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) >300mg/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 events among insulintreated 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 ≥ 300mg/g) from UK general practices between 2007 and 2014. Their corresponding ACR values after one year of follow up were thereafter categorised into: (1) less than 300mg/g (i.e. albuminuria regression) or (2) >300mg/g (i.e. non-regression of albuminuria), and the cohort was followed up for 5 years for all-cause mortality and cardiovascular 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. 682 deaths occurred after a follow-up period of 43,393 person-years with a mortality rate of 16 per 1000 person-years. 5-year survival was markedly reduced in the group whose proteinuria persisted or progressed (91 vs 95%; log-rank p-value less than 0.001). Compared to patients whose ACR levels remained above 300mg/g, all-cause mortality and cardiovascular events were 31% and 27% lower in those whose albuminuria regressed to less than 300mg/g (aHR: 0.69; 95%CI: 0.52 to 0.91; p=0.008 and aHR: 0. 73; 95%CI: 0.54 to 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 glycaemic control) is associated with a significant reduction in all-cause mortality. Thus, albuminuria is not simply a risk marker of renal and cardiovascular disease, but also an independent target for therapy. Albuminuria reduction should be viewed as a goal for renal and cardiovascular protection

Individual and combined relationship between reduced eGFR and/or increased urinary albumin excretion rate with mortality risk among insulin treated patients with Type 2 diabetes in routine practice

Background: Low estimated glomerular filtration rate (eGFR) and increased urinary albumin-to-creatinine ratio (ACR) are well-recognised prognostic markers of cardiovascular (CV) risk, but their individual and combine relationship with CV disease and total mortality among insulin-treated Type 2 Diabetes (T2D) patients in routine clinical care is unclear. Methods: We analysed data for insulin users with T2D from UK general practices between 2007 and 2014 and examined the association between mortality rates and CKD [categorised by low eGFR ((less 60mL/min/1.73 m2); high eGFR (≥60mL/min/1.73 m2); low ACR (less 300mg/g); and high ACR (≥300mg/g) at insulin initiation] after a 5-year follow-up period using Cox proportional hazard models.Results: A total of 18,227 patients were identified (mean age: 61.5±13.8 years, mean HbA1c: 8.6±1.8%). After adjusting for confounders, when compared to adults on insulin therapy with an eGFR less 60 and an ACR ≥300 (low eGFR + high ACR) after a follow up period of 5 years, patients with an eGFR less 60 and an ACR less 300 (low eGFR + low ACR) had a 6% lower mortality rate (aHR: 0.94; 95%CI: 0.79 to1.12); those with an eGFR >60 and an ACR ≥300 (high eGFR + high ACR) had a 20% lower mortality rate (aHR: 0.80; 95%CI: 0.68 to 0.96); and those with an eGFR >60 and an ACR less 300 (high eGFR + low ACR) had the lowest death rate (28% less; aHR: 0.72; 95%CI: 0.59 to 0.87 ).Conclusion: This study shows that among a large cohort of insulin-treated T2D patients in routine practice, the combination of reduced eGFR with increased ACR was associated with the greatest risk of premature death, followed closely by those with reduced eGFR and normal ACR levels. Adoption of aggressive CV risk management strategies to reduce mortality in patients with a low eGFR and albuminuria is essential in these high risk patients with T2D

Effect of Bariatric Surgery on Diagnosed Chronic Kidney Disease and Cardiovascular Events in Patients with Insulin-treated Type 2 Diabetes: a Retrospective Cohort Study from a Large UK Primary Care Database

