Impact of BMI and comorbidities on efficacy of once-weekly semaglutide: Post hoc analyses of the STEP 1 randomized trial.

OBJECTIVE: This study assessed the effects of semaglutide on body weight, cardiometabolic risk factors, and glycemic status in individuals categorized by baseline BMI with or without additional obesity-related comorbidities, including prediabetes and high risk of cardiovascular disease (CVD). METHODS: This was a post hoc exploratory subgroup analysis of the Semaglutide Treatment Effect in People with Obesity (STEP) 1 trial (NCT03548935), in which participants without diabetes and BMI ≥30 kg/m2 , or BMI ≥27 kg/m2 with ≥1 weight-related comorbidity, were randomized to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 68 weeks. For this analysis, individuals were categorized into subgroups based on baseline BMI <35 versus ≥35 kg/m2 (with no additional criteria, with ≥1 comorbidity, with prediabetes, and with prediabetes and high risk of CVD). RESULTS: Mean changes in body weight from baseline to week 68 with semaglutide were -16.2% and -14.0% in the subgroups with baseline BMI <35 and ≥35 kg/m2 , respectively (both p < 0.0001 vs. placebo). Similar changes were observed in individuals with comorbidities, with prediabetes, and with prediabetes plus high CVD risk. The beneficial effects of semaglutide on cardiometabolic risk factors were consistent across all subgroups. CONCLUSIONS: This subgroup analysis confirms that semaglutide is effective in individuals with baseline BMI <35 and ≥35 kg/m2 , including in those with comorbidities.

Association between body mass index, weight loss and the chance of pregnancy in women with polycystic ovary syndrome and overweight or obesity: a retrospective cohort study in the UK.

STUDY QUESTION: What are the associations between baseline BMI (Study 1) and change in body weight (Study 2) with the likelihood of pregnancy in women with polycystic ovary syndrome (PCOS). SUMMARY ANSWER: In women with PCOS, higher baseline BMI was associated with a lower chance of pregnancy; however, weight loss was associated with an increased chance of pregnancy versus maintaining a stable weight or gaining weight. WHAT IS KNOWN ALREADY: Two studies in large cohorts of Danish women with the intention to become pregnant showed a decline in fecundability ratios with higher BMI. Furthermore, a meta-analysis found that overweight/obesity significantly worsened metabolic and reproductive outcomes in women with PCOS. STUDY DESIGN, SIZE, DURATION: Data were extracted from the UK Clinical Practice Research Datalink GOLD database. Patients included women aged 18-45 years with BMI ≥18.5 (Study 1) or ≥25 kg/m2 (Study 2) at time of PCOS diagnosis (index date). The primary outcome was the time to first pregnancy recorded during 36-months' follow-up, analysed with Cox proportional hazard models and presented as hazard ratios (HRs). PARTICIPANTS/MATERIALS, SETTING, METHODS: Study 1 included 9955 women with PCOS. Study 2 included 7593 women with PCOS and median BMI of 34.0 kg/m2. MAIN RESULTS AND THE ROLE OF CHANCE: Higher BMI was associated with a lower chance of pregnancy in the 3 years following diagnosis. It was estimated that 41% of women with normal weight (18.5-24.9 kg/m2) would become pregnant compared to 17% of women with obesity class III (BMI ≥40.0 kg/m2) during follow-up. Furthermore, the chance of pregnancy for women with obesity class III was estimated to be 63% lower than for women with normal weight, with the same age and glycaemic status (HR 0.37, 95% CI 0.31-0.44; P < 0.0001). A significant inverse association was found between BMI change and chance of pregnancy: 10% weight loss was estimated to increase the chance of pregnancy by 68% for women with baseline BMI of 40 kg/m2 (HR 1.68, 95% CI 1.49-1.90). LIMITATIONS, REASONS FOR CAUTION: Multiple factors influence the chance of pregnancy (the ability and willingness to become pregnant), which was addressed by exclusion criteria employed. The real-world nature of the study means that use of non-prescription contraceptives was not available. Bias may have been introduced by the fact that only around 40% of women with PCOS in the CPRD GOLD database had their BMI recorded during the year prior to PCOS diagnosis. BMI categories used in the analyses may not be applicable to women of all ethnicities. The study population was only representative of women in the UK and results may not be generalizable to other regions. PCOS diagnoses were based on codes entered into the system by primary care providers, and no information was available regarding the criteria used for diagnosis, although symptoms used to diagnose PCOS have not changed over time. WIDER IMPLICATIONS OF THE FINDINGS: Our observations provide further evidence of the benefits of weight loss in women with overweight/obesity and PCOS who are seeking to become pregnant. STUDY FUNDING/COMPETING INTEREST(S): Novo Nordisk A/S. A.H.B. declares fees for consultancy from Novo Nordisk. P.N.L. and C.L.H. are employees of Novo Nordisk. V.S. and A.V. are employees of, and hold shares in, Novo Nordisk. TRIAL REGISTRATION NUMBER: N/A.

