Translating trial results into interpretable risk estimates: Systematic analysis of cardiorenal outcome trials of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors.

BACKGROUND AND AIMS: In a randomised controlled trial (RCT), the between-arm difference in the average probability of an event per unit of time (i.e., yearly incidence risk difference, YIRD) is an easy-to-interpret treatment effect metric. We aimed to quantify the YIRD in cardiorenal RCTs of GLP-1RAs or SGLT-2is. METHODS AND RESULTS: We digitally searched for RCTs published up to March 1st, 2023, including subjects with type 2 diabetes randomised to GLP-1RAs or SGLT-2is and investigating cardiorenal outcomes or death. We extracted information from Kaplan-Meier (KM) plots to obtain time-to-event individual data and estimate within-arm yearly incidence risk and YIRD. Data from 19 RCTs (28 kM plots) were analysed: comparing treatment to placebo, in GLP-1RA RCTs the YIRD ranged from 0.2 % (95 % CI: -0.7 %, 1.1 %) to -1.9 % (-3.1, -0.7), for primary outcome; and from -0.2 % (-0.5, 0.2) to -0.4 % (-0.7 %, -0.0 %), for mortality. With the exception of SOLOIST-WHF (YIRD 11.9 % for primary outcome), corresponding estimates in SGLT-2is RCTs were: from -0.1 % (-0.4, 0.1) to -5.0 % (-7.7, -2.6), for primary outcome; and from -0.1 % (-0.2, 0.1) to -1.9 % (-4.4 %, 0.6 %), for mortality. CONCLUSION: The YIRD metric complements other relative treatment effect estimates and helps quantify the absolute benefit of GLP-1RAs and SGLT-2is.

Effect of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors on time to outcome in type 2 diabetes cardiorenal outcome trials.

INTRODUCTION: In randomized controlled trials (RCTs), treatment effects are commonly reported as hazard ratio, a measure often misinterpreted as a relative risk reduction. The acceleration factor (AF) indicates the extent to which a treatment increases/decreases the time before the occurrence of an outcome and gives useful insights in the interpretation of trials' results. METHODS: Using individual time-to-event data reconstructed from Kaplan-Meier plots, we estimated AFs for the primary outcomes (POs) and all-cause mortality in glucagon-like peptide-1 receptor agonists (GLP1-RAs) or sodium-glucose cotransporter-2 inhibitors (SGLT2-is) cardiorenal outcome trials in subjects with type 2 diabetes. RESULTS: AFs were estimated from 28 Kaplan-Meier plots of 19 RCTs. Compared to placebo, most GLP1-RAs increased the time before the onset of POs (from 9 % to 59 %) and all-cause mortality (from 8 to 13 %). Similarly, SGLT2-is increased time before the onset of POs (from 19 % to 87 %) and all-cause mortality (from 13 % to 42 %). CONCLUSIONS: The AFs provide a complementary and easier-to-interpret measure of treatment effect that could be useful to improve the shared decision-making.

Intensive glucose control and recurrent cardiovascular events: 14-year follow-up investigation of the ACCORDION study.

AIMS: While cardiovascular disease in patients with type 2 diabetes commonly progresses with the occurrence of repeated events, most trials consider the effect of glucose-lowering strategies only on the first event. We examined the Action to Control Cardiovascular Risk in Diabetes trial and its observational follow-up study (ACCORDION) to investigate the effect of intensive glucose control on multiple events and further identify any subgroup effects. MATERIALS AND METHODS: A recurrent events analysis, using a negative binomial regression model, was applied to estimate the treatment effect on different consecutive cardiovascular disease events, including non-fatal myocardial infarction, non-fatal stroke, hospitalisation from heart failure, and cardiovascular death. Interaction terms were used to identify potential effect modifiers. The robustness of the results was confirmed in sensitivity analyses using alternative models. RESULTS: The median duration of follow-up was 7.7 years. Of the 5128 participants in the intensive and 5123 in the standard glucose control arm, respectively, 822 (16.0%) and 840 (16.4%) participants experienced a single event; 189 (3.7%) and 214 (4.2%) participants experienced two events; 52 (1.0%) and 40 (0.8%) experienced three events; and 1 (0.02%) and 1 (0.02%) experienced four events. There was no evidence of a treatment effect, with a rate difference of 0.0 (-0.3, 0.3) per 100 person-years comparing intensive versus standard intervention, although with non-significantly lower event rates in younger patients with HbA1c < 7% and higher event rates in older patients with HbA1c ≥ 9%. DISCUSSION: Intensive glucose control may not affect cardiovascular disease progression except in select subgroups. Since time-to-first event analysis may miss beneficial or harmful effects of glucose control on the risk of cardiovascular disease, recurrent events analysis should be routinely analysed in cardiovascular outcome trials, particularly when investigating long-term treatment effects. CLINICAL TRIAL REG NO: NCT00000620, clinicaltrials.gov.

