The real-world observational prospective study of health outcomes with dulaglutide and liraglutide in patients with type 2 diabetes (TROPHIES): Final, 24-month analysis of time to first significant treatment change, treatment persistence and clinical outcomes.

AIMS: To present the final results of the TROPHIES study (The real-world observational prospective study of health outcomes with dulaglutide and liraglutide in patients with type 2 diabetes). MATERIALS AND METHODS: The prospective, real-world TROPHIES study included patients with type 2 diabetes initiating their first injectable glucose-lowering medication (GLM), dulaglutide or liraglutide, in France, Germany and Italy. The primary endpoint was the time spent on dulaglutide or liraglutide until a significant treatment change over 24 months. Other endpoints measured persistence with treatment, clinical outcomes (glycated haemoglobin [HbA1c] and weight) and treatment patterns. Kaplan-Meier estimates of time to first significant treatment change and persistence with treatment were generated. Propensity-score-based inverse probability of treatment weighting (IPTW) was used to adjust for baseline imbalances in the comparison between cohorts. RESULTS: The 286 of 1014 patients (28.2%) in the dulaglutide cohort and 448 of 991 patients (45.2%) in the liraglutide cohort had a significant treatment change over 24 months. By IPTW analysis, dulaglutide-initiating patients were less likely to have a significant treatment change (hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.46-0.63) and more likely to be persistent with treatment (HR 0.69, 95% CI 0.56-0.86) over 24 months than liraglutide-initiating patients. Dulaglutide and liraglutide yielded similar HbA1c (-11.80 mmol/mol [1.08%] and -11.91 mmol/mol [1.09%]) and weight (-3.5 kg and -3.3 kg) reductions from baseline to 24 months. Few changes in patterns of treatment with other GLMs were observed in the two cohorts. CONCLUSIONS: Dulaglutide-initiating patients had a longer time spent without any significant treatment change and higher persistence than those initiating liraglutide. Treatment with either glucagon-like peptide-1 receptor agonist yielded similar and clinically meaningful reductions in HbA1c and body weight.

Changing the approach to type 2 diabetes treatment: A comparison of glucagon-like peptide-1 receptor agonists and sulphonylureas across the continuum of care.

Despite the importance of individualised strategies for patients with type 2 diabetes mellitus (T2DM) and the availability of alternative treatments, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sulphonylureas are still widely used in practice. Clinical evidence shows that GLP-1 RAs may provide better and more durable glycaemic control than sulphonylureas, with lower risk of hypoglycaemia. Other reported benefits of GLP-1 RAs include weight loss rather than weight gain (as observed with sulphonylureas), blood pressure reduction and improvement in lipid profiles. In general, the main adverse events with GLP-1 RAs are gastrointestinal in nature. The respective modes of action of GLP-1 RAs and sulphonylureas contribute to differences in the durability of glycaemic control (related to effects on beta-cells) and effects on body weight. Moreover, the glucose-dependent mode of action of GLP-1 RAs, which favours a low incidence of hypoglycaemia, contrasts with the glucose-independent mode of action of sulphonylureas. Evidence from cardiovascular outcomes trials indicates a consistent finding of cardiovascular safety across the GLP-1 RAs and suggests a class benefit for the long-acting GLP-1 RAs in reducing three-point major adverse cardiovascular events, cardiovascular mortality and all-cause mortality. In contrast, potential concerns relating to an increased incidence of adverse cardiovascular events with sulphonylureas have yet to be fully resolved. Recent updates to management guidelines recommend that treatment selection for patients with T2DM should consider clinical trial evidence of cardiovascular safety. Available evidence suggests that this selection should give preference to GLP-1 RAs over sulphonylureas, especially for patients at high cardiovascular risk.

Incidence of severe hypoglycemia and possible associated factors in pediatric patients with type 1 diabetes in the real-life, post-Diabetes Control and Complications Trial setting: A systematic review.

