A commentary review on endoscopic sleeve gastroplasty: Indications, outcomes and future implications.

Metabolic and bariatric surgeries have been shown to be the most effective strategy to induce and maintain significant weight loss for people living with severe obesity. However, ongoing concerns regarding operative risks, irreversibility and excess costs limit their broader clinical use. Endoscopic bariatric therapies are pragmatic alternatives for patients who are not suitable for metabolic and bariatric surgeries or who are concerned regarding their long-term safety. Endoscopic sleeve gastroplasty has emerged as a novel technique of endoscopic bariatric therapies, which have garnered significant interest and evidence in the past few years. Its safety, efficacy and cost-effectiveness have been shown in various studies, while comparisons with sleeve gastrectomy have been widely made. This review brings together current evidence pertaining to the technicality of the procedure itself, current indications, safety and efficacy, cost-effectiveness, as well as its future role and development.

Sodium-glucose cotransporter-2 inhibitors (SGLT2) in frail or older people with type 2 diabetes and heart failure: a systematic review and meta-analysis.

OBJECTIVE: Sodium-glucose cotransporter-2 inhibitors (SGLT2Is) reduce cardio-metabolic and renal outcomes in patients with type 2 diabetes (T2D) but their efficacy and safety in older or frail individuals remains unclear. METHODS: We searched PubMed, Scopus, Web of Science, Cochrane CENTRA and Google Scholar and selected randomised controlled trials and observational studies comparing SGLT2Is versus placebo/other glucose-lowering agent for people with frailty or older individuals (>65 years) with T2D and heart failure (HF). Extracted data on the change in HbA1c % and safety outcomes were pooled in a random-effects meta-analysis model. RESULTS: We included data from 20 studies (22 reports; N = 77,083 patients). SGLT2Is did not significantly reduce HbA1c level (mean difference -0.13, 95%CI: -0.41 to 0.14). SGLT2Is were associated with a significant reduction in the risk of all-cause mortality (risk ratio (RR) 0.81, 95%CI: -0.69 to 0.95), cardiac death (RR 0.80, 95%CI: -0.94 to 0.69) and hospitalisation for heart failure (HHF) (RR 0.69, 95%CI: 0.59-0.81). However, SGLT2Is did not demonstrate significant effect in reducing in the risk of macrovascular events (acute coronary syndrome or cerebral vascular occlusion), renal progression/composite renal endpoint, acute kidney injury, worsening HF, atrial fibrillation or diabetic ketoacidosis. CONCLUSIONS: In older or frail patients with T2D and HF, SGLT2Is are consistently linked with a decrease in total mortality and the overall burden of cardiovascular (CV) events, including HHF events and cardiac death, but not protective for macrovascular death or renal events. Adverse events were more difficult to quantify but the risk of diabetic ketoacidosis or acute kidney injury was not significantly increase.

Non-invasive imaging of functional pancreatic islet beta-cell mass in people with type 1 diabetes mellitus.

AIMS: To investigate whether manganese-enhanced magnetic resonance imaging can assess functional pancreatic beta-cell mass in people with type 1 diabetes mellitus. METHODS: In a prospective case-control study, 20 people with type 1 diabetes mellitus (10 with low (≥50 pmol/L) and 10 with very low (<50 pmol/L) C-peptide concentrations) and 15 healthy volunteers underwent manganese-enhanced magnetic resonance imaging of the pancreas following an oral glucose load. Scan-rescan reproducibility was performed in 10 participants. RESULTS: Mean pancreatic manganese uptake was 31 ± 6 mL/100 g of tissue/min in healthy volunteers (median 32 [interquartile range 23-36] years, 6 women), falling to 23 ± 4 and 13 ± 5 mL/100 g of tissue/min (p ≤ 0.002 for both) in people with type1 diabetes mellitus (52 [44-61] years, 6 women) and low or very low plasma C-peptide concentrations respectively. Pancreatic manganese uptake correlated strongly with plasma C-peptide concentrations in people with type1 diabetes mellitus (r = 0.73, p < 0.001) but not in healthy volunteers (r = -0.054, p = 0.880). There were no statistically significant correlations between manganese uptake and age, body-mass index, or glycated haemoglobin. There was strong intra-observer (mean difference: 0.31 (limits of agreement -1.42 to 2.05) mL/100 g of tissue/min; intra-class correlation, ICC = 0.99), inter-observer (-1.23 (-5.74 to 3.27) mL/100 g of tissue/min; ICC = 0.85) and scan-rescan (-0.72 (-2.9 to 1.6) mL/100 g of tissue/min; ICC = 0.96) agreement for pancreatic manganese uptake. CONCLUSIONS: Manganese-enhanced magnetic resonance imaging provides a potential reproducible non-invasive measure of functional beta-cell mass in people with type 1 diabetes mellitus. This holds major promise for investigating type 1 diabetes, monitoring disease progression and assessing novel immunomodulatory interventions.

