Jil Mamza

Care in specialist medical and mental health unit compared with standard care for older people with cognitive impairment admitted to general hospital: randomised controlled trial (NIHR TEAM trial)

Objective To develop and evaluate a best practice model of general hospital acute medical care for older people with cognitive impairment. Design Randomised controlled trial, adapted to take account of constraints imposed by a busy acute medical admission system. Setting Large acute general hospital in the United Kingdom. Participants 600 patients aged over 65 admitted for acute medical care, identified as “confused” on admission. Interventions Participants were randomised to a specialist medical and mental health unit, designed to deliver best practice care for people with delirium or dementia, or to standard care (acute geriatric or general medical wards). Features of the specialist unit included joint staffing by medical and mental health professionals; enhanced staff training in delirium, dementia, and person centred dementia care; provision of organised purposeful activity; environmental modification to meet the needs of those with cognitive impairment; delirium prevention; and a proactive and inclusive approach to family carers. Main outcome measures Primary outcome: number of days spent at home over the 90 days after randomisation. Secondary outcomes: structured non-participant observations to ascertain patients’ experiences; satisfaction of family carers with hospital care. When possible, outcome assessment was blind to allocation. Results There was no significant difference in days spent at home between the specialist unit and standard care groups (median 51 v 45 days, 95% confidence interval for difference −12 to 24; P=0.3). Median index hospital stay was 11 versus 11 days, mortality 22% versus 25% (−9% to 4%), readmission 32% versus 35% (−10% to 5%), and new admission to care home 20% versus 28% (−16% to 0) for the specialist unit and standard care groups, respectively. Patients returning home spent a median of 70.5 versus 71.0 days at home (−6.0 to 6.5). Patients on the specialist unit spent significantly more time with positive mood or engagement (79% v 68%, 2% to 20%; P=0.03) and experienced more staff interactions that met emotional and psychological needs (median 4 v 1 per observation; P<0.001). More family carers were satisfied with care (overall 91% v 83%, 2% to 15%; P=0.004), and severe dissatisfaction was reduced (5% v 10%, −10% to 0%; P=0.05). Conclusions Specialist care for people with delirium and dementia improved the experience of patients and satisfaction of carers, but there were no convincing benefits in health status or service use. Patients’ experience and carers’ satisfaction might be more appropriate measures of success for frail older people approaching the end of life. Trial registration Clinical Trials NCT01136148

Biphasic vs basal bolus insulin regimen in Type 2 diabetes: a systematic review and meta‐analysis of randomized controlled trials

We aim to evaluate the effects of biphasic insulin compared with a basal bolus insulin regimen on glycaemic control, total daily insulin requirements, risk of hypoglycaemia, weight and quality of life in patients with diabetes mellitus.

Important differences in the durability of glycaemic response among second-line treatment options when added to metformin in type 2 diabetes: a retrospective cohort study