BACKGROUND/OBJECTIVE: In 1993, the Diabetes Control and Complications Trial (DCCT) found that intensive antihyperglycemic therapy was effective in the primary and secondary prevention of microvascular complications in patients with type 1 diabetes (T1D) but was associated with a 3-fold greater rate of severe hypoglycemia (SH) than conventional therapy. The aim of this analysis was to determine whether, in the real-world setting, the incidence of SH in pediatric patients with T1D has changed since 1993. METHODS: A systematic literature search of PubMed for prospective or retrospective observational studies (≥250 participants) on SH epidemiology or related topics in pediatric patients with T1D, published between October 1993 and June 2016, identified 35 articles (involving >55 000 participants). SH incidence data were analyzed in approximate 5-year blocks: 1993-2000, 2001-2005, 2006-2010, and 2011-2016. Information on factors that might influence the incidence of SH was also collected. RESULTS: A trend for a marked reduction in the incidence of SH in the post-DCCT setting (from 62.0 per 100 patient-years to 1.21-30 per 100 patient-years) was apparent. Factors that could have influenced this temporal trend in SH incidence included the increased use of new types of, and methods of administering, insulin, in particular rapid-acting insulin analogs and continuous subcutaneous insulin infusion. CONCLUSIONS: SH in pediatric patients with T1D has declined in incidence since the DCCT but remains a common problem. The optimal use of new insulin therapies/regimens/technologies, improved education, and dedicated specialized management teams are needed to help reduce the risk of SH in this population.

Rapid-Acting Insulin Analogues Versus Regular Human Insulin: A Meta-Analysis of Effects on Glycemic Control in Patients with Diabetes.

INTRODUCTION: The aim of this meta-analysis was to investigate the impact of rapid-acting insulin analogues (RAIAs) and regular human insulin (RHI) on glycemic control, including long- and short-term glycemic variability as measured by glycated haemoglobin (HbA1c) and pre- and postprandial glucose (PPG). METHODS: PubMed was searched for studies published between 1999 and 29 June 2016. Randomised controlled trials of patients with diabetes that assessed the effects of RAIAs or RHI on glycemic control, focusing on preprandial glucose, PPG and HbA1c, were included. Only studies that reported both means and standard deviations for those outcomes were analysed; from these data, weighted mean differences and 95% confidence intervals were generated to yield overall point estimates. The primary outcomes of the meta-analysis were the mean differences between RAIAs and RHI at the end of the study in PPG, preprandial glucose, and HbA1c. RESULTS: Twenty-seven studies (n = 7452) were included. The difference in PPG between RAIA- and RHI-treated patients was significant-in favour of RAIAs-in patients with type 1 diabetes (T1D) [- 22.2 mg/dL; 95% confidence interval (CI) - 27.4, - 17.0 mg/dL; P < 0.0001] but not in those with type 2 diabetes (T2D). For preprandial glucose, there was a non-significant trend favouring RHIs in T1D; no data were available for patients with T2D. In patients with T1D, the between-group difference in end-of-treatment (EOT) HbA1c favoured RAIAs (- 0.13%; 95% CI - 0.18, - 0.08%; P < 0.0001), but was not significant in patients with T2D. The main study limitations were the small number and heterogeneity of the included studies. CONCLUSIONS: These results demonstrate that RAIAs are more effective at reducing PPG and improving HbA1c than RHIs in T1D. More data are required to assess the effect of these agents on glucose control in T2D. In patients with diabetes, the risk of complications is increased by poor control of blood glucose levels and high blood glucose variability. Complications may include cardiovascular disease, eye problems and amputation. Control and variability of blood glucose levels can be evaluated using a range of measures, including (i) glycated haemoglobin (HbA1c) level at the end of the treatment period; (ii) change in HbA1c level during the treatment period; (iii) fasting plasma glucose level; (iv) postprandial glucose (PPG) level; (v) change in blood glucose level after a meal. PPG levels following a meal are an important measure of overall metabolic control in diabetes, and reduction of glycemic variability (GV) can be achieved via reductions in PPG. Both rapid-acting insulin analogues (RAIAs; aspart, glulisine and lispro) and regular human insulin (RHI) are widely used in the management of diabetes. Using data from 27 randomised controlled trials involving more than 7000 patients, we investigated the impact of RAIAs and RHI on measures of glycemic control and variability in patients with type 1 diabetes (T1D) or type 2 diabetes (T2D). Our results show that, in patients with T1D, RAIAs are more effective than RHI at reducing PPG excursions and HbA1c. This indicates that glycemic control is better with RAIAs than with RHI. More data are required to assess the effects of RAIAs and RHI on glycemic control and variability in patients with T2D. Plain Language Summary: In patients with diabetes, the risk of complications is increased by poor control of blood glucose levels and high blood glucose variability. Complications may include cardiovascular disease, eye problems and amputation. Control and variability of blood glucose levels can be evaluated using a range of measures, including (i) glycated haemoglobin (HbA1c) level at the end of the treatment period; (ii) change in HbA1c level during the treatment period; (iii) fasting plasma glucose level; (iv) postprandial glucose (PPG) level; (v) change in blood glucose level after a meal. PPG levels following a meal are an important measure of overall metabolic control in diabetes, and reduction of glycemic variability (GV) can be achieved via reductions in PPG. Both rapid-acting insulin analogues (RAIAs; aspart, glulisine and lispro) and regular human insulin (RHI) are widely used in the management of diabetes. Using data from 27 randomised controlled trials involving more than 7000 patients, we investigated the impact of RAIAs and RHI on measures of glycemic control and variability in patients with type 1 diabetes (T1D) or type 2 diabetes (T2D). Our results show that, in patients with T1D, RAIAs are more effective than RHI at reducing PPG excursions and HbA1c. This indicates that glycemic control is better with RAIAs than with RHI. More data are required to assess the effects of RAIAs and RHI on glycemic control and variability in patients with T2D.