Non-inferiority and clinical superiority of glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors: Systematic analysis of cardiorenal outcome trials in type 2 diabetes.

AIMS: Most trials leading to the approval of glucagon-like peptide receptor agonists (GLP-1RAs) and sodium-glucose co-transporter-2 inhibitors (SGLT2is) were primarily designed to confirm their non-inferiority to placebo (commonly using an upper 95% confidence limit threshold of 1.3) and, if confirmed, superiority (threshold 1): this asymmetry of margins (1 vs. 1.3) favours the active intervention. We aimed to quantify the probability of clinical superiority of the active treatment by applying the same threshold used to claim non-inferiority. MATERIALS AND METHODS: We searched PubMed and Cochrane CENTRAL for cardiorenal outcome trials in subjects with type 2 diabetes published before 5 December 2021, to reconstruct from Kaplan-Meier plots individual-level data for the primary outcome or all-cause mortality. We calculated Bayesian posterior densities to obtain the probability for a treatment effect (hazard ratio) <0.769, which is symmetric to the 1.3 threshold (i.e. its reciprocal 1/1.3), emulating a scenario where the active treatment is placebo and placebo is the active treatment. RESULTS: We extracted data from 27 Kaplan-Meier plots (18 for the primary outcome, nine for mortality). Probabilities of clinical superiority to placebo varied significantly: for GLP-1RAs, from a minimum of 0% to a maximum of 69% for the primary outcome and from 0% to 8% for mortality; corresponding estimates for SGLT2is were 0% to 96% and 0% to 93%. Probabilities were on average greater for SGLT2is, particularly in trials investigating kidney or heart failure outcomes. CONCLUSIONS: The probability of clinical superiority to placebo varies widely across trials previously reported as showing superiority of GLP-1RAs or SGLT2is compared with placebo. These results showed within- and between-class differences, highlight the drawbacks of a binary interpretation of the results, particularly in the context of the current designs of non-inferiority trials, and have implications for decision makers and future clinical recommendations.

Patterns of multimorbidity and risk of severe SARS-CoV-2 infection: an observational study in the U.K.

