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Examining the Risks of Antihyperglycemic Dual and Triple Therapies for T2D 

Aug 29, 2020
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: Stephen Rubano, PharmD. Candidate, USF Taneja College of Pharmacy

A closer look at the risk of major adverse events, severe hypoglycemia, and all-cause mortality for commonly used therapies in treating type 2 diabetes.   

The typical first-line therapy recommended by the American Diabetes Association guidelines for the treatment of type 2 diabetes (T2D) is metformin and lifestyle modifications. However, for patients who fail to reach target HbA1c goals, guidelines recommend the addition of other glucose-lowering agents. Choosing an agent can make clinical decisions difficult as there are many available options. Understanding the risks and benefits of using these medications together is pivotal. Although previous studies illustrate the potential for more significant HbA1c reductions, prescribers remain cautious due to the increased risk of adverse events and drug interactions. For example, a study found that the use of sitagliptin with metformin was more efficacious compared to standard metformin monotherapy; in this case, dual therapy was well-tolerated. In contrast, pioglitazone addition to metformin therapy has been associated with adverse events such as increased weight gain in patients. Drug combination remains a point of interest with several ongoing randomized control trials testing the safety and efficacy of dual and triple agent therapies.


An article recently published in Diabetes Care provides new evidence on widely used diabetes regimens in Denmark. The cohort study, consisting of 66,807 patients with T2D, aimed to investigate the frequency of major cardiovascular events (MACE), severe hypoglycemia, and mortality in patients on dual or triple medication therapies. Study endpoints were defined as myocardial infarction, stroke, hypoglycemic episodes requiring hospitalization, and death. Using the Danish National Registry and Causes of Death databases, researchers analyzed time-to-event data through Cox proportional hazards models to estimate the effects of therapies. All models were adjusted for confounders such as age, sex, diabetes duration, and current medications. From the registry, eight of the most common regimens were selected, all of which included metformin. Dipeptidyl peptidase-4 inhibitors (DPP-4i), sulfonylurea, glucagon-like peptide-1 (GLP1), sodium-glucose cotransporter-2 inhibitors (SGLT2i), and basal insulins were among the most common therapies.  

Patients treated with metformin and sulfonylurea agents displayed the highest risk of adverse events and all-cause mortality. However, metformin plus basal insulin ranked highest in severe hypoglycemic episodes. As a result, the metformin plus sulfonylurea combination served as the reference group in calculating hazard ratios. Patients using dual or triple therapies using sulfonylurea agents displayed increased risks of MACE, hypoglycemia, and all-cause with hazard ratios of 0.89, 0.84, and 0.92, respectively. Patients taking metformin with DPP4i, SGLT2i, or GLP1 analogs had minimal risk of severe hypoglycemia with hazard ratios at or below 0.10 (95% CI, P < 0.05). MACE’s risk was lowest in patients treated with dual therapies, including GLP1 or SGLT2i, and triple therapies using SGLT2i, GLP1, and basal insulins. Likewise, all-cause mortality rates were reported lowest in therapies, including metformin plus SGLT2i or GLP1 with hazard ratios at or below 0.20 (95% CI, P < 0.001).    

Results from the study highlight the risks associated with using sulfonylureas as add-on therapy in comparison to other drug classes. Although this medication has proven to be highly effective in lowering blood glucose, its risk for hypoglycemia is well-documented. Additionally, the use of sulfonylurea agents with metformin and other anti-hyperglycemia drugs was associated with increased risks of MACE and all-cause mortality, likely secondary to hypoglycemic episodes and unstable glucose control. Evidence from the study suggests that if dual or triple therapy is necessary, the use of SGLT2i or GLP1 agonists in combination with metformin should be considered. These agents displayed much lower risk overall. 

Nevertheless, lowering HbA1c levels to goal remains the cornerstone of diabetes treatment aimed at delaying complications and improving patient outcomes. As diabetes is a progressive disease, there are no definitive answers to treatment. Ultimately, prescribers must exercise sound judgment in deciding the level of risk necessary to treat their patients.  

Practice Pearls: 

  • Danish cohort study compared the risk of using dual and triple antihyperglycemic therapies in patients with diabetes.    
  • Drug therapies using sulfonylurea agents had higher hazard ratios for cardiovascular events, hypoglycemia, and death.  
  • Drug therapies using metformin plus SGLT2i or GLP1 agonists showed a lower risk of adverse events than other combinations.  


  1. 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, no. 6, 2020, pp. 1209–18. doi:10.2337/dc19-2535. 
  2. Williams-Herman, D., et al. “Efficacy and Safety of Sitagliptin and Metformin as Initial Combination Therapy and as Monotherapy over 2 Years in Patients with Type 2 Diabetes.” Diabetes, Obesity, and Metabolism vol. 12, no. 5, 2010, pp. 442–51. doi:10.1111/j.1463-1326.2010.01204.x. 


Stephen Rubano, PharmD. Candidate, USF Taneja College of Pharmacy 


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