Table 4

Limitations of current CVOT structure and opportunities for improvement

Current limitations
 Lack of generalizabilityCurrent CVOTs include participants who are at high risk for a CV event or death and thus are not representative of the larger population.
 Short timeline for assessing potential benefitsCV benefit may not become apparent until long after initiation of treatment. Current CVOTs do not assess outcomes occurring >5 years after the onset of treatment.
 Short timeline for assessing potential harmCVOTs lasting <5 years are not likely to detect risks that may become apparent only after years of treatment. This may be especially concerning for agents with complex mechanisms of action.
 Placebo-controlled designNearly all CVOTs to date have tested one drug against placebo, with both groups attempting to attain comparable glycemic control using regimens that also include other medications. Problems with this design include 1) comparable glycemic control generally has not been achieved and the lower A1Cs found with the study drug may contribute to CV benefits, 2) some drugs used in the comparison groups may themselves have an adverse effect on CV events, and 3) the CV benefits found with four agents to date make the future use of placebo ethically challenging.
Opportunities for improvement
 Lower-risk, more diverse populationsPrimary intervention trials in lower-risk populations could determine whether diabetes medications offer CV protection for those who do not yet have CVD. This would require larger and/or longer studies but would yield valuable information with regard to CVD prevention.
 Longer-term follow-upTrial designs that prespecify longer-term follow-up could better identify longer-term safety issues and late beneficial effects, produce better cost-effectiveness data, and improve understanding of changing treatment requirements over time. Such a design would require new consent procedures to permit lifelong follow-up, strategies to increase therapy adherence and persistence, expanded use of EMRs, and innovative statistical approaches to permit serial reporting of key clinical outcomes over time.
 Active comparatorsUsing an active comparator instead of placebo could address the drawbacks of placebo-controlled trials but will require sufficient knowledge of the CV impact of the comparator to avoid confounding interpretation of the results. Although challenging, this may become feasible as understanding of the CV safety of newer agents increases. Across-trials consistency in enrollment criteria and the capturing of baseline patient characteristics will facilitate such efforts.
 Innovative designsAdoption of factorial or adaptive designs, superiority trials, trials embedded within health care systems or networks, and/or employment of “big data” to dissect the effects of new diabetes medications may provide practical opportunities for further investigation.
 Standardized definitionsStandard definitions of important safety and microvascular outcomes would facilitate better comparisons among agents. Collaborative efforts should be made to standardize definitions of high-priority safety and microvascular outcomes, akin to those established for CV outcomes.
 Modification of end points and analysesIncorporating weighted composite end points that include estimation of the severity of events, as well as multiple events in the same patient, may yield more nuanced findings in future studies. The design of trials for new agents should be informed by data from previous CVOTs within the same drug class. Important secondary outcomes with robust statistical findings that are biologically plausible and supportable by external evidence should be independently considered even if primary composite outcomes are not achieved. Such approaches would require buy-in from regulatory bodies and mechanisms to ensure equity for developers of first-in-class interventions and/or those who willingly adopt more complex trial designs. How best to incorporate predefined safety concerns into primary analyses should also be considered.
 Establishment of biorepositoriesFuture trials should obtain informed consent to store participants’ biological samples in case unexpected results warrant further investigation. Such biorepositories could increase opportunities to investigate various mechanisms contributing to CV events and key subgroups and will become increasingly important for subsequent biomarker, gut microbiota, and genomic analyses to facilitate precision medicine opportunities.
 Enhanced efficiency and cost-sharing optionsConducting a CVOT for each new diabetes drug is cumbersome and expensive. Strategies to enhance trial efficiency, such as collecting CV outcomes data from trials designed for other purposes, should be strongly considered, as should new models for cost-sharing among pharmaceutical, governmental, and other organizations.
 Involvement of patients and advocacy organizationsInvolving patients and their advocates in designing future trials will help to ensure that patients’ views and wishes are taken into account and that patient-related outcome measures are fully integrated. Such efforts would likely increase patient buy-in and help to minimize discontinuation, improve treatment adherence and persistence, and avoid missing data.