Therapeutic inertia related to the injectable glucagon-like peptide-1 receptor agonists dulaglutide and semaglutide in patients with type 2 diabetes in UK primary care.

AIMS: To determine the extent of therapeutic inertia related to the weekly injectable glucagon-like peptide-1 receptor agonists dulaglutide and semaglutide in patients with type 2 diabetes (T2D) in the United Kingdom. MATERIALS AND METHODS: Adults with T2D who received their first primary care prescription of dulaglutide or semaglutide between January and July 2019 were identified from the UK Clinical Practice Research Datalink GOLD primary care database. Doses prescribed, glycated haemoglobin (HbA1c), body mass index (BMI) and concomitant T2D medications were assessed at first prescription and at 3, 6 and 9 months. RESULTS: Of the patients prescribed dulaglutide (N = 748; mean [SD] age 59.0 [11.2] years) and semaglutide (N = 437; mean [SD] age 58.4 [10.6] years), 93.0% and 89.0%, respectively, had an HbA1c level ≥7.5% (≥58.46 mmol/mol), and 56.4% and 54.9%, respectively, had an HbA1c level ≥9.0% (≥74.86 mmol/mol), at first prescription. At 6 to 9 months, 75.0% of those on dulaglutide 0.75 mg and 57.6% of those on semaglutide 0.25 mg or 0.5 mg had an HbA1c level ≥7.5% (≥58.46 mmol/mol). At 9 months, 21.9% of the dulaglutide cohort were on the suboptimal dose of 0.75 mg, and 46.1% of the semaglutide cohort were on the suboptimal doses of 0.25 mg or 0.5 mg. CONCLUSIONS: Multiple examples of therapeutic inertia were identified, including first prescription at HbA1c levels considerably above target and failure to escalate to optimal doses even with evidence of suboptimal metabolic control. A substantial proportion of patients therefore did not achieve optimal HbA1c targets.

Effects of dietary nitrate and vitamin C co-ingestion on blood pressure and hand-grip strength in young adults.

Background: Co-administration of vitamin C and inorganic nitrate ([Formula: see text]) may reduce oxidative stress, boost the conversion of nitrite ([Formula: see text]) into NO and elicit positive vascular effects. Aims: We aimed to test the effects of oral inorganic [Formula: see text] and vitamin C co-supplementation on vascular function, muscular strength, and on concentrations of urinary [Formula: see text], vitamin C, 8-isoprostanes and salivary [Formula: see text] in healthy young adults. Methods: Ten young healthy participants were enrolled in a randomised, double-blind (only for the [Formula: see text] intervention) crossover clinical trial. Participants consumed in random order: 1) nitrate-rich beetroot juice and vitamin C (N+VC), 2) nitrate-rich beetroot juice alone (N) or 3) nitrate-depleted beetroot juice alone (ND). Resting blood pressure (BP) was measured at the research centre and at home. Non-invasive, continuous measurements of BP and cardiac function parameters were performed using a Finometer device. Free-living physical activity and hand-grip strength were assessed. Salivary [Formula: see text] and [Formula: see text] and urinary [Formula: see text], 8-isoprostanes and vitamin C concentrations were measured. Results: There were no significant differences for any of the vascular outcomes between the three interventions groups. However, analyses of within-intervention changes showed a significant lower daily systolic BP in the [Formula: see text]+vitamin C (N+VC) group only (P=0.04). Urinary [Formula: see text] (P=0.002) and salivary [Formula: see text] (P=0.001) were significantly higher in the N+VC group compared to the N and ND groups. Conclusion: These preliminary findings suggest that combining dietary [Formula: see text] with vitamin C could have protective effects on vascular function in young adults and could represent an effective strategy for the maintenance of healthy cardiovascular trajectories.