Abstract Importance There is limited information about the durability of glycaemic control when different oral glucose-lowering therapies (GLTs) are used as add-on treatments to metformin (MET) in patients with type 2 diabetes mellitus (T2DM). Objective To compare time to treatment failure between different classes of oral GLT when used as second line (add-on) treatments to MET monotherapy at HbA1c ≥ 7.5%. Design, setting and participants A retrospective cohort study on 20,070 patients who were newly treated with a sulphonylurea (SU), dipeptidyl-peptidase-4 (DPP-4) inhibitor or thiazolidinedione (TZD) following MET therapy failure (2007–2014). Patients’ data was sourced from UK General Practices via The Health Improvement Network (THIN) database. The risk of dual therapy failure was compared between three treatment groups: MET + SU (reference group, n = 15,508), MET + DPP-4 inhibitor (n = 3,080) and MET + TZD (n = 1,482). Follow-up was until treatment substitution or intensification with a 3rd GLT, or for up to 5 years (totalling 46,430 person-years). Propensity score weighting and Cox proportional hazard regression analyses were employed. Main outcomes and measures Risk of dual therapy failure was compared between treatment groups while adjusting for baseline covariates. Results Unadjusted survival analysis showed the incidence of dual therapy failure at 1 year was 15% with SU, 23% with DPP-4 inhibitor and 8% with TZD. Corresponding failure rates at 2 years were 26, 38 and 12%, respectively. Adjusted multivariate models showed that, compared to the SU group, adding a DPP-4 inhibitor was associated with an increased risk of treatment failure (adjusted hazard ratio, aHR, 1.58; 95% CI: 1.48–1.68), while adding a TZD was associated with a reduced hazard (aHR, 0.45; 95% CI: 0.41–0.50). Baseline parameters associated with an increased hazard of intensification included HbA1c, diabetes duration, gender, smoking status and the use of statins. Conclusions and relevance In routine clinical practice, adding a DPP-4 inhibitor to MET is associated with an increased, earlier requirement for treatment intensification compared to adding an SU or TZD. Adding a TZD to MET resulted in the most durable glycaemic response. Key messages The Agency for Healthcare Research and Quality has suggested that the durability of glycaemic response after treatment intensification is best investigated using well-designed long-term observational studies. In routine clinical practice, among patients with T2DM receiving a second line glucose lowering treatment as add-on to MET, the addition of a Thiazolidinediones is associated with the most durable glycaemic response, followed by a Sulfonylurea and then a DPP-4 inhibitor. Factors associated with earlier dual therapy failure included concomitant use of statin therapy, being female, a smoker, those with longer diabetes duration and higher baseline HbA1c levels. The addition of a Thiazolidinediones was associated with significant weight gain (1.8 kg, p < 0.001), while add-on DPP-4 inhibitor produced a significant weight reduction (−1.8 kg, p < 0.001). A very small reduction in body weight was observed with the SU (−0.2 kg, p < 0.001).

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.

Obesity independently predicts responders to biphasic insulin 50/50 (Humalog Mix50 and Insuman Comb 50) following conversion from other insulin regimens: a retrospective cohort study.

Aims This study aims to examine the metabolic effects of intensification or initiation of insulin treatment with biphasic insulin 50/50, and determine the predictors of responders or non-responders to biphasic insulin 50/50. Methods A cohort of 2183 patients ≥18 years with diabetes, newly treated with biphasic insulin 50/50 between January 2000 and May 2012, were sourced from UK General Practices via The Health Improvement Network (THIN) database. Baseline clinical parameters of 1267 patients with suboptimal glycated hemoglobin (HbA1c) >7.5% (>58 mmol/mol) who had received background insulin regimens for at least 6 months preceding biphasic insulin 50/50 were compared against 12-month outcome data. Responders were defined as those with HbA1c <7.5% (58 mmol/mol) and/or HbA1c reduction of ≥1% (10.9 mmol/mol) at 12 months. Comparative analyses were carried out on subgroups of 237 patients initiating insulin therapy with biphasic insulin 50/50, and between users of the Humalog Mix50 (HM50) versus Insuman Comb 50 (IC50). Associations were examined using t tests and multivariate logistic regression techniques. Results The overall mean HbA1c reduction at 12 months as a result of intensification and initiation with biphasic insulin 50/50 was 0.5% (5.5 mmol/mol) and 1.6% (17.5 mmol/mol), respectively. Adjusted ORs show obesity (body mass index >30 kg/m2), treatment duration for ≥9 months, and baseline HbA1c are independent determinants of responders. In addition, stratified for baseline HbA1c levels, HM50 was associated with better HbA1c outcome compared with IC50. Conclusions biphasic insulin 50/50 is effective for achieving glycemic control in suboptimal HbA1c levels, especially among obese patients with insulin-treated diabetes. Stratified for baseline HbA1c, HM50 was associated with improved HbA1c outcome compared with IC50.

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.

Determinants of Glycemic Response to Add-On Therapy with a Dipeptidyl Peptidase-4 Inhibitor: A Retrospective Cohort Study Using a United Kingdom Primary Care Database.

