In this large observational analysis of insured patients with type 2 diabetes who initiated second-line therapy, GLP-1 receptor agonist use was associated with significant reductions in the composite primary outcome compared with DPP-4 inhibitor use. However, this finding was not significant in some sensitivity analyses.

 

There was a direction toward cardiovascular benefit among patients starting treatment with SGLT-2 inhibitors compared with DPP-4 inhibitors that did not achieve statistical significance.

 

This study found consistent cardiovascular harms associated with use of basal insulin or sulfonylureas compared with DPP-4 inhibitors. Collectively, these findings raise concerns about the cardiovascular safety of sulfonylureas and basal insulin compared with newer ADMs and suggest that short-term cardiovascular outcomes of newer ADM classes may be similar among patients starting second-line treatment.

 

After metformin, current guidelines recommend selecting ADMs based on expected glycemic improvements, potential risks, and other factors, such as their effect on body weight.2,4Some experts suggest that clinicians also consider cardiovascular benefits and harms when prescribing second-line ADM therapy.15 However, limited cardiovascular data are currently available for the large population of patients starting second-line ADMs after metformin alone is not sufficient or not tolerated. Our analysis provides preliminary evidence needed by patients, clinicians, insurance plans, and pharmacy benefit managers to weigh the comparative cardiovascular harms and benefits of each second-line ADM class in this understudied population.

 

Recent randomized clinical trial results (eTable 8 in the Supplement) provide some context for interpreting our findings. Although the trials used the highest level of methodologic rigor, they have limitations. First, the major cardiovascular outcome trials compared a single medication to placebo, hindering comparisons across ADM classes. Second, most participants had known cardiovascular disease, which affects only 18% of all US adults with diabetes.30Therefore, trial findings may not apply to patients with a lower short-term risk of cardiovascular events.31 Future cardiovascular outcome trials in this broader population are unlikely because of the resources required, limited interest among funders, and the lack of a regulatory requirement to conduct such trials for older ADMs.32 Randomized clinical trials also may overestimate medication effects observed in clinical practice by selecting highly adherent participants and other study procedures that are not replicable during routine care.33

This context highlights an important role for observational research comparing the cardiovascular effectiveness of ADMs in more typical patients receiving medication in real-world conditions.34,35 

 

Our findings will be complemented by an ongoing randomized clinical trial comparing the glucose-lowering effects of all ADMs studied here, except TZDs and SGLT-2 inhibitors, among participants who initiate second-line treatment after metformin monotherapy.36 

 

When available, results from that ongoing trial will provide evidence about the glycemic efficacy of these drugs among adherent research volunteers and under ideal conditions.

 

Our primary model showed significantly lower risk of composite cardiovascular events associated with GLP-1 receptor agonist use compared with DPP-4 inhibitor use. Improved cardiovascular outcomes among those who initiated treatment with GLP-1 receptor agonists who did not take metformin previously, relative to those who did, may reflect time-lag bias with a longer duration of diabetes among metformin users. Recent placebo-controlled trials of semaglutide and liraglutide therapy also showed reductions in composite fatal and nonfatal cardiovascular events.12,13 Like the semaglutide trial,13 this study found a significant decrease in the incidence of stroke among patients starting treatment with GLP-1 receptor agonists.

 

Reductions in stroke risk approached statistical significance in other GLP-1 receptor agonist trials despite not being designed to detect this outcome.10-12,37 Our analysis likely had greater statistical power because there was follow-up of many more patients receiving treatment than past cardiovascular outcome trials. Interestingly, none of the patients in our GLP-1 receptor agonist group filled a prescription of semaglutide (data not shown). Although preliminary, these findings suggest a potential class effect of GLP-1 in reducing stroke risk that requires confirmation.

 

Compared with DPP-4 inhibitors, we found no statistically significant cardiovascular benefit from SGLT-2 inhibitor therapy. Our analysis included relatively few data on SGLT-2 inhibitors because of their introduction in 2013. Therefore, including longer follow-up in this group may have increased statistical power to detect significant cardiovascular benefits from these medications. Treatment with SGLT-2 inhibitors and GLP-1 receptor agonists has shown improvements in mortality and some individual cardiovascular events among trial participants with a high burden of cardiovascular disease.14 Prior observational analyses that included patients taking sulfonylureas or insulin in their comparison groups have generally reached similar findings.38-42 If sulfonylureas and insulin are more harmful than other ADMs, this finding may have accentuated estimates of comparative cardiovascular benefit associated with GLP-1 receptor agonists and SGLT-2 inhibitors. Furthermore, observational analyses examining the subgroup of patients without prior cardiovascular disease reported smaller or no benefits on composite cardiovascular outcomes when initiating treatment with these 2 drug classes, which is more similar to our findings.38,39 Finally, most previous research included Europeans, whose cardiovascular outcomes may differ from this US cohort.

 

Sulfonylureas constituted almost half of the second-line ADM prescriptions in our cohort, which is comparable with prior reports.43 We found increased cardiovascular risk with sulfonylureas compared with DPP-4 inhibitors, which was robust across all analyses. This risk is consistent with a large number observational studies describing cardiovascular harms of sulfonylureas, many of which were conducted before statins were widely used in diabetes care.44 Our comparison of sulfonylureas with all newer ADMs in the poststatin era shows continued widespread use despite comparatively greater cardiovascular harms.

