The real-world observational prospective study of health outcomes with dulaglutide and liraglutide in type 2 diabetes patients (TROPHIES): resource use and costs of treatment in clinical practice in France, Germany, and Italy.

AIMS: To describe healthcare resource utilization (HCRU) and associated costs after initiation of injectable glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy by adult patients with type 2 diabetes (T2D) in the prospective, observational, 24-month TROPHIES study in France, Germany, and Italy. MATERIALS AND METHODS: HCRU data for cost calculations were collected by treating physicians during patient interviews at baseline and follow-up visits approximately 6, 12, 18, and 24 months after GLP-1 RA initiation with once-weekly dulaglutide or once-daily liraglutide. Costs were evaluated from the national healthcare system (third-party payer) perspective and updated to 2018 prices. RESULTS: In total, 2,005 patients were eligible for the HCRU analysis (1,014 dulaglutide; 991 liraglutide). Baseline patient characteristics were generally similar between treatment groups and countries. The largest proportions of patients using ≥2 oral glucose-lowering medications (GLMs) at baseline (42.9-43.4%) and month 24 (44.0-45.1%) and using another injectable GLM at month 24 (15.3-23.2%) were in France. Mean numbers of primary and secondary healthcare contacts during each assessment period were highest in France (range = 4.0-10.7) and Germany (range = 2.9-5.7), respectively. The greatest proportions (≥60%) of mean annualized costs per patient comprised medication costs. Mean annualized HCRU costs per patient varied by treatment cohort and country: the highest levels were in the liraglutide cohort in France (€909) and the dulaglutide cohort in Germany (€883). LIMITATIONS: Limitations included exclusion of patients using insulin at GLP-1 RA initiation and collection of HCRU data by physician, not via patient-completed diaries. CONCLUSIONS: Real-world HCRU and costs associated with the treatment of adults with T2D with two GLP-1 RAs in TROPHIES emphasize the need to avoid generalization with respect to HCRU and costs associated with a particular therapy when estimating the impact of a new treatment in a country-specific setting.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become frequent treatments of hyperglycemia in type-2 diabetes (T2D). Not all types of clinical study provide information about the cost of these treatments or the effects they might have on use of other medicines and equipment to control T2D or the need for visits to a doctor or nurse and different types of treatment in hospital. This study collected this information during the regular care of adults in France, Germany, or Italy who were prescribed either dulaglutide or liraglutide (both types of GLP-1 RAs) by their family doctor or a specialist in T2D. There were differences in costs and the need for other medicines and medical services between people using either dulaglutide or liraglutide and for people who were using the same GLP-1 RA in each of the three countries. The information from this study could be used to more accurately understand the overall costs and medical care needed when patients use dulaglutide or liraglutide in France, Germany, or Italy.

Tirzepatide 5, 10 and 15 mg versus injectable semaglutide 0.5 mg for the treatment of type 2 diabetes: An adjusted indirect treatment comparison.

AIMS: To compare the efficacy and safety of tirzepatide 5, 10 and 15 mg with subcutaneous semaglutide 0.5 mg as second-line treatment for adults with type 2 diabetes mellitus, after metformin monotherapy, using adjusted indirect treatment comparisons (aITCs). METHODS: The aITCs were performed using the Bucher method to compare the relative efficacy and safety of tirzepatide 5, 10 and 15 mg versus semaglutide 0.5 mg via a common comparator (subcutaneous semaglutide 1.0 mg) based on trial results from SURPASS-2 (NCT03987919) and SUSTAIN7 (NCT02648204). RESULTS: All tirzepatide doses showed statistically significantly greater reductions in glycated haemoglobin, body weight and body mass index from baseline to week 40, with a comparable adverse event (AE) profile and no statistically significant differences in the odds of gastrointestinal AEs versus semaglutide 0.5 mg. Furthermore, all tirzepatide doses showed greater odds of patients achieving HbA1c targets of ≤ 6.5 % (≤48 mmol/mol) and < 7.0 % (<53 mmol/mol) and weight loss targets of ≥ 5 % and ≥ 10 %, versus semaglutide 0.5 mg. CONCLUSIONS: In these aITCs, glycated haemoglobin and weight reductions were significantly greater for all tirzepatide doses versus semaglutide 0.5 mg with a comparable AE profile. These findings provide comparative effectiveness insights in the absence of a head-to-head clinical trial.

