Uchenna Anyanwagu

Drug-Induced Diabetes Mellitus: Evidence for Statins and Other Drugs Affecting Glucose Metabolism

Abnormalities of glucose metabolism and glucose tolerance, either because of a reduction in tissue sensitivity to insulin (e.g., in liver, skeletal muscle, and adipose tissues) and/or a reduction in pancreatic insulin secretion, are associated with a number of unwanted health outcomes. Even small increases in circulating glucose levels (often described as dysglycemia or prediabetes) may confer an increased risk of cardiovascular (CV) disease and progression to overt type 2 diabetes. A number of drug therapies, many of them used long term in chronic disease management, have adverse effects on glucose metabolism, diabetes risk, and glycemic control among patients with preexisting diabetes. In this study, we review the evidence, underlying mechanisms, and the clinical significance of drug‐related adverse effects on glucose metabolism.

Cardiovascular events and all-cause mortality with insulin versus glucagon-like peptide-1 analogue in type 2 diabetes

Objectives To analyse time to cardiovascular events and mortality in patients with type 2 diabetes (T2D) who received treatment intensification with insulin or a glucagon-like peptide-1 (GLP-1ar) analogue following dual therapy failure with metformin (MET) and sulphonylurea (SU). Methods A retrospective cohort study was conducted in 2003 patients who were newly treated with a GLP-1ar or insulin following dual therapy (MET+SU) failure between 2006 and 2014. Data were sourced from The Health Improvement Network database. Risks of major adverse cardiovascular events (MACE) (non-fatal myocardial infarction, non-fatal stroke and all-cause mortality) were compared between MET+SU+insulin (N=1584) versus MET+SU+GLP-1ar (N=419). Follow-up was for 5 years (6614 person-years). Propensity score matching analysis and Cox proportional hazard models were employed. Results Mean age was 52.8±14.1 years. Overall, the number of MACE was 231 vs 11 for patients who added insulin versus GLP-1ar, respectively (44.5 vs 7.7 per 1000-person-years adjusted HR (aHR): 0.27; 95% CI 0.14 to 0.53; p<0.0001). Insulin was associated with significant increase in weight compared with GLP-1ar (1.78 vs −3.93 kg; p<0.0001) but haemoglobin A1c reduction was similar between both treatment groups (−1.29 vs −0.98; p=0.156). In a subgroup analysis of obese patients (body mass index >30 kg/m2) there were 84 vs 11 composite outcomes (38.6 vs 8.1 per 1000 person-years; aHR: 0.31; 95% CI 0.16 to 0.61; p=0.001) in the insulin and GLP-1ar groups, respectively. Conclusions In this cohort of obese people with T2DM, intensification of dual oral therapy by adding GLP-1ar analogue is associated with a lower MACE outcome in routine clinical practice, compared with adding insulin therapy as the third glucose-lowering agent.

Comparison of cardiovascular and metabolic outcomes in people with type 2 diabetes on insulin versus non-insulin glucose-lowering therapies (GLTs): A systematic review and meta-analysis of clinical trials

OBJECTIVES To compare the cardiovascular and metabolic outcomes of Insulin versus non-insulin glucose lowering therapy (GLT). METHODS We included randomised control trials (RCTs) which randomised patients aged >18years with Type 2 Diabetes (T2D) to insulin vs non-insulin GLT. We used risk ratios (RR), risk difference (RD) and odds ratios (OR) with 95% confidence interval (95%CI) to analyse the treatment effects of dichotomous outcomes and mean differences (with 95% CI) for continuous outcomes. RESULTS We included 18 RCTs with 19,300 participants. There was no significant difference in the risk of all-cause mortality and CV events between the groups (RR=1.01; 95%CI: 0.96-1.06; p=0.69). In 16 trials, insulin showed greater efficacy in glycaemic control (mean diff=-0.20; 95%CI: -0.28 to -0.11) but the proportion achieving HbA1c level of either ⩽7.0% or 7.4% (53 or 57mmol/mol) was similar in both (OR=1.55; 95%CI=0.92-2.62). The non-insulin group had a significant reduction in weight (mean diff=-3.41; 95%CI: -4.50 to -2.32) and an increase in the proportion of adverse events (54.7% vs 45.3%, p=0.044), but the insulin group showed an (RR=1.90; 95%CI: 1.44-2.51) increased risk of hypoglycaemia. CONCLUSION There was no difference in the risk of all-cause mortality and adverse cardiovascular (CV) events between Insulin and non-insulin GLTs. Insulin was associated with superior reduction in HbA1c; least reduction in weight and higher risk of hypoglycaemia. Both showed similar proportion of patients achieving HbA1c target. Non-insulin GLTs were associated with a higher risk in reported adverse drug events.