Changes in Glucose Metabolism and Glycemic Status With Once-Weekly Subcutaneous Semaglutide 2.4 mg Among Participants With Prediabetes in the STEP Program.

OBJECTIVE: This analysis of 3,375 adults with overweight/obesity across the Semaglutide Treatment Effect in People with obesity (STEP) 1, 3, and 4 trials evaluated whether more participants with prediabetes had normoglycemia after 68 weeks' treatment with once-weekly semaglutide 2.4 mg plus lifestyle intervention versus placebo and assessed changes in glucose metabolism in participants with prediabetes. RESEARCH DESIGN AND METHODS: STEP 1, 3, and 4 were phase 3, 68-week, randomized, placebo-controlled, multinational trials; STEP 4 had a 20-week semaglutide run-in and 48-week randomized period. Analyses included changes (week 0-68; before the washout period) in glycemic status (prespecified: STEP 1 and 3; post hoc: STEP 4), and in HbA1c, fasting plasma glucose (FPG), and HOMA insulin resistance (HOMA-IR) among participants with prediabetes (post hoc). RESULTS: Significantly more participants with baseline (week 0) prediabetes (n = 1,536) had normoglycemia at week 68 with semaglutide versus placebo (STEP 1, 84.1% vs. 47.8%; STEP 3, 89.5% vs. 55.0%; STEP 4, 89.8% vs. 70.4%; all P < 0.0001). Fewer participants with baseline normoglycemia had prediabetes at week 68 with semaglutide versus placebo (STEP 1, 2.9% vs. 10.9%; STEP 3, 3.2% vs. 5.8%; STEP 4, 1.1% vs. 5.0%). Semaglutide resulted in greater improvements in HbA1c, FPG, and HOMA-IR than placebo among participants with baseline prediabetes (all P < 0.01). CONCLUSIONS: STEP 1, 3, and 4 collectively provide a robust assessment of the effects of semaglutide on glucose metabolism and prediabetes in a large cohort of adults with overweight/obesity while on treatment. Among participants with baseline prediabetes, 68 weeks' treatment with semaglutide versus placebo led to significant improvements in glucose metabolism and a higher likelihood of normoglycemia.

Validation of the all-comers design: Results of the TARGET-AC substudy.

BACKGROUND: Results of clinical trials are often criticized by low inclusion rate and potential sampling bias in patient recruitment. The aim of this validation registry is to evaluate how far an all-comers design in the context of clinical research can ensure the representation of the true all-comers population. METHODS: This validation registry is a prospective international multicentre registry, conducted at 10 out of the total 21 centers, participating in TARGET-AC (registered under NCT02520180). During a predefined four-week period data were recorded prospectively on all PCIs performed in the participating centers, whether or not patients were enrolled in TARGET-AC. Data were collected on patient demographics, angiographic lesion- and procedural characteristics. For patients who were not enrolled in the study, operators were asked to declare the reason for not enrolling the patient, using a single-choice questionnaire. RESULTS: A total of 131 patients were enrolled in the TARGET-AC study during the investigated period (ER group), standing as 20% (range 4% and 54%) of all eligible cases per protocol. In the ER group more patients presented with stable angina (61% vs. 43%, respectively; P < .001). Whereas ST-elevation infarction was less common (5% vs. 26%, respectively; P < .001), there was no difference in non-ST elevation acute coronary syndrome (32% vs. 27%, respectively; P = .248). Risk factors and comorbidities did not show any difference between the ER and the non-enrolled (NER) groups, except for greater rate of significant valvular disease in the NER group (12% vs 19%, respectively; P = .037). The NER group presented more thrombotic stenoses than the ER group (20% vs 12%, respectively; P = .040). No difference was found in any other investigated angiographic parameters, like target vessels, bifurcation lesion, severe calcification or chronic total occlusions. Admission during regular working hours and availability of study nurse were associated with markedly higher recruitment rate. CONCLUSION: Results suggest that TARGET AC was outbalanced for stable patients over primary PCIs as compared to real world. However in terms of risk factors and comorbidities the trial managed to represent the collective of real world clinical practice. Fairly representative cases were included at an average inclusion-to-eligible rate of 20%.