Vitamin C supplementation showed greater effects on systolic blood pressure in hypertensive and diabetic patients: an updated systematic review and meta-analysis of randomised clinical trials.

Results from randomised controlled trials (RCTs) testing the effect of vitamin C supplementation on blood pressure (BP) have been inconsistent. This systematic review evaluated the effects of vitamin C supplementation on BP and included RCTs testing the effects of vitamin C supplementation alone, on systolic and diastolic BP in adult participants (≥18 years). Random-effect models were conducted to estimate the pooled effects of vitamin C supplementation on BP. A total of 20 studies with 890 participants were included. The median dose of vitamin C was 757.5 mg/d, the median duration was 6 weeks. Vitamin C supplementation was found to reduce systolic BP by -3.0 mmHg (95%CI: -4.7, -1.3 mmHg; p = 0.001). Subgroup analysis showed a more pronounced effect on systolic BP in patients with hypertension (-3.2 mmHg, 95%CI -5.2, -1.2 mmHg, p = 0.002) and diabetes (-4.6 mmHg, 95%CI -8.9, -0.3 mmHg, p = 0.03). Further research needs to evaluate the long-term effect of vitamin C on BP in populations with impaired cardio-metabolic health.

Safety and effectiveness of do-it-yourself artificial pancreas system compared with continuous subcutaneous insulin infusions in combination with free style libre in people with type 1 diabetes.

AIMS: The use of do-it-yourself artificial pancreas systems (DIYAPS) among people with type 1 diabetes is increasing. At present, it is unclear how DIYAPS compares with other technologies such as FreeStyle Libre (FSL) and continuous subcutaneous insulin infusion (CSII). The aim of this analysis is to compare safety, effectiveness and quality-of-life outcomes of DIYAPS use with the addition of FSL to CSII. METHOD: Data from two large UK hospitals were extracted from the Association of British Clinical Diabetologists (ABCD) DIYAPS and FSL audits. Outcomes included HbA1c , glucose TBR (time-below-range), TIR (time-in-range), Diabetes Distress Score (DDS), and Gold hypoglycaemia score. Any adverse events were noted. Changes at follow-up were assessed using paired t-tests and ANOVA in Stata; TIR/TBR at follow-up assessed using unpaired t-tests; chi-square tests assessed the change in frequency of health utilisation (e.g. hospital admissions). RESULTS: DIYAPS (n = 35) and FSL+CSII (n = 149) users, with median follow-up duration of 1.4 (IQR 0.8-2.1) and 1.3 (IQR 0.7-1.8) years, respectively, were included. HbA1c with DIYAPS use changed by -10 mmol/mol [0.9%] (p < 0.001, 95% CI 5, 14 [0.5, 1.3%]) significantly lower (p < 0.001) than in the FSL+CSII group -3 mmol/mol [0.25%] (p < 0.001, 95% CI 1, 4 [0.1, 0.4%]). TIR was higher and TBR was lower in the DIYAPS group. Adverse events were rare in both groups and no significant differences were observed in the frequency of healthcare utilisation. CONCLUSION: DIYAPS use was associated with a lower HbA1c levels, higher TIR and lower TBR compared with FSL+CSII. There was no significant increase in adverse events, although this should be interpreted cautiously given the low numbers of users. Full results from the ABCD DIYAPS audit are awaited.

Significant reduction in chronic kidney disease progression with sodium-glucose cotransporter-2 inhibitors compared to dipeptidyl peptidase-4 inhibitors in adults with type 2 diabetes in a UK clinical setting: An observational outcomes study based on international guidelines for kidney disease.