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.

Effects of obesity on metabolic and cardiovascular outcomes following insulin initiation in patients with type 2 diabetes

OBJECTIVES Insulin therapy induces weight gain but whether it causes long term adverse metabolic and CV outcomes in obese patients remains unclear. METHODS A retrospective cohort study of 12,725 insulin initiators with T2D derived from UK General Practices. Multivariate linear, logistic regression analyses and Cox proportional hazard models were used to estimate HbA1c, BMI, risk of composite CV events between baseline BMI categories at 5 years. RESULTS Mean age was 58.6±13.8years. The proportion of patients achieving HbA1c targets decreased across increasing BMI categories at 6 and at 12 months; p=0.0001, but not significant beyond 24 months. 1095 composite events of all-cause mortality, non-fatal stroke and MI occurred with an adjusted hazard risk (aHR) relative to normal of: (1.10; 95%CI: 0.90-1.35) in the overweight, (1.05; 95%CI: 0.86-1.29) in the obese class I, (1.03; 95%CI: 0.83-1.29) in the obese class II and (1.30; 95%CI: 1.02-1.66) in the obese class III BMI categories. CONCLUSION Among patients with T2D insulin initiators, obesity adversely influences HbA1c up to 12 months, but not beyond 24 months and is associated with a decrease in BMI compared to non-obese groups. Morbidly obese patients initiating insulin have 30% increased risk of composite CV events after 5 years.

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

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.

Premixed vs basal-bolus insulin regimen in Type 2 diabetes: comparison of clinical outcomes from randomized controlled trials and real-world data

To evaluate the concordance between data derived from randomized controlled trial (RCT) and real‐world estimates of HbA1c and weight change after 24 weeks of initiation of a basal‐bolus compared with a premixed insulin regimen in people with Type 2 diabetes.

Continuous subcutaneous insulin infusion (CSII) therapy at Derby Teaching Hospitals: sustained benefits in glucose control

In the short term, continuous subcutaneous insulin infusion (CSII) has been associated with improved glycaemic control, reduced hypoglycaemia and improved quality of life (QOL). However, limited data are available on its long‐term benefits, particularly in the UK. We aimed to assess the impact of CSII on longer term outcomes.

Tier 3 specialist weight management service and pre-bariatric multicomponent weight management programmes for adults with obesity living in the UK: A systemic review

NHS England has recommended a multidisciplinary weight management services (MWMS—Tier 3 services) for patients requiring specialized management of obesity, including bariatric surgery, but clinical and measurable health‐related outcomes from these services remains fragmented. We therefore undertook a systematic review to explore the evidence base of effect on body weight loss and comorbidities outcomes of Tier 3 or UK pre‐bariatric MWMPs.

Demographics, insulin use and clinical targets in type 2 diabetes insulin users: comparison of a local integrated diabetes service vs a UK-wide cohort

Insulin‐treated patients with type 2 diabetes require specialist multidisciplinary input to achieve treatment targets. We compared the demographics, achievement of combined NICE targets for HbA1c (≤7.5%), blood pressure (<140/80mmHg) and total cholesterol (<4mmol/L), and insulin use between patients from a local integrated diabetes service with those from a representative UK population.