Improved Glycaemic and Weight Management Are Associated with Better Quality of Life in People with Type 2 Diabetes Treated with Tirzepatide.

INTRODUCTION: Limited data are available on the relationship between quality of life (QoL) change and significant degrees of reduction in glycated haemoglobin (HbA1c) and/or weight loss in people with type 2 diabetes (T2D). We explored the associations between HbA1c targets and/or weight loss achieved and patient-reported outcomes (PROs) in adults with T2D treated with tirzepatide, a first-in-class once weekly glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, using pooled data from SURPASS-1 to -5 Phase 3 clinical trials. METHODS: PROs were assessed using five instruments at baseline and endpoint (Week 40 in SURPASS-1, -2 and -5; Week 52 in SURPASS-3 and -4): Impact of Weight on Quality of Life-Lite Clinical Trials Version; Impact of Weight on Self-Perception (IW-SP) questionnaire; Ability to Perform Physical Activities of Daily Living (APPADL); Diabetes Treatment Satisfaction Questionnaire change; and EQ-5D-5L. All PROs were assessed in participants receiving pooled doses of tirzepatide (5, 10 or 15 mg) and achieving HbA1c targets of < 5.7%, ≥ 5.7-≤ 6.5% and > 6.5% or achieving ≥ 0-< 5%, ≥ 5-< 10%, ≥ 10-< 15% and ≥ 15% weight loss from baseline at endpoint. The APPADL, IW-SP and EQ visual analogue scores were evaluated in participants achieving each combination of HbA1c target and weight loss. RESULTS: Achievement of lower HbA1c targets or higher body weight percentage losses were each associated with greater improvements in QoL than achievement of higher HbA1c targets or lower body weight percentage losses, respectively. Achievement of lower HbA1c targets in combination with greater weight loss was generally associated with the best QoL ratings. CONCLUSIONS: Our findings demonstrate that HbA1c targets and significant percentage body weight reduction thresholds need to be achieved for people with T2D to help substantially increase their overall health-related QoL. Tirzepatide treatment may allow a high proportion of people with T2D to achieve these targets, enabling improved QoL. CLINICAL TRIAL REGISTRATION: SURPASS-1: NCT03954834; SURPASS-2: NCT03987919; SURPASS-3: NCT03882970; SURPASS-4: NCT03730662; SURPASS-5: NCT04039503.

Limited data exist about the relationship between quality of life (QoL) and changes in clinical measures, for example management of blood sugar levels and weight, in people with type 2 diabetes. We explored the associations between glucose and weight loss targets achieved and QoL outcomes reported by adults treated with tirzepatide, the first glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for the treatment of people with type 2 diabetes, using data from SURPASS-1 to -5 Phase 3 clinical trials.Five questionnaires, developed to evaluate patients' health-related QoL, were completed by patients at the beginning and end of the clinical trials, which was after 40 weeks for SURPASS-1, -2 and -5 and after 52 weeks for SURPASS-3 and -4, or when the person left the trial if this was before the official end. These questionnaires were: EQ-5D-5L (SURPASS-1 to -5); Impact of Weight on Self-Perception questionnaire (SURPASS-1 to -5); Ability to Perform Physical Activities of Daily Living (SURPASS-1 to -5); Diabetes Treatment Satisfaction Questionnaire change (SURPASS-2 to -5); and Impact of Weight on Quality of Life­Lite Clinical Trials Version (SURPASS-2 only).Overall, achievement of lower glucose targets or higher percentage of body weight losses were each associated with greater improvements in QoL. Achievement of lower glucose targets in combination with greater weight loss was generally associated with the highest health-related QoL ratings.Tirzepatide treatment may allow a high proportion of people with type 2 diabetes to achieve lower glucose levels and higher weight loss, enabling improved health-related QoL.

