evidence of underlying heterogeneity. No studies have assessed whether different causes for diabetes change the response to oral hypoglycaemic therapy. In a few cases, patients with diabetes caused by mutations in the hepatocyte nuclear factor 1α (HNF-1α) gene have been described as sensitive to the hypoglycaemic effects of sulphonylureas. We aimed to see whether the glycaemic response to the sulphonylurea gliclazide and the biguanide metformin differed in HNF-1α diabetes and type 2 diabetes, and to investigate the mechanism for differences in sulphonylurea sensitivity. We did a randomised crossover trial of glicazide and metformin in 36 patients, either with diabetes caused by HNF-1α mutations or type 2 diabetes, who were matched for body-mass index and fasting plasma glucose. The primary outcome was reduction in fasting plasma glucose. Analysis was by intention to treat. We assessed possible mechanisms for sulphonylurea sensitivity through insulin sensitivity, insulin secretory response to glucose and tolbutamide, and tolbutamide clearance. Patients with HNF-1α diabetes had a 5.2-fold greater response to gliclazide than to metformin (fasting plasma glucose reduction 4·7 vs 0·9 mmol/L, p=0·0007) and 3.9-fold greater response to gliclazide than those with type 2 diabetes (p=0·002). Patients with HNF-1α diabetes had a strong insulin secretory response to intravenous tolbutamide despite a small response to intravenous glucose, and were more insulin sensitive than those with type 2 diabetes. Sulphonylurea metabolism was similar in both patient groups. The cause of hyperglycaemia changes the response to hypoglycaemic drugs; HNF-1α diabetes has marked sulphonylurea sensitivity. This pharmacogenetic effect is consistent with models of HNF-1α deficiency, which show that the β-cell defect is upstream of the sulphonylurea receptor. Definition of the genetic basis of hyperglycaemia has implications for patient management.

Aims/hypothesis Intensive glucose control reduces the risk of vascular complications while increasing the risk of severe hypoglycaemia at a group level. We sought to estimate individual beneficial and adverse effects of intensive glucose control in patients with type 2 diabetes. Methods We performed a post hoc analysis of the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial, a randomised controlled trial evaluating standard vs intensive glucose control (HbA 1c target ≤6.5% [48 mmol/mol]). In 11,140 participants, we estimated the individual 5 year absolute risk reduction (ARR) for the composite outcome of major micro- and macrovascular events and absolute risk increase (ARI) for severe hypoglycaemia for intensive vs standard glucose control. Predictions were based on competing risks models including clinical characteristics and randomised treatment. Results Based on these models, 76% of patients had a substantial estimated 5 year ARR for major vascular events (>1%, 5 year number-needed-to-benefit [NNTB 5 ] <100) and 1% had a small ARR (<0.5%, NNTB 5 >200). Similarly, 36% of patients had a substantial estimated ARI for severe hypoglycaemia (5 year number-needed-to-harm [NNTH 5 ] <100) and 29% had a small ARI (NNTH 5 >200). When assigning similar or half the weight to severe hypoglycaemia compared with a major vascular event, net benefit was positive in 85% or 99% of patients, respectively. Limiting intensive treatment to the 85% patient subgroup had no significant effect on the overall incidence of major vascular events and severe hypoglycaemia compared with treating all patients. Conclusions/interpretation Taking account of the effects of intensive glucose control on major micro- and macrovascular events and severe hypoglycaemia for individual patients, the estimated net benefit was positive in the majority of the participants in the ADVANCE trial. The estimated individual effects can inform treatment decisions once individual weights assigned to positive and adverse effects have been specified. Trial registration : ClinicalTrials.gov NCT00145925

Aims/hypothesis The hypoglycaemic actions of metformin have been proposed to be mediated by hepatic AMP-activated protein kinase (AMPK). As the effects of metformin and the role of AMPK in adipose tissue remain poorly characterised, we examined the effect of metformin on AMPK activity in adipose tissue of individuals with type 2 diabetes in a randomised glycaemia-controlled crossover study. Methods Twenty men with type 2 diabetes (aged 50–70 years) treated with diet, metformin or sulfonylurea alone were recruited from North Glasgow University National Health Service Trusts’ diabetes clinics and randomised to either metformin or gliclazide for 10 weeks. Randomisation codes, generated by computer, were put into sealed envelopes and stored by the hospital pharmacist. Medication bottles were numbered, and allocation was done in sequence. The participants and investigators were blinded to group assignment. At the end of each phase of therapy adipose biopsy, AMPK activity (primary endpoint) and levels of lipid metabolism and signalling proteins were assessed. In parallel, the effect of metformin on AMPK and insulin-signalling pathways was investigated in 3T3-L1 adipocytes. Results Ten participants were initially randomised to metformin and subsequently crossed over to gliclazide, while ten participants were initially randomised to gliclazide and subsequently crossed over to metformin. No participants discontinued the intervention and the adipose tissue AMPK activity was analysed in all 20 participants. There were no adverse events or side effects in the study group. Adipose AMPK activity was increased following metformin compared with gliclazide therapy (0.057 ± 0.007 vs 0.030 ± 0.005 [mean ± SEM] nmol min −1 [mg lysate] −1 ; p  < 0.005), independent of AMPK level, glycaemia or plasma adiponectin concentrations. The increase was associated with reduced levels of acetyl-CoA carboxylase (ACC) protein and increased ACC Ser80 phosphorylation. In 3T3-L1 adipocytes, metformin reduced levels of ACC protein and stimulated phosphorylation of AMPK Thr172 and hormone-sensitive lipase Ser565. Conclusions These results provide the first evidence that metformin activates AMPK and reduces ACC protein levels in human adipose tissue in vivo. Future studies are required to assess the role of adipose AMPK activation in the pharmacological effects of metformin. Trial registration ISRCTN51336867 Funding This work was supported by grants from the British Heart Foundation, TENOVUS-Scotland, the Biotechnology and Biological Sciences Research Council and Diabetes UK.