BACKGROUND Apart from baseline glycated hemoglobin (HbA1c), little is known about clinical parameters that affect glycemic response to a dipeptidyl peptidase-4 (DPP4) inhibitor when used in routine clinical practice. We aimed to use a large primary care database to assess the variability in response to a DPP4 inhibitor when used as add-on therapy. MATERIALS AND METHODS Data on 25,386 patients with type 2 diabetes, newly treated with a DPP4 inhibitor (2007-2013), were sourced from a United Kingdom general practice database via the Health Improvement Network database. Baseline clinical parameters of patients (n = 13,525) for whom a DPP4 inhibitor was added because of suboptimal glucose control (HbA1c >7%) were compared with 12-month follow-up data. An optimum response to the DPP4 inhibitor was defined as an HbA1c level of <7.0% at 12 months. Descriptive analyses and unadjusted comparisons using χ(2) and t tests were carried out to ascertain glycemic and body weight responses to treatment intensification with a DPP4 inhibitor. Predictor of response analyses were performed using multivariate logistic regression. RESULTS Overall, 1,708 (13%) of our study population achieved an HbA1c level of <7%. Intensification with a DPP4 inhibitor was associated with significant reductions in HbA1c (-0.5%), body weight (-0.9 kg), and total cholesterol (-0.1 mmol/L) (P < 0.001). Independent predictors of achieving optimal HbA1c target of <7% included the use of metformin (adjusted odds ratio [OR] = 2.58; 95% confidence interval [CI], 2.18-3.04) and use of metformin plus sulfonylurea (1.42; 95% CI, 1.21-1.68) as opposed to no use. The independent predictors of suboptimal glucose control included a higher baseline HbA1c level (OR = 0.64; 95% CI, 0.61-0.68) (i.e., 1% increase in HbA1c was associated with a 36% reduced likelihood of response), longer diabetes duration (per every year increase) (OR = 0.85; 95% CI, 0.83-0.88), and intensification therapy below 9 months compared with 9-12 months. CONCLUSIONS There is a significant variability in glycemic response to a DPP4 inhibitor in routine practice. The best effect is achieved as add-on to metformin and metformin plus sulfonylurea, but responses are significantly lower with increased diabetes duration and among patients with high HbA1c levels at baseline.

Clinical use and efficacy of biphasic insulin lispro 50/50 in people with insulin treated diabetes – a nationwide evaluation of clinical practice

Abstract Objectives: This study aims to investigate the metabolic effects of biphasic insulin lispro 50/50 in routine clinical practice. A total of 229 patients who were ≥18 years old with diabetes, newly treated with biphasic insulin lispro 50/50, were sourced from six secondary care services in England. Methods: Detailed clinical parameters were compared at baseline, and 3 and 6 months post-initiation. Responders was defined as those with HbA1c <7.5% (58 mmol/mol) and/or an HbA1c reduction of >1% (11 mmol/mol) at 6 months. Results: HbA1c showed significant reduction: −0.93% (−10 mmol/mol) and −1.2% (−13 mmol/mol) at 3 and 6 months respectively, while no significant change was noted for all the other parameters. When analyzed according to frequencies of injections/day, the greatest reduction was observed with the three times a day regimen (−1.0% [−11.0 mmol/mol] and −1.3% [−14.6 mmol/mol] at 3 and 6 months respectively). HbA1c reduction was greatest in the group who previously received a basal–bolus insulin regimen: (−0.8% [−9.0 mmol/mol] and −1.5% [−16.2 mmol/mol] at 3 and 6 months respectively). Reduction in weight was observed at 3 months (−1.8 kg ± 4.3) only for those who were previously on a basal–bolus insulin regimen. Insulin doses increased following conversion to biphasic insulin lispro 50/50, irrespective of the types of insulin used prior to biphasic insulin lispro 50/50, but this was not associated with weight gain. The independent predictors of response to biphasic insulin lispro 50/50 were baseline HbA1c, Caucasian, presence of nephropathy, prior use of basal–bolus insulin and prior use of other premixed combination. Conclusion: Biphasic insulin lispro 50/50 is therefore an effective therapeutic option for achieving glycemic control in patients with suboptimal HbA1c levels, especially among those who were previously on a basal–bolus insulin regimen and those who received it three times daily, with a neutral effect on weight parameters. Limitations: This was a retrospective study of routine clinical practice and is therefore limited by allocation bias and some missing data. Information on rates of hypoglycemia and quality of life are not available.