The Real-World Observational Prospective Study of Health Outcomes with Dulaglutide and Liraglutide in Type 2 Diabetes Patients (TROPHIES): Final patient-reported outcomes at 24 months.

AIM: To report health-related patient-reported outcomes (PROs) in people with type 2 diabetes (T2D) initiating their first injectable glucose-lowering medication (GLM) with two commonly prescribed glucagon-like peptide-1 receptor agonists (GLP-1RAs) from the prospective, observational TROPHIES study (The Real-World Observational Prospective Study of Health Outcomes with Dulaglutide and Liraglutide in Type 2 Diabetes Patients). MATERIALS AND METHODS: TROPHIES was a two-cohort, 24-month study conducted in France, Germany and Italy. Adults with a T2D diagnosis, naïve to injectable treatment for T2D and prescribed dulaglutide or liraglutide as their first injectable GLM, were eligible for inclusion. Study objectives included describing the following PROs associated with the treatment of T2D with GLP-1RAs: health-related quality of life; impact of weight on self-perception; life and work productivity; and patient satisfaction with treatment and injection device. Additional analyses formally compared PRO measures between the treatment cohorts. RESULTS: Overall, improvements from baseline in PRO scores were observed among people who started dulaglutide or liraglutide. A more pronounced trend of improvement was observed in the dulaglutide cohort for changes from baseline in treatment satisfaction and impact of weight on self-perception, supported by statistically significant differences between treatment cohorts in additional comparative analyses at 12, 18 and 24 months. More positive patient perceptions of the injection device were observed with dulaglutide than with liraglutide. CONCLUSIONS: Improvements in PROs observed in TROPHIES, which were more evident with dulaglutide than liraglutide, reflect a relevant clinical benefit. From the patients' perspective, satisfaction, and confidence in continuing treatment with GLP-1RAs is likely to contribute to long-term treatment persistence.

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.

Patient-Reported Outcomes in People with Type 2 Diabetes Receiving Tirzepatide in the SURPASS Clinical Trial Programme.

INTRODUCTION: Tirzepatide, a novel glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptor agonist, is approved for glycaemic control for people with type 2 diabetes (T2D). The SURPASS-1 to -5 clinical trials assessed the efficacy of once weekly tirzepatide (5, 10 and 15 mg) versus placebo or active comparators (semaglutide 1 mg, insulin degludec and insulin glargine) in T2D. We evaluated patient-reported outcomes (PROs) that measured overall quality of life (QoL), treatment satisfaction and weight-related attributes across the five SURPASS studies. METHODS: PRO instruments utilised at baseline and primary timepoint (40 weeks for SURPASS-1, -2 and -5; 52 weeks for SURPASS-3 and -4) or early termination visit were EQ-5D-5L (SURPASS-1 to -5); Impact of Weight on Self-Perceptions (SURPASS-1 to -5); Ability to Perform Physical Activities of Daily Living (SURPASS-1 to -5); Diabetes Treatment Satisfaction Questionnaire (SURPASS-2 to -5); and Impact of Weight on Quality of Life-Lite Clinical Trials Version (SURPASS-2 only). RESULTS: Across all five studies at week 40/52, tirzepatide improved patients' QoL measured by general health and weight-related PROs over the comparator. Generally, higher doses of tirzepatide resulted in greater increases in PRO scores. CONCLUSION: Overall, tirzepatide produced significant health and weight-related QoL improvements versus comparators in the five SURPASS studies. CLINICAL TRIAL REGISTRATION: SURPASS-1: NCT03954834; SURPASS-2: NCT03987919; SURPASS-3: NCT03882970; SURPASS-4: NCT03730662; SURPASS-5: NCT04039503.

