FDA Approves a Triple Therapy for Type 2 Diabetes in One Tablet 

More may be better unless it involves tablets. Trijardy XR is a newly approved, more straightforward way to treat type 2 diabetes.

A few days ago, the FDA approved Trijardy XR. A combination of three, previously approved medications, Trijardy XR combines empagliflozin, linagliptin, and metformin hydrochloride extended-release. Empagliflozin, a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, linagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, and metformin hydrochloride, a biguanide, are all agents used to treat type 2 diabetes. The advantage of combining these agents is that they each have a different mechanism of action, so they lower blood glucose in different ways. Empagliflozin helps decrease renal glucose reabsorption, thus increasing urinary glucose elimination. Linagliptin inhibits the breakdown of incretin peptides by inhibiting the DPP4 enzyme, allowing the incretin peptides to exert their effects longer, resulting in increased insulin release and decreased secretion of glucagon. Metformin works by reducing glucose production while increasing insulin sensitivity in the body’s tissues. Previously, metformin came in combination with either linagliptin or empagliflozin and linagliptin came in a combination product with empagliflozin. This new combination product combines all three in one tablet. 

Six hundred eighty-six patients with type 2 diabetes were enrolled in a double-blind, active-controlled study that looked at the safety and efficacy of empagliflozin 10 or 25 mg in combination with linagliptin 5 mg, as compared to the individual components. Patients had to be on at least 1500 mg of metformin per day, all of whom were inadequately controlled with an HbA1c from 7 to 10.5%. These patients were randomized into one of five treatment arms: empagliflozin 10 or 25 mg, linagliptin 5 mg, or linagliptin 5 mg in combination with either 10 or 25 mg empagliflozin as a fixed-dose combination tablet. At the end of the 24th week, patients on any combination of empagliflozin with linagliptin had statistically significant improvements in HbA1c (P < 0.0001) and fasting blood glucose (P < 0.001) when compared to the individual medications. The combination also resulted in a significant reduction in body weight (P < 0.0001) when compared to the arm that received linagliptin 5mg, though there was no significant difference when compared to empagliflozin alone. For any patient receiving empagliflozin, the percent decrease in body weight ranged from 3 to 3.5%. The combination of empagliflozin 10 mg with linagliptin 5 mg resulted in an improvement of HbA1c of 1.1% and the combination of empagliflozin 25 mg with linagliptin 5 mg resulted in an A1c decrease of 1.2%, with 58 and 62% of patients achieving an A1c of <7%, respectively. Empagliflozin 10 and 25 mg resulted in meeting an A1c of <7 in 28 and 33% of people, respectively, while linagliptin 5 mg resulted in 36% of participants meeting that same cut-off. 

While the combination therapy is beneficial, it also combines adverse effects seen with each product. Thankfully, there were no additional adverse effects observed. Some of the possible side effects include lactic acidosis, pancreatitis, heart failure (DPP4 inhibitors have a class warning for this), hypotension, acute kidney injury, hypersensitivity reactions, and ketoacidosis. Again, these are all side effects of the individual medications, so prescribing the combination product should include counseling on each medication contained in the combination product. The contraindications are eGFR <30 mL/min/1.73m², end-stage renal disease, or on dialysis; metabolic acidosis, including diabetic ketoacidosis; or hypersensitivity to empagliflozin, linagliptin, metformin, or any of the excipients used. The prescription information of Trijardy XR also includes a black box warning for lactic acidosis due to the metformin. While the side effects of each drug are included, so are the benefits. Aside from type 2 diabetes, empagliflozin is also indicated to reduce the risk of cardiovascular death in adults with type 2 diabetes and with established cardiovascular disease. The inclusion of empagliflozin resulted in a net decrease in weight when taking Trijardy XR. The most common side effects of this combination product were: Upper respiratory tract infection, urinary tract infection, nasopharyngitis, diarrhea, constipation, headache, and gastroenteritis. Hypoglycemia occurred in 0.7% of patients receiving any strength of Trijardy XR with no events of severe hypoglycemia. 

While it is convenient to have three medications in one tablet, any newly approved drug is likely to come with a steep price tag, so it may be cheaper to take all three separately. Trijardy XR is an extended-release so it should be swallowed whole, not crushed or chewed. With any medication, diet, and lifestyle changes should be discussed, and this product is no different – it is meant as an adjunct to diet and lifestyle changes. 

Trijardy XR comes in four different doses: 

• Empagliflozin 25 mg, linagliptin 5 mg, and metformin HCl 1,000 mg 
• Empagliflozin 12.5 mg, linagliptin 2.5 mg, and metformin 1,000HCl mg 
• Empagliflozin 10 mg, linagliptin 5 mg, and metformin 1,000 HCl mg 
• Empagliflozin 5 mg, linagliptin 2.5 mg, and metformin 1,000 HCl mg 

Practice Pearls 

• A1c was reduced by 1.1 or 1.2% using the combination of empagliflozin 10 mg with linagliptin 5 mg or empagliflozin 25mg with linagliptin 5 mg, respectively.  
• There were no new side effects or safety concerns with this combination tablet when compared to the individual medications taken together. 
• This medication may be preferred if patients have a hard time taking multiple prescriptions. 
• Hypoglycemia occurred in 0.7% of patients given Trijardy XR, with no incidences of severe hypoglycemia.  

“Glucophage Full Prescribing Information.” Accessdata.Fda.Gov, 2018, https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020357s034,021202s018lbl.pdf.  

“Jardiance Full Prescribing Information.” Accessdata.Fda.Gov, 2020, https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/204629s023lbl.pdf. 

PR Newswire. US FDA Approves Only Triple-Combination Tablet With Jardiance® For Adults With Type 2 Diabetes. 2020, https://www.prnewswire.com/news-releases/us-fda-approves-only-triple-combination-tablet-with-jardiance-for-adults-with-type-2-diabetes-300993928.html.  

“Tradjenta Full Prescribing Information”. Accessdata.Fda.Gov, 2019, https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/201280s021lbl.pdf. 

“Trijardy XR Full Prescribing Information.” Accessdata.Fda.Gov, 2020, https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212614s000lbl.pdf 

Zinman, Bernard et al. “Empagliflozin, Cardiovascular Outcomes, And Mortality In Type 2 Diabetes”. New England Journal Of Medicine, vol 373, no. 22, 2015, pp. 2117-2128. Massachusetts Medical Society, doi:10.1056/nejmoa1504720.  

George McConnell, PharmD. Candidate, LECOM School of Pharmacy