 

We also found that basal insulin treatment was associated with higher cardiovascular risk than DPP-4 inhibitor treatment. Recent trials studying insulin as part of intensive diabetes treatment have reported conflicting findings on cardiovascular outcomes.45 However, a large body of research reveals common mechanisms linking basal insulin and sulfonylureas with increased cardiovascular risk, namely, hyperinsulinemia, weight gain, and hypoglycemia.45-47Hypoglycemia may be most important for short-term cardiovascular outcomes.48 Despite the observed cardiovascular harms associated with initiating sulfonylureas and basal insulin, prescriptions for these 2 ADM classes were filled by 60% of patients in our nationwide analysis. The cardiovascular effects of TZDs have been debated for many years,49-53 and we found no significant associations in this group.

 

To our knowledge, this is the first study comparing cardiovascular outcomes among initiators of all major second-line ADM. Examining a large, population-based, nationwide cohort enabled the ascertainment of sufficient cardiovascular events to perform this current analysis. Our study design provided adequate power to examine stroke as an individual outcome, which was not possible in clinical trials with smaller numbers of participants receiving treatment. Our rates of nonfatal cardiovascular events were comparable with those observed in the UK Prospective Diabetes Study and prior analyses of similar populations.54-56 The consistency of this study’s findings across multiple cardiovascular outcomes, modeling approaches, and subpopulations supports its internal validity. Our observational design also captured real-world conditions that randomized clinical trials do not, which promotes generalizability of the results in diverse US practice settings. This analysis is also timely, providing data on all major ADMs in a contemporary context where prescribers have little available cardiovascular evidence to inform initiation of second-line therapy.

 

Our study also has limitations. Patients were required to fill the index ADM at least twice, which was chosen to represent a level of exposure that has been associated with cardiovascular outcomes.8,9,12,13 This requirement may have introduced bias if reasons for discontinuation after the first fill were correlated with cardiovascular outcomes.57 Although this is likely not the case for most ADMs studied here,2 the systematic exclusion of some patients with early discontinuation of sulfonylureas and basal insulin owing to hypoglycemia may have underestimated the cardiovascular harms reported.58,59 We analyzed administrative claims data, which may be prone to misclassification and do not include granular information used by clinicians when prescribing second-line ADMs. Medical record data, which may contain some of these factors, have been used in similar studies but were not available in our data source.60 Nonrandomized studies like ours are also prone to selection bias. Multivariable adjustment for observed differences in cardiovascular risk among ADM groups, as well as falsification testing to address potential unobserved confounders, were approaches used to mitigate selection bias.61 Propensity score matching was not used because it would have limited statistical power for comparing 6 ADM groups,62 especially those with relatively smaller numbers of patients. Like similar observational studies, we had no body weight data. Although we used diagnosis codes to ascertain obesity identically for all ADM groups, this strategy underestimates its true prevalence and lacks detail about obesity severity.63

 

Our data sources included HbA1c values for one-third of the study population, which represents a proportion comparable to similar cohort studies using claims data.64 Compared with patients who had no HbA1c data, those with available values were younger with a higher burden of other cardiovascular risk factors (eTable 9 in the Supplement). However, the cardiovascular effectiveness of ADM classes was similar in these 2 subpopulations (Table 3). Furthermore, adjustment for HbA1c in the primary model did not change our findings, which supports a growing consensus that short-term cardiovascular events are not primarily mediated by glycemic control and its association with atherosclerosis progression.65 A large body of research has identified other mechanisms that may explain the short-term association of ADM with cardiovascular outcomes.48,50,66-70 Although the mean duration of follow-up in our was 1.3 years, this represents a comparable or longer time interval than other recent observational analyses of second-line ADMs.38,39,41,71

 

We also had no information on diabetes duration, which is an important determinant of cardiovascular risk.72 However, our selection of patients who were early in their medical treatment of diabetes was intended to compare those at a similar disease stage. In addition, all analyses adjusted for individual cardiovascular risk factors and evidence of existing microvascular and macrovascular complications that are a proxy for diabetes duration. Because we selected patients at a relatively early point in their pharmacologic management of diabetes, our findings may not apply to patients who have a longer duration of diabetes, are already taking multiple ADMs, or have a higher risk of cardiovascular events. Such populations have been studied elsewhere.5-14,38-42,71 Our data source did not allow us to examine mortality, hindering comparisons with studies that assessed fatal cardiovascular events. We did not analyze individual drugs within ADM classes or total costs of diabetes care. These are important directions for future research.

 

Among the large population of insured adult patients with type 2 diabetes who initiated second-line antidiabetic medication therapy, an increased risk of cardiovascular events was associated with starting sulfonylureas or basal insulin treatment compared with newer ADM alternatives.

 

Therefore, clinicians may consider prescribing GLP-1 receptor agonists, DPP-4 inhibitors, or SGLT-2 inhibitors more routinely after metformin rather than sulfonylureas or basal insulin. Furthermore, our findings may suggest a role for these newer ADMs in managing cardiovascular risk among patients with type 2 diabetes who either are taking metformin alone or have received no ADM previously. Although our findings should be interpreted with some caution due to the observational design of this study, they were robust to several rigorous sensitivity analyses and are supported by prior mechanistic and clinical evidence. Future research should compare ADM classes on glycemic effectiveness and additional metabolic end points.

 

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