Tirzepatide is the first glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptor agonist approved for the treatment of people with type 2 diabetes. The SURPASS-1 to -5 clinical trials evaluated the efficacy and safety of tirzepatide (5, 10 and 15 mg) compared with placebo or active comparators (including semaglutide 1 mg and basal insulins) in people with type 2 diabetes. We evaluated other outcomes reported by patients that measured overall quality of life, treatment satisfaction and weight-related attributes across the five SURPASS studies.Five validated questionnaires were completed by patients at the beginning and end of the clinical trials, which was after 40 weeks for SURPASS-1, -2 and -5 and after 52 weeks for SURPASS-3 and -4, or when the person left the trial if this was before the official end. These questionnaires were EQ-5D-5L (SURPASS-1 to -5); Impact of Weight on Self-Perceptions (SURPASS-1 to -5); Ability to Perform Physical Activities of Daily Living (SURPASS-1 to -5); Diabetes Treatment Satisfaction Questionnaire (SURPASS-2 to -5); and Impact of Weight on Quality of Life-Lite Clinical Trials Version (SURPASS-2 only).Across all five studies, treatment with tirzepatide resulted in greater improvements in people's quality of life at the end of the study compared with placebo or treatment with the comparators. Generally, higher doses of tirzepatide resulted in greater increases in questionnaire scores than lower doses of tirzepatide.Overall, tirzepatide 5, 10 or 15 mg treatment resulted in significant health- and weight-related quality of life improvements versus comparators in the five SURPASS studies.

The Real-World Observational Prospective Study of Health Outcomes with Dulaglutide and Liraglutide in Patients with Type 2 Diabetes (TROPHIES): Patient disposition, clinical characteristics and treatment persistence at 12 months.

AIMS: The primary objective of the TROPHIES observational study is to estimate the duration of treatment on dulaglutide or liraglutide without a significant treatment change by 24 months in patients with type 2 diabetes (T2D) initiating their first injectable treatment with these glucagon-like peptide-1 receptor agonists (GLP-1 RAs). This manuscript presents 12-month interim data. MATERIALS AND METHODS: TROPHIES is a prospective, non-comparative, observational study of patients with T2D in Europe, naïve to injectable antihyperglycaemic treatments and initiating dulaglutide or liraglutide. Data on clinical characteristics, GLP-1 RA persistence and treatment patterns of glucose-lowering medication were collected at initiation of first injectable therapy and by 12 months. RESULTS: By 12 months, 1014 dulaglutide and 991 liraglutide patients were eligible across France, Germany and Italy. Both cohorts presented a high probability [95% confidence interval (CI)] of GLP-1 RA persistence [dulaglutide, 0.88 (0.86 to 0.90); liraglutide, 0.83 (0.80 to 0.85)] and reduction in mean glycated haemoglobin percentage (95% CI) from baseline [dulaglutide, -1.18 (-1.27 to -1.08); liraglutide, -1.15 (-1.26 to -1.05)] with 48.2% of dulaglutide and 41.2% of liraglutide patients reaching their individualized glycated haemoglobin percentage target set by the physician at baseline. Mean weight (95% CI) change from baseline was -3.2 kg (-3.6 to -2.8) for dulaglutide and -3.4 kg (-3.9 to -3.0) for liraglutide. Slight changes in concomitant medications were observed compared with baseline. CONCLUSIONS: In the real-world setting, dulaglutide and liraglutide cohorts achieved good persistence with similarly improved glycaemic control that was accompanied by weight loss at 12 months, consistent with previous clinical trial results.

Efficacy of tirzepatide 5, 10 and 15 mg versus semaglutide 2 mg in patients with type 2 diabetes: An adjusted indirect treatment comparison.

AIM: To conduct an adjusted indirect treatment comparison (aITC) of the efficacy of tirzepatide 5/10/15 mg versus semaglutide 2 mg in patients with type 2 diabetes. MATERIALS AND METHODS: The primary analysis was a Bucher aITC of the change from baseline at week 40 in HbA1c (%) and body weight (kg). Aggregate data from the SURPASS-2 study that met the HbA1c inclusion criterion of the SUSTAIN FORTE study and from SUSTAIN FORTE metformin-only treated patients were used for primary analysis. RESULTS: The SURPASS-2 refined population comprised 238/245/240 and 240 participants for tirzepatide 5/10/15 mg and semaglutide 1 mg, respectively. The SUSTAIN FORTE metformin-only population comprised 222 and 227 participants for semaglutide 1 and 2 mg, respectively. In this aITC, tirzepatide 10 and 15 mg significantly reduced HbA1c versus semaglutide 2 mg with an estimated treatment difference (ETD) of -0.36% (95% confidence interval [CI] -0.63, -0.09) and -0.4% (95% CI -0.67, -0.13), respectively. Tirzepatide 10 and 15 mg significantly reduced body weight versus semaglutide 2 mg with an ETD of -3.15 kg (95% CI -4.84, -1.46) and -5.15 kg (95% CI -6.85, -3.45), respectively. There were no significant differences between tirzepatide 5 mg and semaglutide 2 mg on change from baseline in HbA1c and body weight. CONCLUSIONS: In this aITC, HbA1c and weight reductions were significantly greater for tirzepatide 10 and 15 mg versus semaglutide 2 mg and were similar for tirzepatide 5 mg versus semaglutide 2 mg. These findings provide comparative effectiveness insights in the absence of a head-to-head clinical trial.