Aims: To compare the effect of bariatric surgery on renal, chronic kidney disease (CKD), and cardiovascular (CV) outcomes among obese patients with insulin-treated type 2 diabetes (T2D) with and without microalbuminuria (i.e. uACR > 3.0 mg/mmol).Methods: A retrospective cohort study was conducted among 11,125 active patients with T2D from The Health Improvement Network (THIN) database. Propensity score matching (up to 1:6 ratio) was used to identify patients who underwent bariatric surgery (N=131) with a non-bariatric cohort (N=579). Follow-up was undertaken for 10 years (6,487 person-years) to compare differences in risk of cardiovascular events and in renal outcomes.Results: For the matched cohort at baseline: mean age 52±13 years (60% female); weight 116±25kg, Body Mass Index (BMI) 41±9kg/m2, estimated Glomerular Filtration Rate (eGFR); 70.4±20mL/min/1.73m2, and median Albumin-Creatinine Ratio (uACR) 2.0 mg/mmol (interquartile range (IQR): 0.9–5.2 mg/mmol). Bariatric surgery was associated with a 54% reduction in developing CKD compared to their matched non-bariatric cohort (adjusted Hazard Ratio [aHR]: 0.46; 95%CI: 0.24–0.85, P=0.02). Among patients with microalbuminuria at baseline, bariatric surgery was protective against CKD (aHR: 0.42, 95%CI: 0.18–0.99, P=0.050). eGFR was significantly increased from baseline favouring the bariatric group during 75% of the follow-up time (calculated mean difference between groups: 4.1mL/min/1.73m2;

Effect of Bariatric Surgery on Cardiovascular Events and Metabolic Outcomes in Obese Patients with Insulin-Treated Type 2 Diabetes: a Retrospective Cohort Study

© 2019, Springer Science+Business Media, LLC, part of Springer Nature. Aims: To compare non-fatal cardiovascular (CV) events and metabolic outcomes, among obese patients with insulin-treated type 2 diabetes who underwent bariatric surgery compared with a propensity-matched non-bariatric cohort. Methods: A retrospective cohort study was conducted among 11,125 active patients with type 2 diabetes from The Health Improvement Network (THIN) database. Propensity score matching (up to 1:6 ratio) was used to identify patients who underwent bariatric surgery (N = 131) with a non-bariatric cohort (N = 579). Follow-up was undertaken for 10years (9686 person-years) to compare differences in metabolic outcomes and CV risk events that included the following: acute myocardial infarction (AMI), stroke, coronary heart disease (CHD), heart failure (HF) and peripheral artery disease (PAD). Cox proportional regression was used to compute the outcomes between groups. Results: The mean age was 52 (SD 13) years (60% female); the baseline weight and BMI were 116 (SD 25) kg and 41 (SD 9) kg/m2, respectively. Significant reductions in weight and BMI were observed in bariatric group during 10years of follow-up. Bariatric surgery had a significant cardioprotective effect by reducing the risk of non-fatal CHD (adjusted hazard ratio [aHR] 0.29, 95% CI 0.16–0.52, p < 0.001) and PAD events (aHR 0.31, 95% CI 0.11–0.89, p = 0.03). However, the surgery had no significant effect on AMI (aHR 0.98, p = 0.95), stroke (HR 0.87, p = 0.76) and HF (HR 0.89, p = 0.73) risks. Bariatric surgery had favourable effects on insulin independence, HbA1c and BP. Conclusion: Among obese insulin-treated patients with type 2 diabetes, bariatric surgery is associated with significant reductions in non-fatal CHD and PAD events, lower body weight, HbA1c, BP and a greater likelihood of insulin independency during 10years of follow-up

Clinical characteristics and patient treatment satisfaction with Humalog U-200 in patients with type 2 diabetes mellitus: an observational study