AIMS: To confirm the reno-protective effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors compared with dipeptidyl peptidase-4 (DPP-4) inhibitors on the onset and progression of chronic kidney disease (CKD) in routine clinical practice. MATERIALS AND METHODS: We conducted a retrospective cohort study using the Clinical Practice Research Datalink Aurum database linked to Hospital Episode Statistics. The primary outcome was risk of the composite CKD endpoint based on the recent consensus guidelines for kidney disease: >40% decline in estimated glomerular filtration rate (eGFR), kidney death or end-stage kidney disease (ESKD; a composite of kidney transplantation, maintenance of dialysis, sustained low eGFR <15 ml/min/1.73m² or diagnosis of ESKD). Secondary outcomes were components of the composite CKD endpoint, analysed separately. Patients were propensity-score-matched 1:1 for SGLT2 inhibitor versus DPP-4 inhibitor use. RESULTS: A total of 131 824 people with type 2 diabetes (T2D) were identified; 79.0% had no known history of CKD. During a median follow-up of 2.1 years, SGLT2 inhibitor initiation was associated with lower risk of progression to composite kidney endpoints than DPP-4 inhibitor initiation (7.48 vs. 11.77 events per 1000 patient-years, respectively). Compared with DPP-4 inhibitor initiation, SGLT2 inhibitor initiation was associated with reductions in the primary composite CKD endpoint (hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.56-0.74), all-cause mortality (HR 0.74, 95% CI 0.64-0.86) and ESKD (HR 0.37, 95% CI 0.25-0.55), reduced the rate of sustained low eGFR (HR 0.33, 95% CI 0.19-0.57), and reduced diagnoses of ESKD in primary care (HR 0.04, 95% CI 0.01-0.18). Results were consistent across subgroup and sensitivity analyses. CONCLUSIONS: In adults with T2D, initiation of an SGLT2 inhibitor was associated with a significantly reduced risk of CKD progression and death compared with initiation of a DPP-4 inhibitor.

Cardiovascular risk profiles: A cross-sectional study evaluating the generalizability of the glucagon-like peptide-1 receptor agonist cardiovascular outcome trials REWIND, LEADER and SUSTAIN-6 to the real-world type 2 diabetes population in the United Kingdom.

AIMS: To determine the proportion of UK patients with type 2 diabetes (T2D) who meet the cardiovascular (CV) or combined CV/core eligibility criteria used for the CV outcome trials (CVOTs) of UK-marketed glucagon-like peptide-1 receptor agonists (GLP-1RAs) showing CV benefit (dulaglutide in REWIND, liraglutide in LEADER and injectable semaglutide in SUSTAIN-6). MATERIALS AND METHODS: Adults with T2D on/before June 2018 were identified from the UK Clinical Practice Research Datalink GOLD primary care database and linked to Hospital Episode Statistics data (Protocol 19_262). Patient CV and clinical data were evaluated against the CVOT eligibility criteria. Data were analysed descriptively. RESULTS: The study cohort (N = 33 118 patients with T2D) had a mean (standard deviation) age of 66.0 (13.3) years and 56.6% were male. Almost two-thirds (64.5%) of the study cohort met the CV criteria for REWIND, versus 43.0% for both LEADER and SUSTAIN-6. The proportions of the study cohort who met the CVOT criteria of "established CV disease" and "CV risk factors only" for REWIND were 22.4% and 42.1%, respectively, versus 38.7% and 4.3%, respectively, for both LEADER and SUSTAIN-6. The proportions of patients satisfying both CV and core criteria were 44.4% for REWIND, 13.3% for LEADER and 13.5% for SUSTAIN-6. Study findings remained consistent when restricted to GLP-1RA users. CONCLUSIONS: REWIND captured a trial population more representative of the real-world T2D population in the United Kingdom than LEADER or SUSTAIN-6 with regard to both CV and combined CV/core eligibility criteria.

Injectable semaglutide and reductions in HbA1c and weight in the real world in people switched from alternative glucagon-like peptide-1 receptor agonists.

The ABCD semaglutide audit was designed to capture the routine clinical outcomes of people commenced on semaglutide in the UK. Previous work showed differential reductions in HbA1c and weight dependent on previous glucagon-like peptide-1 receptor agonist (GLP-1RA) exposure. The analysis, in this research letter, shows that decreases in HbA1c and weight associated with semaglutide occur irrespective of previous GLP-1RA use. However, HbA1c reductions were less if switched from dulaglutide or liraglutide and weight changes were attenuated if switched from dulaglutide or exenatide, potentially suggesting differing potencies between GLP-1RAs. Dedicated studies with head-to-head comparisons are needed to confirm these findings.

Effectiveness of the Transformation model, a model of care that integrates diabetes services across primary, secondary and community care: A retrospective study.

