A unified Bayesian framework for bias adjustment in multiple comparisons from clinical trials.

In clinical trials, multiple comparisons arising from various treatments/doses, subgroups, or endpoints are common. Typically, trial teams focus on the comparison showing the largest observed treatment effect, often involving a specific treatment pair and endpoint within a subgroup. These findings frequently lead to follow-up pivotal studies, many of which do not confirm the initial positive results. Selection bias occurs when the most promising treatment, subgroup, or endpoint is chosen for further development, potentially skewing subsequent investigations. Such bias can be defined as the deviation in the observed treatment effects from the underlying truth. In this article, we propose a general and unified Bayesian framework to address selection bias in clinical trials with multiple comparisons. Our approach does not require a priori specification of a parametric distribution for the prior, offering a more flexible and generalized solution. The proposed method facilitates a more accurate interpretation of clinical trial results by adjusting for such selection bias. Through simulation studies, we compared several methods and demonstrated their superior performance over the normal shrinkage estimator. We recommended the use of Bayesian Model Averaging estimator averaging over Gaussian Mixture Models as the prior distribution based on its performance and flexibility. We applied the method to a multicenter, randomized, double-blind, placebo-controlled study investigating the cardiovascular effects of dulaglutide.

Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity.

BACKGROUND: Obesity is a major risk factor for many leading causes of illness and death worldwide. Data are needed regarding the efficacy and safety of the nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist orforglipron as a once-daily oral therapy for weight reduction in adults with obesity. METHODS: In this phase 2, randomized, double-blind trial, we enrolled adults with obesity, or with overweight plus at least one weight-related coexisting condition, and without diabetes. Participants were randomly assigned to receive orforglipron at one of four doses (12, 24, 36, or 45 mg) or placebo once daily for 36 weeks. The percentage change from baseline in body weight was assessed at week 26 (primary end point) and at week 36 (secondary end point). RESULTS: A total of 272 participants underwent randomization. At baseline, the mean body weight was 108.7 kg, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 37.9. At week 26, the mean change from baseline in body weight ranged from -8.6% to -12.6% across the orforglipron dose cohorts and was -2.0% in the placebo group. At week 36, the mean change ranged from -9.4% to -14.7% with orforglipron and was -2.3% with placebo. A weight reduction of at least 10% by week 36 occurred in 46 to 75% of the participants who received orforglipron, as compared with 9% who received placebo. The use of orforglipron led to improvement in all prespecified weight-related and cardiometabolic measures. The most common adverse events reported with orforglipron were gastrointestinal events, which were mild to moderate, occurred primarily during dose escalation, and led to discontinuation of orforglipron in 10 to 17% of participants across dose cohorts. The safety profile of orforglipron was consistent with that of the GLP-1 receptor agonist class. CONCLUSIONS: Daily oral orforglipron, a nonpeptide GLP-1 receptor agonist, was associated with weight reduction. Adverse events reported with orforglipron were similar to those with injectable GLP-1 receptor agonists. (Funded by Eli Lilly; GZGI ClinicalTrials.gov number, NCT05051579.).

General versus central adiposity as risk factors for cardiovascular-related outcomes in a high-risk population with type 2 diabetes: a post hoc analysis of the REWIND trial.

