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

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 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.</p

Use of Metformin and Cardiovascular Effects of New Classes of Glucose-Lowering Agents: A Meta-analysis of Cardiovascular Outcome Trials in Type 2 Diabetes

Over the last two decades, the large majority of clinical guidelines on the treatment of hyperglycaemia in subjects with type 2 diabetes have suggested metformin as the first-line glucose-lowering treatment alongside lifestyle changes to reach personalized glycemictargets. Recently, the European Society of Cardiology (ESC) recommended using glucagon-like peptide 1 receptor agonists (GLP-1RAs) or sodium-glucose cotransporter 2 inhibitors(SGLT-2is) as first line glucose-lowering therapy in subjects with type 2 diabetes at high or very high risk of cardiovascular disease (CVD), ahead of metformin treatment, to reduce cardiovascular events

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

BackgroundPeople 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.MethodsWe 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.Results15,044 (53.0% women) South Asian and black and 392,786 (55.2% women) white individuals were included. 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 to 1,471 (0.4%), 895 (0.2%) and 313 (0.1%), respectively, in white individuals. Compared to 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 40-50% 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.ConclusionsThe excess risk of COVID-19 outcomes in South Asian and black communities could be substantially reduced with population level policies targeting material deprivation