BACKGROUND: Pre-existing comorbidities have been linked to SARS-CoV-2 infection but evidence is sparse on the importance and pattern of multimorbidity (2 or more conditions) and severity of infection indicated by hospitalisation or mortality. We aimed to use a multimorbidity index developed specifically for COVID-19 to investigate the association between multimorbidity and risk of severe SARS-CoV-2 infection. METHODS: We used data from the UK Biobank linked to laboratory confirmed test results for SARS-CoV-2 infection and mortality data from Public Health England between March 16 and July 26, 2020. By reviewing the current literature on COVID-19 we derived a multimorbidity index including: (1) angina; (2) asthma; (3) atrial fibrillation; (4) cancer; (5) chronic kidney disease; (6) chronic obstructive pulmonary disease; (7) diabetes mellitus; (8) heart failure; (9) hypertension; (10) myocardial infarction; (11) peripheral vascular disease; (12) stroke. Adjusted logistic regression models were used to assess the association between multimorbidity and risk of severe SARS-CoV-2 infection (hospitalisation/death). Potential effect modifiers of the association were assessed: age, sex, ethnicity, deprivation, smoking status, body mass index, air pollution, 25-hydroxyvitamin D, cardiorespiratory fitness, high sensitivity C-reactive protein. RESULTS: Among 360,283 participants, the median age was 68 [range 48-85] years, most were White (94.5%), and 1706 had severe SARS-CoV-2 infection. The prevalence of multimorbidity was more than double in those with severe SARS-CoV-2 infection (25%) compared to those without (11%), and clusters of several multimorbidities were more common in those with severe SARS-CoV-2 infection. The most common clusters with severe SARS-CoV-2 infection were stroke with hypertension (79% of those with stroke had hypertension); diabetes and hypertension (72%); and chronic kidney disease and hypertension (68%). Multimorbidity was independently associated with a greater risk of severe SARS-CoV-2 infection (adjusted odds ratio 1.91 [95% confidence interval 1.70, 2.15] compared to no multimorbidity). The risk remained consistent across potential effect modifiers, except for greater risk among older age. The highest risk of severe infection was strongly evidenced in those with CKD and diabetes (4.93 [95% CI 3.36, 7.22]). CONCLUSION: The multimorbidity index may help identify individuals at higher risk for severe COVID-19 outcomes and provide guidance for tailoring effective treatment.

Association Between Accelerometer-Assessed Physical Activity and Severity of COVID-19 in UK Biobank.

OBJECTIVE: To quantify the association between accelerometer-assessed physical activity and coronavirus disease 2019 (COVID-19) outcomes. METHODS: Data from 82,253 UK Biobank participants with accelerometer data (measured 2013-2015), complete covariate data, and linked COVID-19 data from March 16, 2020, to March 16, 2021, were included. Two outcomes were investigated: severe COVID-19 (positive test result from in-hospital setting or COVID-19 as primary cause of death) and nonsevere COVID-19 (positive test result from community setting). Logistic regressions were used to assess associations with moderate to vigorous physical activity (MVPA), total activity, and intensity gradient. A higher intensity gradient indicates a higher proportion of vigorous activity. RESULTS: Average MVPA was 48.1 (32.7) min/d. Physical activity was associated with lower odds of severe COVID-19 (adjusted odds ratio per standard deviation increase: MVPA, 0.75 [95% CI, 0.67 to 0.85]; total, 0.83 [0.74 to 0.92]; intensity, 0.77 [0.70 to 0.86]), with stronger associations in women (MVPA, 0.63 [0.52 to 0.77]; total, 0.76 [0.64 to 0.90]; intensity, 0.63 [0.53 to 0.74]) than in men (MVPA, 0.84 [0.73 to 0.97]; total, 0.88 [0.77 to 1.01]; intensity, 0.88 [0.77 to 1.00]). In contrast, when mutually adjusted, total activity was associated with higher odds of a nonsevere infection (1.10 [1.04 to 1.16]), whereas the intensity gradient was associated with lower odds (0.91 [0.86 to 0.97]). CONCLUSION: Odds of severe COVID-19 were approximately 25% lower per standard deviation (∼30 min/d) MVPA. A greater proportion of vigorous activity was associated with lower odds of severe and nonsevere infections. The association between total activity and higher odds of a nonsevere infection may be through greater community engagement and thus more exposure to the virus. Results support calls for public health messaging highlighting the potential of MVPA for reducing the odds of severe COVID-19.

Microvascular Disease and Risk of Cardiovascular Events and Death From Intensive Treatment in Type 2 Diabetes: The ACCORDION Study.