Background There is limited data on the real world evidence of Humalog 200 units/ml KwikPen (U-200) insulin. We assessed the use of U-200 insulin in UK routine clinical practice to provide information on clinical characteristics, treatment satisfaction and short-term clinical outcomes. Methods Nine patients with type 2 diabetes who initiated U-200 in secondary care and a further 12 identified from primary care electronic database were enrolled. A treatment satisfaction questionnaire was administered to the nineteen secondary care patients. Follow-up data on clinical parameters was collected at 3 and 6 months following initial U-200 insulin administration and the data was used to assess changes in clinical outcomes from baseline. Results Secondary care patients has a mean age 60±11 years, mean HbA1c of 8.6%±1.3% and a mean BMI of 39.7±5.3 kg/m2 at baseline. Primary care database patients has a mean age 57±13 years, mean HbA1c 10.3%±1.7 and a mean BMI 42.3±3.8 kg/m2. The 9 participants’ responses to the questionnaire suggested a high preference for U-200 over a previous mealtime insulin pen (PMIP). On average, the patients agreed that U-200 was quicker to inject, had a better controlled home blood glucose reading and less discomfort at the injection site compared to a PMIP. Patients were willing to continue with their U-200 treatment. No significant HbA1c reduction observed at 3 months in the secondary care group (-0.5%), but marked significant reduction in HbA1c was seen at three months in the primary care dataset to (-2.8%; P [less than] 0.0004). There were also some suggestion of weight loss in both secondary and primary care groupsConclusion Humalog U-200 insulin users comprised mainly of older patients with diabetes complications and high HbA1c levels at the time of U-200 initiation. Overall, U-200 improved patients’ satisfaction of diabetes treatment and short-term metabolic outcomes

Effects of background statin therapy on glycemic response and cardiovascular events following initiation of insulin therapy in type 2 diabetes: a large UK cohort study.

AIM: Statins may increase the risk of new-onset diabetes and adversely affect glycaemic control, but their effects on the glycemic response and mortality outcomes following commencement of insulin therapy in patients with Type 2 Diabetes (T2D) are unclear. METHODS: A retrospective cohort study was conducted in 12,725 insulin initiators with T2D using The Health Improvement Network (THIN) UK database. Changes in HbA1c at 6, 12, 24 and 36 months, and the 5-year risk of mortality and (3-point) major adverse cardiovascular events (MACE), were compared between prior users (n = 10,682) and non-users (n = 2043) of statin therapy who were newly commenced on insulin treatment. Cox proportional hazard models were used to estimate the hazard ratios of the different outcomes. RESULTS: Mean age of the cohort was 58.7 ± 14.0 years (51% male) and mean baseline HbA1c was 8.7 ± 1.8%. A greater initial reduction in HbA1c was observed following insulin initiation in the non-users of statins compared with the users, which was significant in the short term (-0.34% vs -0.26% at 6 months; mean diff = -0.09%, p = 0.004) but not in the long term: -0.31% versus -0.35% at 3 years (mean diff = 0.05%, p = 0.344). CV events (3-point MACE) were 878 versus 217 in statin users versus non-users (20.7 vs 30.9 per 1000 person-years; adjusted Hazard Ratio (aHR) 1.36 (95% CI 1.15-1.62; p < 0.0001). In a subgroup analysis of individual statins, HbA1c was higher throughout the study duration with all statins relative to non-users of statin therapy (p < 0.05). The aHRs for 3-point MACE for atorvastatin, simvastatin, rosuvastatin and pravastatin were 0.82 (95% CI 0.68-0.98), 0.67 (0.55-0.82), 0.56 (0.39-0.81) and 0.78 (0.60-1.01), respectively. CONCLUSIONS: Following initiation of insulin therapy in patients with T2D in routine care, concurrent use of a statin was associated with less good glycaemic control in the short-term but a much lower risk of major adverse CV events

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

Cardiovascular and metabolic outcomes associated with insulin use in type 2 diabetes: evidence from insulin users in the UK primary care