The Real-World Observational Prospective Study of Health Outcomes with Dulaglutide and Liraglutide in Type 2 Diabetes Patients (TROPHIES): Baseline Patient-Reported Outcomes.

INTRODUCTION: Although patient-reported outcome (PRO) measures provide important information beyond clinical data, studies that assess the PROs of type 2 diabetes mellitus (T2DM) patients initiating injectable glucose-lowering medications in routine clinical practice are limited. We describe the perspectives of patients based on a diversified panel of generic and disease-specific PRO measures at the time of enrollment (baseline) in the TROPHIES study. METHODS: TROPHIES is a 24-month prospective observational study performed in France, Germany, and Italy in patients with T2DM who initiated their first injectable glucose-lowering medication with once-weekly dulaglutide or once-daily liraglutide. To better understand the perspectives of these patients regarding their overall health, treatment satisfaction, and quality of life and work, the patients' responses to the following questionnaires were collected at baseline before they initiated treatment with dulaglutide or liraglutide: EQ-5D-5L (scale: 0-1), EQ-VAS (visual analog scale: 0-100), Impact of Weight on Self-Perceptions Questionnaire (IW-SP; scale: 0-100), Diabetes Treatment Satisfaction Questionnaire Status (DTSQs; scale: 0-36), and Diabetes Productivity Measure (DPM; scale: 0-100). Analyses were descriptive in nature, with higher scores reflecting better outcomes. RESULTS: Data from patients at the time of enrollment were analyzed. At baseline, patients initiating dulaglutide (N = 1130) or liraglutide (N = 1051) rated their quality of life in terms of mean EQ-5D-5L index as 0.84 and 0.83, and in terms of mean EQ-VAS as 67.5 and 67.5, respectively. The mean baseline scores in patients initiating dulaglutide or liraglutide were 59.8 and 61.3 for IW-SP, 24.6 and 25.8 for DTSQs, 78.6 and 79.5 for DPM Life Productivity, and 87.5 and 86.8 for DPM Work Productivity, respectively. CONCLUSION: The information from this varied panel of PRO instruments collected at baseline complements clinical outcomes data.

Patient preferences in Italy: health state utilities associated with attributes of weekly injection devices for treatment of type 2 diabetes.

OBJECTIVES: Several glucagon-like peptide-1 receptor agonists are administered as weekly injections for treatment of type 2 diabetes (T2D). These medications vary in their injection processes, and a recent study in the UK found that these differences had an impact on patient preference and health state utilities. The purpose of this study was to replicate the UK study in Italy to examine preferences of an Italian patient sample, while allowing for comparison between utilities in the UK and Italy. MATERIALS AND METHODS: Participants with T2D in Italy valued health states in time trade-off interviews. All health states had the same description of T2D, but differed in description of the treatment process. As in the original UK study, the first health state described an oral treatment regimen, while additional health states added a weekly injection. The injection health states differed in three injection-related attributes: requirements for reconstituting the medication, waiting during medication preparation, and needle handling. RESULTS: Interviews were completed by 238 patients (58.8% male; mean age = 60.2 years; 118 from Milan, 120 from Rome). The oral treatment health state had a mean (SD) utility of 0.90 (0.10). The injection health states had significantly (p < 0.0001) lower utilities, which ranged from 0.87 (requirements for reconstitution, waiting, and handling) to 0.89 (weekly injection with none of these requirements). Differences in health state utility scores suggest that each administration requirement was associated with a disutility (ie, negative utility difference): -0.006 (reconstitution), -0.006 (needle handling), -0.011 (reconstitution, needle handling), and -0.022 (reconstitution, waiting, needle handling). CONCLUSION: Disutilities associated with the injection device characteristics were similar to those reported with the UK sample. Results suggest that injection device attributes may be important to some patients with T2D, and it may be useful for clinicians to consider these attributes when choosing medication for patients initiating these weekly treatments.

Clinical validation of a new control-oriented model of insulin and glucose dynamics in subjects with type 1 diabetes.

