Study Provides Insight Into Dual and Triple Therapy Options for Diabetes

Danish study makes strong recommendations for diabetes pharmacotherapy beyond metformin, examining dual and triple therapy for type 2. 

In the treatment of type 2 diabetes (T2D), the first-line option is typically straightforward, with metformin being the preferred first-line drug. However, when it comes to the second and third-line options for pharmacological treatment of T2D, that is where the preferred option becomes less clear. There are multiple drug classes to choose from and multiple drugs within those classes, making the potential combinations for dual and triple therapy overwhelming. Randomized controlled trials (RCT) provide evidence to guide clinicians in the selection of second and third-line treatments for T2D; for instance, the EMPA-REG OUTCOME trial showed that the sodium-glucose co-transporter 2 inhibitor (SGLT2i) empagliflozin decreased the risk of cardiovascular mortality, thus making it a preferred treatment for T2D patients at risk for ASCVD events. Despite the benefits of having RCTs to guide evidence-based medicine, they do have limitations, such as stringent exclusion criteria, which may bar their results from being easily applied in real life. Prospective observational studies allow us to look at outcomes in patients under real-world conditions without the limitations RCTs present.  

In a large prospective study of Danish adults with T2D, Jensen et al. used cox regression models to analyze time-to-event outcomes for major adverse cardiovascular events (MACE), severe hypoglycemia, and all-cause mortality. Researchers identified 66,807 Danish adults with T2D on metformin plus one to two other medications from distinct classes. The researchers narrowed the analyses to the eight most common combinations: metformin + DPP-4i (n=9,703), metformin + sulfonylurea (n=24,983), metformin + SGLT2i (n=3,405), metformin + GLP-1-RA (n=6,515), metformin + basal insulin (n=12,906), metformin + DPP-4i + sulfonylurea (n=2,551), metformin + SGLT2i + GLP-1-RA (n=1,823), and metformin + GLP-1-RA + basal insulin (n=4,921). Researchers adjusted their cox regression models for age, sex, duration of diabetes, history of chronic kidney disease (CKD), history of non-fatal MACE, treatment start date, medication use (statins, antihypertensives, and antithrombotics), and socioeconomic factors.  

All of the regimens showed statistically significant risk reductions in MACE, severe hypoglycemia, and all-cause mortality in comparison to metformin + sulfonylurea except metformin + basal insulin, which had a higher risk of severe hypoglycemia (HR: 1.09, CI:0.93-1.29, p=0.2832). Regimens that included a GLP-1-RA or SGLT2i had lower risk in all categories compared to other regimens. In comparing metformin + GLP-1-RA to metformin + SGLT2i, metformin + GLP-1-RA showed a slight advantage in the risk of MACE (HR: 0.51 versus 0.67). Importantly, the number of users of the metformin + SGLT2i was nearly half that of the metformin + GLP-1-RA group (n=3,405 versus n=6,515) resulting in a full confidence interval potentially providing a statistical advantage to the metformin + GLP-1-RA group. The addition of a GLP-1-RA to metformin + basal insulin decreased the risk of severe hypoglycemia (HR: 0.47 versus 1.09). In the subgroup analysis of time to MACE for patients with and without a high risk of cardiovascular disease, all the regimens reduced the risk for patients with high risk. Still, only metformin + GLP-1-RA showed statistical significance. 

One of the limitations of this study is that results were not stratified by individual drugs, but instead analyzed by class. While analyzing by class allows one to make broad generalizations, drugs within a class may exhibit different effects. Analyzing by class may, in part, explain why the results of this study contradict the results of the EMPA-REG OUTCOME trial, which showed a significant reduction in MACE in patients who were at high cardiovascular risk treated with empagliflozin. In contrast, this study, where 50% of the patients in the metformin + SGLT2i group were on dapagliflozin, did not show significant risk reduction for MACE in the metformin +SGLT2i group, a difference potentially owed to drugs within the same class exhibiting different effects. Another limitation is the lack of GFR data to determine the severity of CKD. CKD, a risk factor for MACE, severe hypoglycemia, and all-cause mortality, is an indication for SGLT2is. The study only accounting for CKD requiring hospitalization may have resulted in an overrepresentation of CKD  in the SGLT2i group. 

Clinically speaking, two points stand out from this study. First, compared to other regimens, metformin + sulfonylurea showed an increased risk for MACE, severe hypoglycemia, and all-cause mortality, providing strong evidence that a sulfonylurea is not the best option for a second-line agent. Second, adding a GLP-1-RA to metformin + basal insulin regimen resulted in a substantial decrease in the risk of severe hypoglycemia, indicating it would be prudent to do so in practice. 

Practice Pearls: 

• Metformin plus a sulfonylurea showed an increased risk for MACE, severe hypoglycemia, and all-cause mortality compared to all other regimens in the study. 
• Addition of a GLP-1-RA to metformin plus basal insulin regimen resulted in decreased severe hypoglycemia, potentially due to decreased basal insulin requirements. 
• In the risk reduction of MACE, a GLP-1-RA regimen showed a slight advantage over an SGLT2i regimen. 

Reference for “Study Provides Insight Into Dual and Triple Therapy Options for Diabetes”:
Jensen, Morten Hasselstrøm et al. “Risk of Major Adverse Cardiovascular Events, Severe Hypoglycemia, and All-Cause Mortality for Widely Used Antihyperglycemic Dual and Triple Therapies for Type 2 Diabetes Management: A Cohort Study of All Danish Users.“ Diabetes care vol. 43,6 (2020): 1209-1218. doi:10.2337/dc19-2535 

David Clarke, PharmD Candidate, University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences 

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