OBJECTIVE: To assess whether the presence of microvascular complications modifies the effect of intensive glucose reduction on long-term outcomes in patients with type 2 diabetes. PATIENTS AND METHODS: Using ACCORD and ACCORDION study data, we investigated the risk of the primary outcome (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) or death in relation to the prerandomization type and extent of microvascular complications. Interaction terms were fitted in survival models to estimate the risk of both outcomes across levels of an overall microvascular disease score (range 0 to 100) and its individual components: diabetic nephropathy, retinopathy, and neuropathy. RESULTS: During a mean follow-up of 7.7 years, 1685 primary outcomes and 1806 deaths occurred in 9405 participants. The outcome-specific microvascular score was ≤30 in 97.9% of subjects for the primary outcome and in 98.5% for death. For participants with scores of 0 and 30, respectively, the 10-year absolute risk difference between intensive glucose control and standard treatment ranged from -0.8% (95% CI, -2.6, 1.1) to -3.0% -7.1, 1.1) for the primary outcome and from -0.5% (-2.1, 1.1) to 0.7% (-4.2, 5.6) for mortality. Retinopathy was associated with the largest effects, with a 10-year absolute risk difference of -6.5% (-11.1 to -2.0) for the primary outcome and -3.9% (-7.8 to 0.1) for mortality. CONCLUSION: This hypothesis-generating study identifies diabetic retinopathy as predictor of the beneficial effect of intensive glucose control on the risk of cardiovascular disease and possibly death. Further long-term studies are required to confirm these findings.

Cardiovascular effects of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists: The P value and beyond.

Despite growing awareness of the dangers of a dichotomous interpretation of trial results based on the 'statistical significance' of a treatment effect, the uptake of new approaches has been slow in diabetes medicine. We showcase a number of ways to interpret the evidence for a treatment effect applied to the cardiovascular outcome trials of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose co-transporter-2 inhibitors (SGLT-2is): the P value function (or confidence curves), which depicts the treatment effect across the whole spectrum of confidence levels; the counternull value, which is the hazard ratio (i.e. treatment effect size) supported by the same amount of evidence as the null value (i.e. no treatment effect); and the S value, which quantifies the strength of the evidence against the null hypothesis in terms of the number of coin tosses yielding the same side. We show how this approach identifies potential treatment effects, highlights similarities among trials straddling the threshold of statistical significance, and quantifies differences in the strength of the evidence from trials reporting statistically significant results. For example, while REWIND, CANVAS and CREDENCE failed to reach statistical significance at the .05 level for all-cause mortality, their counternull values indicate that reduced death rates by 19%, 24% and 31%, respectively, are supported by the same amount of evidence as that indicating no treatment effect. Moreover, similarities among results emerge in trials of GLP-1RAs (REWIND, EXSCEL and LEADER) lying closely around the threshold of 'statistical significance'. Lastly, several S values, such as for the primary outcome in HARMONY Outcomes (S value 10.9) and all-cause death in EMPAREG-OUTCOME (S value 15.0), stand out compared with values for other outcomes and other trials, suggesting much larger differences in the evidence between these studies and several others that cluster around the .05 significance threshold. P value functions, counternull values and S values should complement the standard reporting of the treatment effect to help interpret clinical trials and make decisions among competing glucose-lowering medications.

Ethnic minorities and COVID-19: examining whether excess risk is mediated through deprivation.

BACKGROUND: People from South Asian and black minority ethnic groups are disproportionately affected by the COVID-19 pandemic. It is unknown whether deprivation mediates this excess ethnic risk. METHODS: We used UK Biobank with linked COVID-19 outcomes occurring between 16th March 2020 and 24th August 2020. A four-way decomposition mediation analysis was used to model the extent to which the excess risk of testing positive, severe disease and mortality for COVID-19 in South Asian and black individuals, relative to white individuals, would be eliminated if levels of high material deprivation were reduced within the population. RESULTS: We included 15 044 (53.0% women) South Asian and black and 392 786 (55.2% women) white individuals. There were 151 (1.0%) positive tests, 91 (0.6%) severe cases and 31 (0.2%) deaths due to COVID-19 in South Asian and black individuals compared with 1471 (0.4%), 895 (0.2%) and 313 (0.1%), respectively, in white individuals. Compared with white individuals, the relative risk of testing positive for COVID-19, developing severe disease and COVID-19 mortality in South Asian and black individuals were 2.73 (95% CI: 2.26, 3.19), 2.96 (2.31, 3.61) and 4.04 (2.54, 5.55), respectively. A hypothetical intervention moving the 25% most deprived in the population out of deprivation was modelled to eliminate between 40 and 50% of the excess risk of all COVID-19 outcomes in South Asian and black populations, whereas moving the 50% most deprived out of deprivation would eliminate over 80% of the excess risk of COVID-19 outcomes. CONCLUSIONS: The excess risk of COVID-19 outcomes in South Asian and black communities could be substantially reduced with population level policies targeting material deprivation.