BACKGROUND: In clinical practice, anthropometric measures other than BMI are rarely assessed yet may be more predictive of cardiovascular (CV) risk. We analyzed the placebo group of the REWIND CV Outcomes Trial to compare several anthropometric measures as baseline risk factors for cardiovascular disease (CVD)-related outcomes in participants with type 2 diabetes (T2D). METHODS: Data from the REWIND trial placebo group (N = 4952) were analyzed. All participants had T2D, age ≥ 50 years, had either a previous CV event or CV risk factors, and a BMI of ≥ 23 kg/m2. Cox proportional hazard models were used to investigate if BMI, waist-to-hip ratio (WHR), and waist circumference (WC) were significant risk factors for major adverse CV events (MACE)-3, CVD-related mortality, all-cause mortality, and heart failure (HF) requiring hospitalization. Models were adjusted for age, sex, and additional baseline factors selected by LASSO method. Results are presented for one standard deviation increase of the respective anthropometric factor. RESULTS: Participants in the placebo group experienced 663 MACE-3 events, 346 CVD-related deaths, 592 all-cause deaths, and 226 events of HF requiring hospitalization during the median follow-up of 5.4 years. WHR and WC, but not BMI, were identified as independent risk factors of MACE-3 (hazard ratio [HR] for WHR: 1.11 [95% CI 1.03 to 1.21]; p = 0.009; HR for WC: 1.12 [95% CI 1.02 to 1.22]; p = 0.012). WC adjusted for hip circumference (HC) showed the strongest association with MACE-3 compared to WHR, WC, or BMI unadjusted for each other (HR: 1.26 [95% CI 1.09 to 1.46]; p = 0.002). Results for CVD-related mortality and all-cause mortality were similar. WC and BMI were risk factors for HF requiring hospitalization, but not WHR or WC adjusted for HC (HR for WC: 1.34 [95% CI 1.16 to 1.54]; p < 0.001; HR for BMI: 1.33 [95% CI 1.17 to 1.50]; p < 0.001). No significant interaction with sex was observed. CONCLUSIONS: In this post hoc analysis of the REWIND placebo group, WHR, WC and/or WC adjusted for HC were risk factors for MACE-3, CVD-related mortality, and all-cause mortality; while BMI was only a risk factor for HF requiring hospitalization. These findings indicate the need for anthropometric measures that consider body fat distribution when assessing CV risk.

Gender differences in cardiovascular risk, treatment, and outcomes: a post hoc analysis from the REWIND trial.

Objectives. To assess whether the use of cardioprotective therapies for type 2 diabetes varies by gender and whether the risk of cardiovascular events is higher in women versus men in the REWIND trial, including an international type 2 diabetes patient population with a wide range of baseline risk. Design. Gender differences in baseline characteristics, cardioprotective therapy, and the achieved clinical targets at baseline and two years were analyzed. Hazards for cardiovascular outcomes (fatal/nonfatal stroke, fatal/nonfatal myocardial infarction, cardiovascular death, all-cause mortality, and heart failure hospitalization), in women versus men were analyzed using two Cox proportional hazard models, adjusted for randomized treatment and key baseline characteristics respectively. Time-to-event analyses were performed in subgroups with or without history of cardiovascular disease using Cox proportional hazards models that included gender, subgroup, randomized treatment, and gender-by-subgroup interactions. Results. Of 9901 participants, 46.3% were women. Significantly fewer women than men had a cardiovascular disease history. Although most women met treatment targets for blood pressure (96.7%) and lipids (72.8%), fewer women than men met the target for cardioprotective therapies at baseline and after two years, particularly those with prior cardiovascular disease, who used less renin-angiotensin-aldosterone system inhibitors, statins, and aspirin than men. Despite these differences, women had lower hazards than men for all outcomes except stroke. No significant gender and cardiovascular disease history interactions were identified for cardiovascular outcomes. Conclusions. In REWIND, most women met clinically relevant treatment targets, but in lower proportions than men. Women had a lower risk for all cardiovascular outcomes except stroke. Clinical trials.gov registration number: NCT01394952.

HbA1c Reduction in Dulaglutide-Treated Patients Irrespective of Duration of Diabetes, Microvascular Disease, and BMI: A Post Hoc Analysis From the REWIND Trial.