AIMS: The primary aim was to evaluate the effectiveness of a model integrating diabetes services across primary, secondary and community care (Transformation model). The secondary aim was to understand whether changes resulted from the model. METHODS: The model was implemented In Leicester, Leicestershire and Rutland (UK) across three clinical commissioning groups, the acute trust and accompanying stakeholders. One clinical commissioning group (Leicester City) implemented the entire model and was the primary evaluation population. A quasi-experimental interrupted time series design was employed. The primary outcome was number of Type 2 diabetes-related bed-days per 1000 patients. RESULTS: In the primary population, the mean number of Type 2 diabetes-related bed-days per 1000 patients was increasing before model implementation by 0.33/month (95% confidence interval: -0.07, 0.72), whereas it was decreasing after implementation by a mean value of -0.14/month (-0.33, 0.06); a statistically significant difference (p = 0.04). Secondary analyses showed: nationally, there was no significant change between the pre- and post-periods so it is unlikely that large secular change drove the improvement; the other two Leicestershire clinical commissioning groups saw improvement or stability; underlying processes worked as hypothesised overall; diabetes biomedical markers deteriorated in the primary care population suggesting a change in case-mix due to moving some patients out of secondary care. CONCLUSIONS: Given that the initial aim was to shift services from secondary to primary care without causing harm, an improvement is better than expected. This observational evaluation cannot show conclusively that improvements were due to the Transformation model, but secondary analyses support this.

Phenylbutyrate, a branched-chain amino acid keto dehydrogenase activator, promotes branched-chain amino acid metabolism and induces muscle catabolism in C2C12 cells.

NEW FINDINGS: What is the central question of this study? The compound sodium phenylbutyrate (PB) has been shown to promote branched-chain amino acid (BCAA) catabolism, and as such has been proposed as a treatment for disorders with enhanced BCAA levels: does PB induce muscle protein catabolism by forcing BCAA degradation away from muscle protein synthesis and mechanistic target of rapamycin (mTOR) inhibition? What is the main finding and its importance? Accelerated BCAA catabolism using PB resulted in adverse effects related to mTOR signalling and muscle protein metabolism in skeletal muscle cells, which may limit its application in conditions where muscle wasting is a risk. ABSTRACT: The compound sodium phenylbutyrate (PB) has been used for reducing ammonia in patients with urea cycle disorders and proposed as a treatment for disorders with enhanced branched-chain amino acid (BCAA) levels, due to its effects on promoting BCAA catabolism. In skeletal muscle cells, we hypothesised that PB would induce muscle protein catabolism due to forcing BCAA degradation away from muscle protein synthesis and downregulating mechanistic target of rapamycin (mTOR). PB reduced medium BCAA and branched-chain keto acid (BCKA) concentrations, while total cell protein (-21%; P < 0.001 vs. control) and muscle protein synthesis (-25%; P < 0.001 vs. control; assessed by measurement of puromycin incorporation into polypeptides) were decreased with PB. The regulator of anabolic pathways mTOR and its downstream components were impaired with PB treatment. The present results indicate that accelerated BCAA catabolism using PB resulted in adverse effects related to mTOR signalling and muscle protein metabolism, which may limit its application in settings where muscle wasting is a risk.

Lower risk of hospitalization for heart failure, kidney disease and death with sodium-glucose co-transporter-2 inhibitors compared with dipeptidyl peptidase-4 inhibitors in type 2 diabetes regardless of prior cardiovascular or kidney disease: A retrospective cohort study in UK primary care.

AIM: To assess if sodium-glucose co-transporter-2 inhibitors (SGLT2is) reduce the risk of all-cause mortality, cardiovascular death and hospitalization for heart failure (HF) or chronic kidney disease (CKD) to a greater extent than dipeptidyl peptidase-4 inhibitors (DPP4is) in people with type 2 diabetes (T2D) with or without established cardiovascular and/or renal disease (CVRD). METHODS: This retrospective cohort study propensity-matched 24 438 patients receiving an SGLT2i 1:1 to a patient receiving a DDP4i, stratified based on the presence of CVRD. The primary outcomes were the time to each of the following: all-cause mortality, cardiovascular death or hospitalization for HF, myocardial infarction, stroke and CKD. RESULTS: Overall, SGLT2is were associated with reductions in all-cause mortality, cardiovascular mortality, hospitalization for HF and hospitalization for CKD compared with DPP4is. In patients with no CVRD history, SGLT2is were associated with reductions in all-cause mortality (HR 0.71, 95% CI 0.57-0.88; P = .002), hospitalization for HF (HR 0.76, 95% CI 0.59-0.98; P = .035) and hospitalization for CKD (HR 0.75, 95% CI 0.63-0.88; P < .001). In patients with established cardiovascular disease (CVD) or at high risk, SGLT2is were associated with reductions in all-cause mortality (HR 0.69, 95% CI 0.59-0.82; P < .001), cardiovascular mortality (HR 0.76, 95% CI 0.62-0.95; P = .014), hospitalization for HF (HR 0.73, 95% CI 0.63-0.85; P < .001), hospitalization for stroke (HR 0.75, 95% CI 0.59-0.94; P = .013) and hospitalization for CKD (HR 0.49, 95% CI 0.43-0.54; P < .001). CONCLUSION: There was consistency across subgroups and sensitivity analyses. SGLT2is were associated with a reduced risk of all-cause mortality and hospitalization for HF and CKD compared with DPP4-is, highlighting the need to introduce SGLT2is early in the management of patients with T2D.