Association of Timing and Balance of Physical Activity and Rest/Sleep With Risk of COVID-19: A UK Biobank Study.

Behavioral lifestyle factors are associated with cardiometabolic disease and obesity, which are risk factors for coronavirus disease 2019 (COVID-19). We aimed to investigate whether physical activity, and the timing and balance of physical activity and sleep/rest, were associated with SARS-CoV-2 positivity and COVID-19 severity. Data from 91,248 UK Biobank participants with accelerometer data and complete covariate and linked COVID-19 data to July 19, 2020, were included. The risk of SARS-CoV-2 positivity and COVID-19 severity-in relation to overall physical activity, moderate-to-vigorous physical activity (MVPA), balance between activity and sleep/rest, and variability in timing of sleep/rest-was assessed with adjusted logistic regression. Of 207 individuals with a positive test result, 124 were classified as having a severe infection. Overall physical activity and MVPA were not associated with severe COVID-19, whereas a poor balance between activity and sleep/rest was (odds ratio [OR] per standard deviation: 0.71; 95% confidence interval [CI], 0.62 to 0.81]). This finding was related to higher daytime activity being associated with lower risk (OR, 0.75; 95% CI, 0.61 to 0.93) but higher movement during sleep/rest being associated with higher risk (OR, 1.26; 95% CI, 1.12 to 1.42) of severe infection. Greater variability in timing of sleep/rest was also associated with increased risk (OR, 1.21; 95% CI, 1.08 to 1.35). Results for testing positive were broadly consistent. In conclusion, these results highlight the importance of not just physical activity, but also quality sleep/rest and regular sleep/rest patterns, on risk of COVID-19. Our findings indicate the risk of COVID-19 was consistently approximately 1.2-fold greater per approximately 40-minute increase in variability in timing of proxy measures of sleep, indicative of irregular sleeping patterns.

Number needed to treat in cardiovascular outcome trials of glucagon-like peptide-1 receptor agonists: A systematic review with temporal analysis.

Cardiovascular outcome trials (CVOTs) investigating the safety and efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RAs) have highlighted some important differences among these medications. The recent American Diabetes Association and European Association for the Study of Diabetes consensus underlines that each trial constitutes a single experiment; therefore, it remains unclear if, and to what extent, the observed differences reflect the heterogeneous pharmacological properties of each compound. To help clarify the evidence, in this systematic review we investigated differences in trial characteristics which may have had an impact on the primary and secondary trial results, including baseline control of risk factors, prevalence of cardiovascular diseases, absolute rates of events, duration of the study, and definitions of the inclusion criteria and outcomes. Aiming at enhancing the clinical interpretation of these CVOTs, we quantified the absolute treatment effect over time in terms of the number needed to treat to avoid one major adverse cardiovascular event, showing variations among GLP-1RAs.

Uses and Limitations of the Restricted Mean Survival Time: Illustrative Examples From Cardiovascular Outcomes and Mortality Trials in Type 2 Diabetes.

The restricted mean survival time (RMST) has been advocated as an alternative or a supplement to the hazard ratio for reporting the effect of an intervention in a randomized clinical trial. The RMST difference allows quantification of the postponement of an outcome during a specified (restricted) interval and corresponds to the difference between the areas under the 2 survival curves for the intervention and control groups. This article presents examples of the use of the RMST in a research and a clinical context. First, the authors demonstrate how the RMST difference can answer research questions about the efficacy of different treatments. Estimates are presented for the effects of pharmacologic or strategy-driven glucose-lowering interventions for adults with type 2 diabetes from 36 trials and 9 follow-up studies reporting cardiovascular outcomes and mortality. The authors show how these measures may be used to mitigate uncertainty about the efficacy of intensive glucose control. Second, the authors demonstrate how the RMST difference may be used in the setting of a clinical consultation to guide the decision to start or discontinue a treatment. They then discuss the advantages of the RMST over the absolute risk difference, the number needed to treat, and the median survival time difference. They argue that the RMST difference is both easy to interpret and flexible in its application to different settings. Finally, they highlight the major limitations of the RMST, including difficulties in comparing studies of heterogeneous designs and in inferring the long-term effects of treatments using trials of short duration, and summarize the available statistical software for calculating the RMST.