Dulaglutide is an effective treatment for lowering HbA1c in patients with type 2 diabetes regardless of body mass index.

AIM: To assess the relationship between baseline body mass index (BMI) and glycaemic control in dulaglutide-treated patients, a post hoc analysis was conducted on HbA1c and baseline BMI data from eight AWARD studies, with a total of 5770 patients. MATERIALS AND METHODS: Changes from baseline in HbA1c data from patients treated with 1.5 mg or 0.75 mg dulaglutide, active comparator or placebo, were analyzed in each study (AWARD-1 to -6, -8 and - 9) at approximately 6 months (26, 24 and 28 weeks, respectively). Within each study, data were analyzed by the following baseline BMI categories: <30, ≥30 to <35, and ≥ 35 kg/m2 . RESULTS: In this post hoc analysis, 1.5 mg or 0.75 mg dulaglutide treatment achieved statistically significant HbA1c reductions from baseline in all BMI categories (least-squares mean change from -0.62 to -1.75%) across the AWARD studies. No statistically significant treatment-by-BMI category interactions were found for reductions in HbA1c. CONCLUSION: This post hoc analysis of eight AWARD studies indicates that baseline BMI does not affect the relative treatment efficacy of dulaglutide as measured by HbA1c change from baseline in any study. Dulaglutide is an effective treatment option for adult patients with type 2 diabetes regardless of their baseline BMI category.

Patient-reported outcomes among patients using exenatide twice daily or insulin in clinical practice in six European countries: the CHOICE prospective observational study.

BACKGROUND: Improvements in the clinical condition of patients with type 2 diabetes are often accompanied by improvements in health-related quality of life and other patient-reported outcomes (PROs), but data assessing injectable treatment initiation from the patient's perspective in routine clinical practice are lacking. We examined PROs in patients initiating injectable treatment in the CHOICE (CHanges to treatment and Outcomes in patients with type 2 diabetes initiating InjeCtablE therapy) study. METHODS: CHOICE was a 24-month, prospective observational study conducted in six European countries. Patients initiated exenatide twice daily (BID) or insulin based on a physician's clinical judgement. Clinical and PRO data were collected at baseline (injectable therapy initiation) and after approximately 3, 6, 12, 18 and 24 months. The two treatment cohorts had different baseline characteristics; therefore, no statistical comparisons of endpoints between main cohorts were conducted. RESULTS: There were 2388 patients eligible for analysis (exenatide BID cohort, n = 1114; insulin cohort, n = 1274). Mean positive changes in Impact of Weight on Quality of Life-Lite (IWQOL-Lite) total score and EuroQoL5-Dimension (EQ-5D) index and visual analogue scale (VAS) scores were observed in both cohorts with most changes observed during the first 6 months after injectable therapy initiation. Patients who experienced weight loss (≥ 1 kg) at 24 months appeared to have higher mean improvements in IWQOL-Lite total score than did patients with weight gain or no weight change. Patients who met the composite clinical endpoint of glycated haemoglobin (HbA1c) <7.0%, no weight gain (≤ 1 kg) and no hypoglycaemia generally experienced higher mean improvements in EQ-5D index and VAS scores (compared with patients who did not meet this endpoint) and Diabetes Health Profile-18 scores (versus the main cohorts). High levels of missing data were observed for all PRO measures in both cohorts compared with those for clinical outcomes. CONCLUSIONS: These data from a clinical practice study support those from clinical trials, suggesting that PROs are not adversely affected, and may be improved, by injectable therapy initiation. PRO data may aid appropriate treatment selection for individual patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00635492.