BACKGROUND: The development of an artificial pancreas requires an accurate representation of diabetes pathophysiology to create effective and safe control systems for automatic insulin infusion regulation. The aim of the present study is the assessment of a previously developed mathematical model of insulin and glucose metabolism in type 1 diabetes and the evaluation of its effectiveness for the development and testing of control algorithms. METHODS: Based on the already existing "minimal model" a new mathematical model was developed composed of glucose and insulin submodels. The glucose model includes the representation of peripheral uptake, hepatic uptake and release, and renal clearance. The insulin model describes the kinetics of exogenous insulin injected either subcutaneously or intravenously. The estimation of insulin sensitivity allows the model to personalize parameters to each subject. Data sets from two different clinical trials were used here for model validation through simulation studies. The first set had subcutaneous insulin injection, while the second set had intravenous insulin injection. The root mean square error between simulated and real blood glucose profiles (G(rms)) and the Clarke error grid analysis were used to evaluate the system efficacy. RESULTS: Results from our study demonstrated the model's capability in identifying individual characteristics even under different experimental conditions. This was reflected by an effective simulation as indicated by G(rms), and clinical acceptability by the Clarke error grid analysis, in both clinical data series. CONCLUSIONS: Simulation results confirmed the capacity of the model to faithfully represent the glucose-insulin relationship in type 1 diabetes in different circumstances.

Nonlinear model predictive control of glucose concentration in subjects with type 1 diabetes.

A nonlinear model predictive controller has been developed to maintain normoglycemia in subjects with type 1 diabetes during fasting conditions such as during overnight fast. The controller employs a compartment model, which represents the glucoregulatory system and includes submodels representing absorption of subcutaneously administered short-acting insulin Lispro and gut absorption. The controller uses Bayesian parameter estimation to determine time-varying model parameters. Moving target trajectory facilitates slow, controlled normalization of elevated glucose levels and faster normalization of low glucose values. The predictive capabilities of the model have been evaluated using data from 15 clinical experiments in subjects with type 1 diabetes. The experiments employed intravenous glucose sampling (every 15 min) and subcutaneous infusion of insulin Lispro by insulin pump (modified also every 15 min). The model gave glucose predictions with a mean square error proportionally related to the prediction horizon with the value of 0.2 mmol L(-1) per 15 min. The assessment of clinical utility of model-based glucose predictions using Clarke error grid analysis gave 95% of values in zone A and the remaining 5% of values in zone B for glucose predictions up to 60 min (n = 1674). In conclusion, adaptive nonlinear model predictive control is promising for the control of glucose concentration during fasting conditions in subjects with type 1 diabetes.

Treatment of type 2 diabetes with combined therapy: what are the pros and cons?

Type 2 diabetes is a progressive syndrome that evolves toward complete insulin deficiency during the patient's life. A stepwise approach for its treatment should be tailored according to the natural course of the disease, including adding insulin when hypoglycemic oral agent failure occurs. Treatment with insulin alone should eventually be considered in a relevant number of cases. Experience has shown the protective effects of insulin on beta-cell survival and function, resulting in more stable metabolic control. On the contrary, treatment with most insulin secretagogues has been associated with increased beta-cell apoptosis, reduced responsiveness to high glucose, and impairment of myocardial function during ischemic conditions. In addition, macrovascular complications are associated with postprandial hyperglycemia, indicating the need for tight glycemic control. Insulin treatment, especially with rapid-acting analogs, has been demonstrated to successfully control postprandial glucose excursions. Finally, a reason for concern with regard to combined therapy is represented by the evidence that polipharmacy reduces compliance to the treatment regimen. This can be particularly relevant in patients with type 2 diabetes usually taking drugs for complications and for concomitant diseases with consequent deterioration not only of metabolic control but also of other conditions. In conclusion, therapy with insulin alone immediately after hypoglycemic oral agent failure may be a useful and safe therapeutic approach in type 2 diabetes.

The artificial pancreas.

In type 1 diabetes an absolute deficiency of insulin secretion requires exogenous insulin supply to guarantee the patient's life avoiding ketoacidotic coma and to prevent the chronic complications of diabetes. In order to obtain a more physiological replacement therapy different approaches have been pursued since the early 70s to create an artificial wearable pancreas able to deliver insulin according to the blood glucose values as determined by continuous monitoring. Four components are considered essential for the realisation of an artificial pancreas: the sampling system, the glucose sensor, the mathematical models and the related algorithms for the calculation of the insulin doses and the infusion system for the insulin delivery. At present the still unsolved issues are mainly represented by the availability of reliable continuous glucose monitor and control algorithms, while the new technologies allow for the miniaturisation of the system.