Efficacy and tolerability of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists: A systematic review and network meta-analysis.

AIM: To compare the efficacy and tolerability of sodium-glucose co-transporter 2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) in adults with type 2 diabetes. MATERIALS AND METHODS: Electronic databases were searched from inception to 24 April 2019 for randomized controlled trials reporting change in glycated haemoglobin (HbA1c) at approximately 24 and/or 52 weeks for SGLT-2is and/or GLP-1RAs (classified as short- and long-acting). Bayesian network meta-analyses were conducted to compare within and between SGLT-2i and GLP-1RA classes for cardiometabolic efficacy and adverse events (PROSPERO registration number: CRD42018091306). RESULTS: Sixty-four trials (53 trials of 24 weeks; seven trials of 52 weeks; four trials of both 24 and 52 weeks), comprising 31 384 participants were identified. Compared with placebo, all treatments improved HbA1c. Long-acting GLP-1RAs reduced HbA1c compared with short-acting GLP-1RAs and SGLT-2is, with semaglutide showing greater reduction compared with placebo [24 weeks: -1.49% (95% credible interval: -1.76, -1.22); 52 weeks: -1.38% (-2.05, -0.71)] and all other treatments. Long-acting GLP-1RAs showed benefits in body weight and waist circumference reduction, while SGLT-2is reduced blood pressure. SGLT-2is showed increased risk of genital infection in comparison with long-acting GLP-1RAs [odds ratio (95% credible interval): 5.26 (1.45, 25.00)], while GLP-1RAs showed increased risk of diarrhoea in comparison with SGLT-2is [short-acting GLP-1RAs: 1.65 (1.09, 2.49); long-acting GLP-1RAs: 2.23 (1.51, 3.28)]. No other differences were found between SGLT-2is and GLP-1RAs in adverse events. CONCLUSION: Long-acting GLP-1RAs showed superiority in reducing HbA1c levels, body weight and waist circumference. SGLT-2is showed reductions in blood pressure levels. This review provides essential evidence to guide treatment recommendations in the management of type 2 diabetes.

Efficacy of low- and very-low-energy diets in people with type 2 diabetes mellitus: A systematic review and meta-analysis of interventional studies.

AIMS: To review systematically and quantify the weight loss achieved through low- (LEDs) and very-low-energy diets (VLEDs) in people with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Studies reporting the effects of diet-only interventions of up to 1600 kcal/d in people with T2DM were searched in MEDLINE, EMBASE and CINAHL up to July 2018. Changes in the primary (body weight and body mass index [BMI]) and secondary outcomes (glycated haemoglobin, blood lipids) according to energy restriction and duration of diet were modelled using restricted cubic splines. RESULTS: Forty-four studies (3817 participants) were included. The overall quality of the evidence was moderate and limited to short-term interventions up to 4 months. Baseline mean weight and BMI were 92.1 kg and 36.6 kg/m2 . VLEDs of 400 kcal/d led to 5.4% weight loss at 2 weeks, increasing to 17.9% at 3 months. More modest reductions of 7.3% were observed on LEDs of 1200 kcal/d and 2.0% on 1600 kcal/d after 3 months. No clear patterns emerged for secondary outcomes. Publication bias was significant for primary outcomes. CONCLUSIONS: Through modelling, we were able to describe effective dietary deficit strategies to achieve weight reduction up to 4 months in people with T2DM. High-quality studies are required to further support clinical practice with evidence-based dietary interventions.