OBJECTIVE: To evaluate participant characteristics and long-term changes in glycated hemoglobin (HbA1c) levels in patients treated with dulaglutide 1.5 mg in a post hoc analysis of the Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial. RESEARCH DESIGN AND METHODS: Change from baseline in HbA1c was assessed during and up to 72 months of treatment before and after adjustment for duration of diabetes, prior microvascular disease (nephropathy or retinopathy), and BMI. Slope analyses were used to assess the change in HbA1c during 0-12 months and 12-72 months of therapy. RESULTS: HbA1c was significantly reduced in patients treated with dulaglutide compared with placebo during 72 months of treatment (least-squares mean difference = -0.61%, P < 0.001), regardless of diabetes duration, prior microvascular disease, and BMI (all interaction P > 0.07). Significant reductions were apparent at all time points and were independent of these baseline characteristics. Slope analyses revealed that the dulaglutide group experienced a higher rate of HbA1c reduction compared with the placebo group from 0 to 12 months before and after adjustment. The dulaglutide group also experienced a higher rate of HbA1c increase from 12 to 72 months compared with the placebo group that became nonsignificant after adjustment for diabetes duration, prior microvascular disease, and BMI combined. Despite the greater rate of HbA1c increase in the dulaglutide group during this period, mean HbA1c values remained below baseline in the dulaglutide group and below mean HbA1c values in the placebo group. CONCLUSIONS: Dulaglutide 1.5-mg treatment was statistically associated with a long-lasting decrease in HbA1c over 72 months, irrespective of baseline duration of diabetes, microvascular disease, and BMI.

Exploring potential mediators of the cardiovascular benefit of dulaglutide in type 2 diabetes patients in REWIND.

BACKGROUND: The REWIND trial demonstrated cardiovascular (CV) benefits to patients with type 2 diabetes and multiple CV risk factors or established CV disease. This exploratory analysis evaluated the degree to which the effect of dulaglutide on CV risk factors could statistically account for its effects on major adverse cardiovascular events (MACE) in the REWIND trial. METHODS: Potential mediators of established CV risk factors that were significantly reduced by dulaglutide were assessed in a post hoc analysis using repeated measures mixed models and included glycated hemoglobin (HbA1c), body weight, waist-to-hip ratio, systolic blood pressure, low-density lipoprotein (LDL), and urine albumin/creatinine ratio (UACR). These factors, for which the change in level during follow-up was significantly associated with incident MACE, were identified using Cox regression modeling. Each identified variable was then included as a covariate in the Cox model assessing the effect of dulaglutide on MACE to estimate the degree to which the hazard ratio of dulaglutide vs placebo was attenuated. The combined effect of the variables associated with attenuation was assessed by including all variables in an additional Cox model. RESULTS: Although all evaluated variables were significantly improved by treatment, only changes in HbA1c and UACR were associated with MACE and a reduction in the effect of dulaglutide on this outcome was observed. The observed hazard ratio for MACE for dulaglutide vs placebo reduced by 36.1% by the updated mean HbA1c, and by 28.5% by the updated mean UACR. A similar pattern was observed for change from baseline in HbA1c and UACR and a reduction of 16.7% and 25.4%, respectively in the hazard ratio for MACE with dulaglutide vs placebo was observed. When HbA1c and UACR were both included, the observed hazard ratio reduced by 65.4% for the updated mean and 41.7% for the change from baseline with no HbA1c-UACR interaction (P interaction = 0.75 and 0.15, respectively). CONCLUSIONS: Treatment-induced improvement in HbA1c and UACR, but not changes in weight, systolic blood pressure, or LDL cholesterol, appear to partly mediate the beneficial effects of dulaglutide on MACE outcomes. These observations suggest that the proven effects of dulaglutide on cardiovascular disease benefit are partially related to changes in glycemic control and albuminuria, with residual unexplained benefit. Clinicaltrials.gov; Trial registration number: NCT01394952. URL: https://clinicaltrials.gov/ct2/show/NCT01394952.

Gastrointestinal Tolerability of Once-Weekly Dulaglutide 3.0 mg and 4.5 mg: A Post Hoc Analysis of the Incidence and Prevalence of Nausea, Vomiting, and Diarrhea in AWARD-11.