Unreported exclusion and sampling bias in interpretation of randomized controlled trials in patients with STEMI.

AIMS: To assess the impact of sampling bias due to reported as well as unreported exclusion of the target population in a multi-center randomized controlled trial (RCT) of ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: We compared clinical characteristics and mortality between participants in the DANAMI-3 trial to contemporary non-participants with STEMI using unselected registries. A total of 179 DANAMI-3 participants (8%) and 617 contemporary non-participants (22%) had died (Log-Rank: P < 0.001) after a median follow-up of 1333 days (range: 1-2021 days). In an unadjusted Cox regression model all groups of non-participants had a higher hazard ratio to predict mortality compared to participants: eligible excluded (n = 144) (hazard ratio: 3.41 (95% CI: (2.69-4.32)), ineligible excluded (n = 472) (hazard ratio: 3.42 (95% CI: (2.44-4.80), eligible non-screened (n = 154) (hazard ratio: 3.37 (95% CI: (2.36-4.82)), ineligible non-screened (n = 154) (hazard ratio: 6.48 (95% CI: (4.77-8.80). CONCLUSION: Sampling bias had occurred due to both reported and unreported exclusion of eligible patients and the difference in mortality between participants and non-participants could not be explained only by the trial exclusion criteria. Thus, screening logs may not be suited to address the risks of sampling bias.

Bleeding Events After ST-segment Elevation Myocardial Infarction in Patients Randomized to an All-comer Clinical Trial Compared With Unselected Patients.

Most studies reporting bleedings in patients with ST-segment elevation myocardial infarction (STEMI) are reports from clinical trials, which may be unrepresentative of incidences in real-life. In this study, we investigated 1-year bleeding and mortality incidences in an unselected STEMI population, and compared participants with nonparticipants of a randomized all-comer clinical trial (The Third DANish Study of Optimal Acute Treatment of Patients with STEMI (DANAMI-3)). Hospital charts were read and bleedings classified according to thrombolysis in myocardial infarction (TIMI) and Bleeding Academic Research Consortium (BARC) criteria in 2,490 consecutive STEMI patients who underwent primary percutaneous coronary intervention in a single, large, and tertiary heart center. Thrombolysis in myocardial infarction minor and/or major bleeding (TMMB) occurred in 4.4% day 0 to 30 and 2.1% day 31 to 365. DANAMI-3 nonparticipants (n = 887) had significantly higher 30-day bleeding rates than DANAMI-3-participants (n = 1,603) (7.2% vs 2.9%, p <0.0001), but not thereafter (p = 0.8). DANAMI-3 nonparticipation was significantly associated with 30-day TMMB (hazard ratio, 1.8, 95% confidence interval, 1.2 to 2.8, p = 0.007), but this did not persist after adjusting for resuscitated cardiac arrest, Killip-class>2 and anemia. Patients with cardiac arrest, Killip-class>2, and anemia accounted for 70.0% of 30-day TMMBs, and the majority of these patients were DANAMI-3 nonparticipants. TMMB day 0 to 30 was associated with increased 30-day mortality (hazard ratio 3.1, 95% confidence interval 1.9 to 5.2, p <0.0001) but not thereafter (p = 0.9). In conclusion, we found that clinical trial (DANAMI-3) nonparticipants had significantly more TMMBs within 30 days than participants. Patients with resuscitated cardiac arrest, anemia, and Killip-class>2 were accountable for a high rate of TMMBs. Bleeding incidences from clinical trials cannot be translated to an unselected STEMI population.

Comparison between patients included in randomized controlled trials of ischemic heart disease and real-world data. A nationwide study.

BACKGROUND: The objective was to compare patients with ischemic heart disease (IHD) undergoing percutaneous coronary intervention (PCI) who were included in randomized controlled trials (RCTs) (trial participants) with patients who were not included (nonparticipants) on a trial-by-trial basis and according to indication for PCI. METHODS: In this cohort study, we compared patients with IHD who were randomized in RCTs in relation to undergoing PCI in Denmark between 2011 and 2015 were considered as RCT-participants in this study. The RCT-participants were compared with contemporary nonparticipants with IHD undergoing PCI in the same period, and they were identified using unselected national registry data. The primary end point was all-cause mortality. RESULTS: A total of 10,317 (30%) patients were included in 10 relevant RCTs (trial participants), and a total of 23,644 (70%) contemporary patients did not participate (nonparticipants). In all the included RCTs, nonparticipants had higher hazard ratios for mortality compared to trial participants (P < .001). Among all patients treated with PCI, the pooled estimates showed a significantly higher mortality rate for nonparticipants compared to trial participants (hazard ratio: 2.03, 95% CI: 1.88-2.19) (P < .001). When patients were stratified according to indication for PCI, the pooled estimates showed a significantly lower mortality rate for trial participants compared to nonparticipants in all strata (P for all < .001). CONCLUSIONS: Trial participants in recently performed RCTs including patients undergoing PCI were not representative of the general population of patients with IHD treated with PCI according to clinical characteristics and mortality. The difference in mortality was found irrespective of the indication for PCI. Thus, results from RCTs including patients undergoing PCI should be extrapolated with caution to the general patient population.