Exploring mechanistic links between extracellular branched-chain amino acids and muscle insulin resistance: an in vitro approach.

Branched-chain amino acids (BCAAs) are essential for critical metabolic processes; however, recent studies have associated elevated plasma BCAA levels with increased risk of insulin resistance. Using skeletal muscle cells, we aimed to determine whether continued exposure of high extracellular BCAA would result in impaired insulin signaling and whether the compound sodium phenylbutyrate (PB), which induces BCAA metabolism, would lower extracellular BCAA, thereby alleviating their potentially inhibitory effects on insulin-mediated signaling. Prolonged exposure of elevated BCAA to cells resulted in impaired insulin receptor substrate 1/AKT signaling and insulin-stimulated glycogen synthesis. PB significantly reduced media BCAA and branched-chain keto acid concentrations and increased phosphorylation of AKT [+2.0 ± 0.1-fold; P < 0.001 versus without (-)PB] and AS160 (+3.2 ± 0.2-fold; P < 0.001 versus -PB); however, insulin-stimulated glycogen synthesis was further reduced upon PB treatment. Continued exposure of high BCAA resulted in impaired intracellular insulin signaling and glycogen synthesis, and while forcing BCAA catabolism using PB resulted in increases in proteins important for regulating glucose uptake, PB did not prevent the impairments in glycogen synthesis with BCAA exposure.

The relationship between urinary albumin excretion, cardiovascular outcomes and total mortality among a large cohort of insulin-treated patients with type 2 diabetes in routine primary care practices.

BACKGROUND: Albuminuria is a recognized diagnostic and prognostic marker of chronic kidney disease and cardiovascular (CV) risk but the well-known relationship between increments in urinary albumin:creatinine ratio (UACR) and CV outcomes and mortality has not been fully explored in insulin-treated patients with type 2 diabetes (T2D) in routine clinical care. METHODS: We investigated data for insulin users with T2D from UK general practices between 2007 and 2014. The UACR at the time of insulin initiation was measured and categorized as <10, 10- 29, 30-300 and >300 mg/g. Patients were followed up for 5 years or the earliest occurrence of all-cause mortality, non-fatal myocardial infarction or stroke. Cox proportional hazards models were fitted to estimate the risk of a composite of these events. RESULTS: A total of 12 725 patients with T2D (mean age 58.6 ± 13.8 years, mean haemoglobin A1c 8.7 ± 1.8%) initiating insulin therapy between 2007 and 2014 met the inclusion criteria. Compared with patients whose ACR levels at insulin initiation were <10 mg/g, the adjusted risk of the 3-point composite endpoint was 9, 30 and 98% higher in those with ACR levels between 10-29, 30-300 and >300 mg/g, respectively, after a follow-up period of 5 years. The ACR category on its own did not predict risk of all-cause mortality. CONCLUSIONS: This study shows that in patients with T2D on insulin therapy, increased urinary ACR is independently associated with an increased risk of major adverse CV events and all-cause mortality.

Albuminuria Regression and All-Cause Mortality among Insulin-Treated Patients with Type 2 Diabetes: Analysis of a Large UK Primary Care Cohort.