BACKGROUND: Gastrointestinal (GI) events are the most frequent treatment-emergent adverse events (TEAEs) reported for glucagon-like peptide-1 receptor agonist therapies. This post hoc analysis of the AWARD-11 phase 3 trial assessed the GI tolerability of dulaglutide at once-weekly doses of 1.5, 3.0, and 4.5 mg. METHODS: The AWARD-11 trial randomized patients to once-weekly dulaglutide 1.5 mg (n = 612), 3.0 mg (n = 616), or 4.5 mg (n = 614) for 52 weeks. Patients started on dulaglutide 0.75 mg for 4 weeks before escalating stepwise every 4 weeks until the final randomized dose was reached. This study analyzes the onsets, incidences, prevalences, and severities of nausea, vomiting, and diarrhea events reported through 52 weeks. RESULTS: The highest incidences of nausea (≤ 8%), vomiting (≤ 2%), and diarrhea (≤ 4%) were primarily observed soon after the initiation of dulaglutide treatment at 0.75 mg. Incidence then declined throughout the remainder of the study, even with dose escalation to 1.5, 3.0, and 4.5 mg. Most of these GI TEAEs were mild to moderate in severity, with severe nausea, vomiting, or diarrhea events occurring in ≤ 0.6% of patients. Treatment discontinuation due to nausea was low across treatment groups (≤ 1.5%). CONCLUSIONS: The tolerability profiles of dulaglutide 3.0 mg and 4.5 mg were consistent with that of the 1.5-mg dose. Patients experiencing GI events were most likely to do so within 2 weeks of treatment initiation, and few patients experienced a new GI event after escalating to the 3.0-mg or 4.5-mg dose. Severe events were infrequent, and when they did occur, no relationship with dose at time of event was observed. Supplementary file1 (MP4 33880 kb).

Dulaglutide is a glucagon-like peptide 1 receptor agonist (GLP-1 RA) prescribed for the treatment of type 2 diabetes (T2D). The most frequently reported side effects of GLP-1 RAs are nausea, vomiting, or diarrhea. This analysis of a 52-week study in adult patients with T2D details the tolerability of dulaglutide injected once weekly at a dose of 1.5 mg, 3 mg, or 4.5 mg, as assessed by looking at the nausea, vomiting, and diarrhea events reported during the study. All patients started dulaglutide at 0.75 mg before escalating to 1.5 mg after 4 weeks. Depending on the group they were randomly assigned to, the patients then either remained on the 1.5-mg dose, escalated to 3 mg after another 4 weeks and remained on this dose, or escalated further to 4.5 mg after another 4 weeks. The minority of patients who experienced nausea, vomiting, or diarrhea events (less than 16% of patients in each case) generally did so at the beginning of treatment, when all groups were taking the same dose (0.75 mg). Episodes of nausea, vomiting, or diarrhea then became less frequent, even as patients escalated to each of the higher doses. Most of these events were mild to moderate in severity, and most did not cause patients to stop taking the treatment. In general, this analysis shows that, for the minority of patients who experienced nausea, vomiting, or diarrhea, these events were most likely to happen shortly after starting treatment and lessened over time, even as patients escalated to higher dulaglutide doses.

Glycaemic efficacy of an expanded dose range of dulaglutide according to baseline glycated haemoglobin (HbA1c) subgroup: Post hoc analysis of AWARD-11.

The AWARD-11 trial demonstrated the safety and efficacy of dulaglutide 3.0 and 4.5 mg compared to dulaglutide 1.5 mg in patients with type 2 diabetes inadequately controlled with metformin. This post hoc analysis examined the change from baseline in glycated haemoglobin (HbA1c) and proportions of patients achieving HbA1c <7% at weeks 36 and 52 with dulaglutide 1.5 mg, 3.0 mg or 4.5 mg across clinically relevant baseline HbA1c subgroups (<8%; 8.0% to < 9.0%; 9.0% to < 10%; and ≥ 10%). Mean reductions in HbA1c were observed across all baseline HbA1c subgroups at 36 weeks (range of HbA1c change: 1.5 mg: -1.0% to -2.2%; 3.0 mg: -1.2% to -2.5%; and 4.5 mg: -1.2% to -3.2%). More patients randomized to 3.0 mg or 4.5 mg (vs. 1.5 mg) achieved HbA1c <7% at 36 weeks regardless of baseline HbA1c; the difference in proportions was greater at higher baseline HbA1c (P-interaction = 0.096). Similar patterns in glycaemic improvement and proportions achieving HbA1c <7% were observed at 52 weeks. Hypoglycaemia and gastrointestinal adverse events were similar among the HbA1c subgroups. Glycaemic control was improved with dulaglutide dose escalation from 1.5 mg to 3.0 mg or 4.5 mg across baseline HbA1c subgroups (<8%; 8.0% to < 9.0%; 9.0% to < 10%; and ≥ 10%).