Relation of Bleeding Events to Mortality in Patients With ST-Segment Elevation Myocardial Infarction Treated by Percutaneous Coronary Intervention (a DANAMI-3 Substudy).

Bleeding events in relation to treatment of ST-segment elevation myocardial infarction (STEMI) have previously been associated with mortality. In this study, we investigated the incidence and prognosis of, and variables associated with serious bleedings within 30 days after primary percutaneous coronary intervention in patients from The Third Danish Study of Optimal Acute Treatment of Patients with ST-Segment Elevation Myocardial Infarction (DANAMI-3) (n = 2,217). Hospital charts were read within 30 days postadmission to assess bleeding events using thrombolysis in myocardial infarction (TIMI) and Bleeding Academic Research Consortium criteria. TIMI minor/major bleeding (TMMB) occurred in 59 patients (2.7%). Variables associated with TMMB were female gender (hazard ratio [HR] 3.9, 95% confidence interval [CI] 2.2 to 6.7, p <0.0001), symptom-to-catheterization time >3 hours (HR 1.9, 95% CI 1.1 to 3.3, p = 0.02), use of glycoprotein IIb/IIIa inhibitor (HR 2.1, 95% CI 1.2 to 3.7, p = 0.01), and increasing S-creatinine (HR 1.1, 95% CI 1.0 to 1.2, p = 0.001). Undergoing 2 in-hospital procedures were not associated with increased risk of TMMB. TMMB was strongly associated with 30-day mortality in multivariable analysis (HR 4.8, 95% CI 2.2 to 10.4, p <0.0001) but not with mortality days 31 to 365. When excluding fatal bleedings from the analysis, a TMMB was no longer associated with 30-day mortality. In conclusion, we found that in a contemporary STEMI-population, the incidence of 30-day TMMB was low. A TMMB was strongly associated with 30-day mortality but not with mortality days 31 to 365. If patients survived a serious bleeding, their short- and long-term prognoses were not affected.

Drop-out from cardiovascular magnetic resonance in a randomized controlled trial of ST-elevation myocardial infarction does not cause selection bias on endpoints.

BACKGROUND: The extent of selection bias due to drop-out in clinical trials of ST-elevation myocardial infarction (STEMI) using cardiovascular magnetic resonance (CMR) as surrogate endpoints is unknown. We sought to interrogate the characteristics and prognosis of patients who dropped out before acute CMR assessment compared to CMR-participants in a previously published double-blinded, placebo-controlled all-comer trial with CMR outcome as the primary endpoint. METHODS: Baseline characteristics and composite endpoint of all-cause mortality, heart failure and re-infarction after 30 days and 5 years of follow-up were assessed and compared between CMR-drop-outs and CMR-participants using the trial screening log and the Eastern Danish Heart Registry. RESULTS: The drop-out rate from acute CMR was 28% (n = 92). These patients had a significantly worse clinical risk profile upon admission as evaluated by the TIMI-risk score (3.7 (± 2.1) vs 4.0 (± 2.6), p = 0.043) and by left ventricular ejection fraction (43 (± 9) vs. 47 (± 10), p = 0.029). CMR drop-outs had a higher incidence of known hypertension (39% vs. 35%, p = 0.043), known diabetes (14% vs. 7%, p = 0.025), known cardiac disease (11% vs. 3%, p = 0.013) and known renal function disease (5% vs. 0%, p = 0.007). However, the 30-day and 5-years composite endpoint rate was not significantly higher among the CMR drop-out ((HR 1.43 (95%-CI 0.5; 3.97) (p = 0.5)) and (HR 1.31 (95%-CI 0.84; 2.05) (p = 0.24)). CONCLUSION: CMR-drop-outs had a higher incidence of cardiovascular risk factors at baseline, a worse clinical risk profile upon admission. However, no significant difference was observed in the clinical endpoints between the groups.