In clinical use, insulin improves glycaemic control at the cost, typically, of weight gain and more hypoglycaemia – both being risk factors for cardiovascular (CV) disease mortality. The issue of the effect of exogenous insulin on CV disease meanwhile has been debated for a long time. Data on the CV outcomes associated with insulin-treated diabetes in both randomised trials and observational studies have largely been inconsistent. Thus, a balance of the positives and the negatives of insulin therapy needs to be taken into account when prescribing insulin in routine clinical practice, particularly in the context of the progressive nature of diabetes, its requirement for combination glucose-lowering therapy and the availability of novel glucose lowering agents. So, in a cohort of only insulin-users in ‘real-world’ condition, this thesis aims to explore the association between insulin use and CV and metabolic outcomes. Firstly, a systematic review and meta-analysis of clinical trials that compared only insulin vs other non-insulin glucose-lowering therapies (GLTs) within the past decade was performed and the risk of CV events and important metabolic outcomes were compared between both treatment groups. Then, data from RCTs were compared with ‘real-world’ data (using the UK Primary Care database – The Health improvement Network (THIN)) in terms of clinical outcomes between insulin regimens. Thirdly, using THIN database, retrospective cohort studies were conducted to explore the CV outcomes associated with insulin as regards to the use of newer GLTs, concurrent use of other medications, target HbA1c outcome levels and baseline metabolic profile of insulin-users. Logistic, linear, and Cox regression models; and propensity-score matching models were fitted to explore these associations. Finally, a comparative cross-sectional study was conducted to explore clinical outcomes between the insulin users in a representative UK population database (THIN) vs the local Derbyshire integrated Diabetes service database. A meta-analysis of RCTs first provided insight that allayed fears on the CV concerns on insulin use. It showed no difference in the risk of death and adverse CV events between insulin and non-insulin GLTs. Although insulin was associated with better glycaemic control, similar proportions of both insulin and non-insulin users attained their target HbA1c. The increase in the risks of hypoglycaemia and weight-gain seen in insulin users did not translate to adverse CV events. Furthermore, although RCTs provide superior evidence from which clinical guidelines are built, they do not mirror what happens in ‘real-world’. The discrepancies in glycaemic control (which is lower in real-world) and weight (higher in RCTs) were highlighted. Thus, caution is needed in the extrapolation of RCT-derived estimates of clinical outcomes when formulating guidelines for routine clinical practice. Given the observed discrepancies between weight and HbA1c outcomes between real world and RCT, I investigated the CV and metabolic effects of insulin therapy in the context of baseline weight and insulin-induced weight gain. I observed that in a background of obesity, the use of insulin did not lead to poorer glycaemic control beyond 24 months, instead, patients who were obese experienced a significant reduction in weight and BMI. In the morbidly obese, the risk of composite adverse CV outcomes was, however, increased by 30%. Also, insulin-induced weight-gain was associated with significant reductions in HbA1c and no adverse CV outcomes and mortality. When compared with newer GLTs like the glucagon-like peptide receptor agonists (GLP-1RA), insulin was associated with greater weight-gain and a higher risk of composite CV events and mortality; but in combination with GLP1-RA, it showed both a decrease in the risk of CV event and a reduction in weight. In the elderly insulin users with multiple comorbidities and longer duration of diabetes, extreme HbA1c targets were associated with increased mortality – representing a U-shaped relationship between mortality and HbA1c targets. Furthermore, background statin use among insulin users did not worsen glycaemic control in the long term, but was associated with reduction in composite adverse CV events and mortality independent of the statin type. Finally, the Derby model of integrated diabetes service appeared to confer better clinical outcomes compared with the UK population in terms of the achievement of the combined National Institute for Health and Care Excellence (NICE) targets of HbA1c (<7.5%), blood pressure (<140/80) and total cholesterol (<4mmol/L). This research highlights the important central role insulin plays in the management of T2D; and adds to the growing evidence on its safety and benefits among the high risk groups – the elderly, obese and those with longer duration of diabetes. It also highlights the benefits of the combination of insulin with newer novel GLTs; and concomitant use of other medications which modify CV risk factors. Above all, it recommends individualised treatment approach with full consideration of individual’s metabolic profile and other social factors. Further trials focusing on insulin therapy combinations with newer GLTs will be invaluable in providing more water-tight evidence in insulin use

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; p30 kg/m(2)) 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

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 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 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