Once-weekly exenatide versus once- or twice-daily insulin detemir: randomized, open-label, clinical trial of efficacy and safety in patients with type 2 diabetes treated with metformin alone or in combination with sulfonylureas.

OBJECTIVE: This multicenter, open-label, parallel-arm study compared the efficacy and safety of exenatide once weekly (EQW) with titrated insulin detemir in patients with type 2 diabetes inadequately controlled with metformin (with or without sulfonylureas). RESEARCH DESIGN AND METHODS: Patients were randomized to EQW (2 mg) or detemir (once or twice daily, titrated to achieve fasting plasma glucose ≤5.5 mmol/L) for 26 weeks. The primary outcome was proportion of patients achieving A1C ≤7.0% and weight loss ≥1.0 kg at end point, analyzed by means of logistic regression. Secondary outcomes included measures of glycemic control, cardiovascular risk factors, and safety and tolerability. RESULTS: Of 216 patients (intent-to-treat population), 111 received EQW and 105 received detemir. Overall, 44.1% (95% CI, 34.7-53.9) of EQW-treated patients compared with 11.4% (6.0-19.1) of detemir-treated patients achieved the primary outcome (P < 0.0001). Treatment with EQW resulted in significantly greater reductions than detemir in A1C (least-square mean ± SE, -1.30 ± 0.08% vs. -0.88 ± 0.08%; P < 0.0001) and weight (-2.7 ± 0.3 kg vs. +0.8 ± 0.4 kg; P < 0.0001). Gastrointestinal-related and injection site-related adverse events occurred more frequently with EQW than with detemir. There was no major hypoglycemia in either group. Five (6%) patients in the EQW group and six (7%) patients in the detemir group experienced minor hypoglycemia; only one event occurred without concomitant sulfonylureas (detemir group). CONCLUSIONS: Treatment with EQW resulted in a significantly greater proportion of patients achieving target A1C and weight loss than treatment with detemir, with a low risk of hypoglycemia. These results suggest that EQW is a viable alternative to insulin detemir treatment in patients with type 2 diabetes with inadequate glycemic control using oral antidiabetes drugs.

Exenatide twice daily versus glimepiride for prevention of glycaemic deterioration in patients with type 2 diabetes with metformin failure (EUREXA): an open-label, randomised controlled trial.

BACKGROUND: Glycaemic control deteriorates progressively over time in patients with type 2 diabetes. Options for treatment escalation remain controversial after failure of first-line treatment with metformin. We compared add-on exenatide with glimepiride for durability of glycaemic control in patients with type 2 diabetes inadequately controlled by metformin alone. METHODS: We did an open-label, randomised controlled trial at 128 centres in 14 countries between Sept 5, 2006, and March 29, 2011. Patients aged 18-85 years with type 2 diabetes inadequately treated by metformin were randomly assigned via a computer-generated randomisation sequence to receive exenatide twice daily or glimepiride once daily as add-on to metformin. Randomisation was stratified by predetermined categories of glycated haemoglobin (HbA(1C)) concentration. The primary outcome was time to inadequate glycaemic control and need for alternative treatment, defined as an HbA(1c) concentration of more than 9% after the first 3 months of treatment, or more than 7% at two consecutive visits after the first 6 months. Analysis was by intention to treat. This trial is registered with EudraCT, number 2005-005448-21, and ClinicalTrials.gov, number NCT00359762. FINDINGS: We randomly assigned 515 patients to the exenatide group and 514 to the glimepiride group, of whom 490 versus 487 were the intention-to-treat population. 203 (41%) patients had treatment failure in the exenatide group compared with 262 (54%) in the glimepiride group (risk difference 12·4 [95% CI 6·2-18·6], hazard ratio 0·748 [0·623-0·899]; p=0·002). 218 (44%) of 490 patients in the exenatide group, and 150 (31%) of 487 in the glimepiride group achieved an HbA(1c) concentration of less than 7% (p<0·0001), and 140 (29%) versus 87 (18%) achieved concentrations of 6·5% and less (p=0·0001). We noted a significantly greater decrease in bodyweight in patients given exenatide than in those given glimepiride (p<0·0001). Five patients in each treatment group died from causes unrelated to treatment. Significantly fewer patients in the exenatide group than in the glimepiride group reported documented symptomatic (p<0·0001), nocturnal (p=0·007), and non-nocturnal (p<0·0001) hypoglycaemia. Discontinuation because of adverse events (mainly gastrointestinal) was significantly higher (p=0·0005) in the exenatide group than in the glimepiride group in the first 6 months of treatment, but not thereafter. INTERPRETATION: These findings provide evidence for the benefits of exenatide versus glimepiride for control of glycaemic deterioration in patients with type-2 diabetes inadequately controlled by metformin alone. FUNDING: Eli Lilly and Company; Amylin Pharmaceuticals.