BACKGROUND: Overt albuminuria (urinary albumin-creatinine ratio [ACR] > 300 mg/g) is an established risk factor for progression of nephropathy and total mortality. However, whether a reduction in ACR translates into a reduction in mortality and/or cardiovascular (CV) events among insulin-treated patients with type 2 diabetes (T2D) in routine practice is currently not known. METHODS: We obtained data on a large cohort of insulin users with T2D and nephropathy (baseline ACR ≥300 mg/g) from UK general practices between 2007 and 2014. Their corresponding ACR values after 1year of follow-up were thereafter categorized into: (1) < 300 mg/g (i.e., albuminuria regression) or (2) > 300 mg/g (i.e., nonregression of albuminuria), and the cohort was followed-up for 5 years for all-cause mortality and CV events. Cox proportional hazard models were fitted to estimate the risk of all-cause death. RESULTS: A total of 11,074 patients with insulin-treated T2D met the inclusion criteria. Their mean age was 62.3 (13.6) years; mean HbA1c: 8.7 (1.8) and 53% were male. A total of 682 deaths occurred after a follow-up period of 43,393 person-years with a mortality rate of 16 per 1,000 person-years. Five-year survival was markedly reduced in the group whose proteinuria persisted or progressed (91 vs. 95%; log-rank p value < 0.001). Compared to patients whose ACR levels remained above 300 mg/g, all-cause mortality and CV events were 31 and 27% lower in those whose albuminuria regressed to < 300 mg/g (adjusted hazard ratio [aHR] 0.69; 95% CI 0.52-0.91; p = 0.008 and aHR 0. 73; 95% CI 0.54-0.98; p = 0.041), respectively. CONCLUSION: In patients with insulin-treated T2D and nephropathy in routine practice, a regression in albuminuria (e.g., via better BP or glycemic control) is associated with a significant reduction in all-cause mortality. Thus, albuminuria is not only simply a risk marker of renal and CV disease but also an independent target for therapy. Albuminuria reduction should be viewed as a goal for renal and CV protection.

Genetic polymorphisms of the endocannabinoid system in obesity and diabetes.

The endocannabinoid system (ECS) is involved in many physiological processes including fertility, pain and energy regulation. The aim of this systematic review was to examine the contribution of single nucleotide polymorphisms (SNPs) of the ECS to adiposity and glucose metabolism. Database searches identified 734 articles, of which 65 were included; these covered 70 SNPs in genes coding for cannabinoid receptors 1 and 2 (CB1 , CB2 ), fatty acid amide hydrolase (FAAH) and N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD). No studies included SNPs relating to monoacylglycerol lipase or diacylglycerol lipase. The CB1 receptor SNP rs1049353 showed 17 associations with lower body mass index (BMI) and fat mass (five studies). It also showed three associations with lower insulin levels (one study). Conversely, the CB1 receptor SNP rs806368 was associated with increased BMI and waist circumference (two studies). The FAAH SNP rs324420 was associated with increased obesity (three studies). A haplotype of NAPE-PLD was associated with decreased BMI (one study). A total of 60 SNPs showed no association with any measured outcome. This review suggests a complex but important role of ECS SNPs in energy and glucose metabolism.

Relationship between HbA1c and all-cause mortality in older patients with insulin-treated type 2 diabetes: results of a large UK Cohort Study.

BACKGROUND: our aim was to study the relationship between HbA1c and cardiovascular morbidity and all-cause mortality among older insulin-treated patients with type 2 diabetes (T2D) after adjustment for multiple confounders. METHODS: data for 4589 adults with T2D (>65 years) on insulin treatment were sourced from 532 UK General Practices via the Health Improvement Network (THIN) database. Cox proportional hazard models and Kaplan-Meier estimators were fitted to derive the hazards of all-cause mortality by HbA1c categories (<6.5, 6.5-7.4, 7.5-8.4, 8.5-9.4, 9.5-10.4, 10.5-11.4%; and 11.5% and above) after 5 years of follow-up following insulin initiation. RESULTS: we observed a U-shaped relationship between all-cause mortality and HbA1c, with the lowest risk seen in the HbA1c range of 6.5-7.4% and marked increased in risk with HbA1c > 11%. The highest mortality risks of 31 and 40% were significantly associated with the lowest (<6.5%) and highest (11.5% and above) HbA1c categories: aHR: 1.31; (95%CI: 1.10-1.56; P = 0.002) and aHR: 1.40; (95%CI: 1.01-1.96; P = 0.039), respectively. CONCLUSIONS: both low and high HbA1c were associated with increased all-cause mortality, among older patients with insulin-treated T2D. This cohort study supports the need for individualisation of care and suggests better outcomes with HbA1c levels around 6.5-7.4% and markedly excess risk with HbA1c > 11.