Efficacy and safety of dulaglutide 3.0 and 4.5 mg in patients aged younger than 65 and 65 years or older: Post hoc analysis of the AWARD-11 trial.

AIM: To evaluate the efficacy and safety of dulaglutide 3.0 and 4.5 mg versus 1.5 mg when used as an add-on to metformin in subgroups defined by age (<65 and ≥65 years). MATERIALS AND METHODS: Of 1842 patients included in this post hoc analysis, 438 were aged 65 years or older and 1404 were younger than 65 years. The intent-to-treat (ITT) population, while on treatment without rescue medication, was used for all efficacy analyses; the ITT population without rescue medication was used for hypoglycaemia analyses; all other safety analyses used the ITT population. RESULTS: Patients aged 65 years or older and those younger than 65 years had a mean age of 69.5 and 53.2 years, respectively. In each age subgroup, the reduction from baseline in HbA1c and body weight (BW), and the proportion of patients achieving a composite endpoint of HbA1c of less than 7% (<53 mmol/mol) with no weight gain and no documented symptomatic or severe hypoglycaemia, were larger for dulaglutide 3.0 and 4.5 mg compared with dulaglutide 1.5 mg, but the treatment-by-age interactions were not significant. The safety profile for the additional dulaglutide doses was consistent with that of dulaglutide 1.5 mg and was similar between the age subgroups. CONCLUSION: Dulaglutide doses of 3.0 or 4.5 mg provided clinically relevant, dose-related improvements in HbA1c and BW with no significant treatment-by-age interactions, and with a similar safety profile across age subgroups.

Efficacy and Safety of Dulaglutide in Older Patients: A post hoc Analysis of the REWIND trial.

CONTEXT: Dulaglutide reduced major adverse cardiovascular events (MACE) in the Researching Cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial. Its efficacy and safety in older vs younger patients have not been explicitly analyzed. OBJECTIVE: This work aimed to assess efficacy and safety of dulaglutide vs placebo in REWIND by age subgroups (≥ 65 and < 65 years). METHODS: A post hoc subgroup analysis of REWIND was conducted at 371 sites in 24 countries. Participants included type 2 diabetes patients aged 50 years or older with established cardiovascular (CV) disease or multiple CV risk factors, and a wide range of glycemic control. Patients were randomly assigned (1:1) to dulaglutide 1.5 mg or placebo as an add-on to country-specific standard of care. Main outcomes measures included MACE (first occurrence of the composite of nonfatal myocardial infarction, nonfatal stroke, or death from CV or unknown causes). RESULTS: There were 5256 randomly assigned patients who were 65 years or older (mean = 71.0), and 4645 were younger than 65 years (mean = 60.7). Baseline characteristics were similar in randomized treatment groups. Dulaglutide treatment showed a similar reduction in the incidence (11% vs 13%) of MACE in older vs younger patients. The rate of permanent study drug discontinuation, incidence of all-cause mortality, hospitalizations for heart failure, severe hypoglycemia, severe renal or urinary events, and serious gastrointestinal events were similar between randomized treatment groups within each age subgroup. The incidence rate of serious cardiac conduction disorders was numerically higher in the dulaglutide group compared to placebo within each age subgroup but the difference was not statistically significant. CONCLUSION: Dulaglutide had similar efficacy and safety in REWIND in patients65 years and older and those younger than 65 years.