Genotypes and phenotypes of children with SHOX deficiency in France.

CONTEXT: The prevalence of SHOX deficiency in children with short stature (SS) is variable in the literature and various genotypes have been identified. OBJECTIVES: The aim of our study was to determine the frequency and distribution of SHOX genotypes in a large sample of children with SS in France. DESIGN, SETTING, AND PATIENTS: Children were enrolled in 38 French pediatric endocrinology centers and were either diagnosed with Leri-Weill syndrome (LWS), idiopathic short stature (ISS), or disproportionate short stature (DSS). INTERVENTION AND MAIN OUTCOME MEASURE: SHOX analysis was performed centrally as part of the Genetics and Neuroendocrinology of Short Stature International Study observational study. We compared patients with (SHOX-D) and without SHOX deficiency (non-SHOX-D). RESULTS: Among the 537 patients tested [58.3% females, mean age 11.0 (4.2) yr], 27.7% had SHOX deficiency (LWS, 48.9%; ISS, 16.9%; DSS, 18.8%). Mean height [-2.3 (0.9) sd score] was similar in SHOX-D and non-SHOX-D patients. The majority of SHOX-D patients with LWS had either a deletion encompassing SHOX or a point mutation (69%), whereas 59% of those with ISS had a deletion downstream of SHOX in the enhancer region. The height of the parents carrying a deletion downstream of SHOX was higher than the height of the parents carrying the other gene anomalies. CONCLUSIONS: SHOX deletions and point mutations as well as downstream SHOX enhancer deletions were identified in almost one third of the patients tested. An anomaly in this latter region seemed to be linked to a milder phenotype. Although further confirmation is needed, we suggest that the enhancer region should be systematically analyzed in patients suspected of SHOX deficiency.

Efficiency of bone density testing by dual-biphotonic X-rays absorptiometry for diagnosis of osteoporosis according to French guideline recommendations: the PRESAGE study.

OBJECTIVES AND METHODS: Bone mineral density is a major risk factor of fracture. Its measurement is reimbursed by French national health insurance according to clinical criteria. In this multicentre cross-sectional observational study, we estimated the proportion of postmenopausal women with osteoporosis among those referred for a bone mineral density measurement. Risk factors for osteoporosis and therapeutic recommendations were described. RESULTS: Six hundred and forty-six postmenopausal women were evaluated. Osteoporosis was diagnosed in 57.6%, osteopenia in 38.7% and a normal bone mineral density in 3.7%. The main risk factors for fracture were personal history of fracture (40%), family fracture (23%), smoking (15%) and glucocorticoids use (15%). Anti-osteoporosis drug was recommended for 93% of women with osteoporosis and for 45% of women with osteopenia. A logistic regression analysis showed that a T-score=-2.5 was the most important factor related to the treatment decision-making. Cluster analysis identified five types of women with different combinations of fracture risk factors. The percentage of postmenopausal women -96.3% - referred for bone mineral density and for whom a treatment could be recommended had osteoporosis or osteopenia. CONCLUSION: In spite of recommendations, the physician therapeutic decision-making was mainly based on the bone mineral density result.