Effect of adding GLP-1RA on mortality, cardiovascular events, and metabolic outcomes among insulin-treated patients with type 2 diabetes: A large retrospective UK cohort study.

BACKGROUND: Combining a GLP-1 receptor agonist (GLP-1RA) with insulin is often an effective treatment strategy for overweight patients with type 2 diabetes (T2D), but little is known about the longer-term effects on cardiovascular and mortality outcomes in routine clinical practice in the United Kingdom. We therefore compared the times to a major nonfatal cardiovascular (CV) event and all-cause mortality among overweight patients with T2D treated with insulin alone versus insulin+GLP-1RA in a large UK database. METHODS: A retrospective cohort study was conducted in 18,227 patients with insulin-treated T2D from UK General Practices using The Health Improvement Network database. The 5-year risk of mortality and a 3-point composite of all-cause mortality and nonfatal CV outcomes (myocardial infarction or stroke) was compared between a propensity score-matched cohort of those on insulin alone (n=1,793) and insulin+GLP-1RA (n=1,793), irrespective of other diabetes therapies, providing a total of 12,682 person-years of follow-up. Cox proportional hazard models were used to estimate the hazard ratios of the outcomes. RESULTS: Hemoglobin A1c reduction was similar between both groups (-0.42 vs -0.33%, P=.089 at 12 months). Overall, 3-point composite events of all-cause mortality and CV events (major adverse cardiovascular even) were 98 versus 55 for the insulin alone versus insulin+GLP-1RA groups, respectively (14.7 vs 9.2 per 1,000 person-years; adjusted hazard ratio [aHR]: 0.64; 95% CI: 0.42-0.98; P=.038). Corresponding composite nonfatal CV events were 33 versus 28 (6.0 vs 5.6 per 1,000 person-years; aHR: 0.76; 95% CI: 0.41-1.42; P=.393), whereas all-cause mortality events were 49 versus 13 (6.9 vs 2.0 per 1,000 person-years; aHR: 0.35; 95% CI: 0.17-0.73; P=.005). CONCLUSION: Based on a large UK cohort in routine clinical practice, adding a GLP-1RA to insulin therapy is associated with a reduction in risk of composite CV events and all-cause mortality but a nonsignificant higher risk of hospitalization for heart failure in overweight patients with T2D.

Association between insulin-induced weight change and CVD mortality: Evidence from a historic cohort study of 18,814 patients in UK primary care.

BACKGROUND: This study explores the association of insulin-induced weight (wt) gain on cardiovascular outcomes and mortality among patients with type 2 diabetes (T2D) following insulin initiation using real-world data. METHODS: A historical cohort study was performed in 18,814 adults with insulin-treated T2D derived from the UK The Health Improvement Network database. Based on the average weight change of 5 kg, 1 year postinsulin initiation, patients were grouped into 5 categories (>5 kg wt loss; 1.0-5.0 kg wt loss; no wt change; 1.0-5.0 kg wt gain; >5.0 kg wt gain) and followed-up for 5 years. Cox proportional hazard models and Kaplan-Meier estimators were fitted to estimate the hazards of a 3-point composite of nonfatal myocardial infarction, stroke, and all-cause mortality between categories. RESULTS: The median age was 62.8 (IQR: 52.3-71.8) years, HbA1c : 8.6% (IQR: 7.4-9.8) and mean BMI: 31.8 (6.5) kg/m2 . The 5 year probability of survival differed significantly within the wt-change categories (log-rank test P value = .0005). Only 1963 composite events occurred. Compared with the weight-neutral group, the risk of composite events was 31% greater in the >5 kg wt-loss group (aHR: 1.31; 95% CI: 1.02, 1.68), the same in the 1.0 to 5.0 kg wt-gain category, but nonsignificantly increased in the 1.0 to 5.0 kg wt loss (15%) and >5.0 kg wt gain (13%) categories, respectively. In the obese subgroup, this risk was 50% (aHR: 1.50, 95% CI: 1.08-2.08) more in the >5 kg weight-loss group compared with the weight-neutral group. CONCLUSION: Insulin-induced weight gain did not translate to adverse cardiovascular outcomes and mortality in patients with T2D. These data provide reassurance on the cardiovascular safety of insulin patients with T2D.