Among patients with type 2 diabetes initiating second-line diabetes therapy, the short-term cardiovascular outcomes of GLP-1 receptor agonists, SGLT-2 inhibitors, and DPP-4 inhibitors were similar.
Higher cardiovascular risk was associated with use of sulfonylureas or basal insulin compared with newer drug classes.
Clinicians may consider prescribing GLP-1 receptor agonists, SGLT-2 inhibitors, or DPP-4 inhibitors more routinely after metformin rather than sulfonylureas or basal insulin.
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Understanding cardiovascular outcomes after initiating second-line antidiabetic medications (ADMs) may help inform treatment decisions after metformin alone is not enough or not tolerated.
To date, no studies have compared the cardiovascular effects of all major second-line ADMs during this early decision point in the pharmacologic management of type 2 diabetes.
To examine the association of second-line ADM classes with major adverse cardiovascular events.
Retrospective cohort study among 132,737 insured adults with type 2 diabetes who started therapy with a second-line ADM after taking either metformin alone or no prior ADM. This study used 2011-2015 US nationwide administrative claims data. Data analysis was performed from January 2017 to October 2018.
Dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, thiazolidinediones (TZDs), basal insulin, and sulfonylureas or meglitinides (both referred to as sulfonylureas hereafter). The DPP-4 inhibitors served as the comparison group in all analyses.
The primary outcome was time to first cardiovascular event after starting the second-line ADM.
This composite outcome was based on hospitalization for the following cardiovascular conditions: congestive heart failure, stroke, ischemic heart disease, or peripheral artery disease.
Among 132 737 insured adult patients with type 2 diabetes (men, 55%; aged 45-64 years, 58%; white, 63%), there were 3,480 incident cardiovascular events during 169,384 person-years of follow-up. Patients were censored after the first cardiovascular event, discontinuation of insurance coverage, transition from International Classification of Diseases, Ninth Revision (ICD-9) to end of ICD-9 coding, or 2 years of follow-up.
After adjusting for patient, prescriber, and health plan characteristics, the risk of composite cardiovascular events after starting GLP-1 receptor agonists was lower than DPP-4 inhibitors (HR 0.78, p<0.05), but this finding was not significant in all sensitivity analyses. Cardiovascular event rates after starting treatment with SGLT-2 inhibitors (HR, 0.81, p>0.05) and TZDs (HR, 0.92, p>0.05) were not statistically different from DPP-4 inhibitors.
The comparative risk of cardiovascular events was higher after starting treatment with sulfonylureas (HR, 1.36, p<0.05) or basal insulin (HR, 2.03, p<0.05) than DPP-4 inhibitors.
Among insured adult patients with type 2 diabetes initiating second-line ADM therapy, the short-term cardiovascular outcomes of GLP-1 receptor agonists, SGLT-2 inhibitors, and DPP-4 inhibitors were similar.
Higher cardiovascular risk was associated with use of sulfonylureas or basal insulin compared with newer ADM classes. Clinicians may consider prescribing GLP-1 receptor agonists, SGLT-2 inhibitors, or DPP-4 inhibitors more routinely after metformin rather than sulfonylureas or basal insulin.
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Cardiovascular disease is the leading cause of morbidity and mortality in type 2 diabetes, and reducing its burden is an important goal of antidiabetic medications (ADMs). Metformin, which may have cardiovascular benefits, is widely recommended as first-line therapy. However, there is a lack of consensus about choosing subsequent ADMs among patients who do not achieve adequate glycemic control with metformin or do not tolerate it. Comparing cardiovascular outcomes of second-line ADMs during this early transition in diabetes pharmacotherapy may help improve treatment decisions after metformin or in place of it.
Use of ADMs has increased owing to the rising prevalence of diabetes and a proliferation of novel therapeutic classes. Recent placebo-controlled trials of dipeptidyl peptidase 4 (DPP-4) inhibitors generally found no cardiovascular benefits or harms. However, some trials of glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT-2) inhibitors reported reductions in composite cardiovascular outcomes and some individual cardiovascular events.
These trials specifically recruited participants with a high burden of cardiovascular disease who were taking multiple ADMs. Therefore, it is not known whether their findings apply to the broader population with diabetes. Older research on second-line ADMs suggested cardiovascular harms associated with sulfonylureas, thiazolidinediones (TZDs), and insulin. To date, no studies have directly compared the cardiovascular effects of all contemporary ADM options among patients starting second-line therapy.
Our study investigated the comparative effectiveness of all major second-line ADM classes on major adverse cardiovascular events among insured adult patients with type 2 diabetes. By examining cardiovascular outcomes among patients initiating second-line ADMs in the real world, this study aimed to complement findings from individual drug trials and further inform ADM choices for the broad population of patients currently receiving these medications.
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. Some experts suggest that clinicians also consider cardiovascular benefits and harms when prescribing second-line ADM therapy. 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 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. Therefore, trial findings may not apply to patients with a lower short-term risk of cardiovascular events. 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. 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.
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. 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. 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. Like the semaglutide trial, 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. 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. Prior observational analyses that included patients taking sulfonylureas or insulin in their comparison groups have generally reached similar findings. 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. 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. 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. 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. However, a large body of research reveals common mechanisms linking basal insulin and sulfonylureas with increased cardiovascular risk, namely, hyperinsulinemia, weight gain, and hypoglycemia. Hypoglycemia may be most important for short-term cardiovascular outcomes. 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, and we found no significant associations in this group.
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.