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Another Oral Combination Antidiabetic Agent

Oct 24, 2020
 
Editor: Steve Freed, R.PH., CDE

Author: Melinda Rodriguez, PharmD Candidate 2021, Lake Erie College of Osteopathic Medicine – L|E|C|O|M School of Pharmacy

Dual and triple therapy just got a little easier with Steglujan, which combines the mechanisms of an SGLT2 inhibitor, ertugliflozin, and a DPP-4 inhibitor, sitagliptin. 

Many patients with diabetes struggle to reach glycemic control despite treatment with metformin, particularly those with higher HbA1c levels. Since the development of sodium-glucose cotransporter 2 (SGTL2) and dipeptidyl peptidase-4 (DPP-4) inhibitors, there have been many strides toward optimizing antidiabetic therapy in patients uncontrolled with metformin alone. Adherence to dual and triple oral therapy, however, remains an issue. A new drug, Steglujan, combines the complementary mechanisms of an SGLT2 inhibitor, ertugliflozin, and a DPP-4 inhibitor, sitagliptin, to achieve greater glycemic control with fewer tablets. Ertugliflozin reduces the reabsorption of glucose from the tubular lumen, thus increasing glucose excretion. In contrast, sitagliptin works by inhibiting the DPP-4 enzyme responsible for degrading incretins such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), resulting in greater insulin synthesis and release. Steglujan is available in two strengths: ertugliflozin 5 mg/sitagliptin 100 mg tablets or ertugliflozin 15 mg/sitagliptin 100 mg tablets. This combination tablet is indicated as an adjunct to diet and exercise in patients with type 2 diabetes mellitus (T2DM). 

Extensive research and clinical experience have established the efficacy of DPP-4 inhibitors. When used as monotherapy, this class of drugs can reduce HbA1c levels by 0.5 to 1%. DPP-4 inhibitors, such as sitagliptin, have favorable side effect profiles with low hypoglycemia and weight gain risks. Similarly, SGLT2 inhibitors have shown promising results in recent studies. Patients taking SGLT2 inhibitors as monotherapy may experience reductions in HbA1c levels of up to 1%. The Canadian Agency for Drugs and Technologies in Health (CADTH) published a systematic review of the beneficial and harmful effects of ertugliflozin 5 mg and 15 mg tablets on glycemic control in adult patients with T2DM. The data were obtained from five major drug trials. The studies were each phase three randomized controlled trials sponsored by Merck Sharp & Dohme Corp., in collaboration with Pfizer Inc. In terms of efficacy, ertugliflozin monotherapy was associated with significant reductions in HbA1c versus placebo. When added to metformin, the reductions were even more significant. The VERTIS MONO and VERTIS MET trials showed improved glycemic control, reduced body weight, and lower blood pressure in the ertugliflozin groups (regardless of strength) with or without metformin compared to placebo or metformin alone. Both studies, however, indicated an increased risk of genital mycotic infections in patients taking ertugliflozin.  

Researchers in the VERTIS SITA trials have found greater reductions in HbA1c levels in patients on ertugliflozin/sitagliptin-containing therapies. The SITA1 trial assessed the safety and efficacy of co-initiation of ertugliflozin and sitagliptin 100mg in patients with T2DM not controlled with diet and exercise. Patients were randomized on a 1:1:1 ratio to receive either ertugliflozin 5mg plus sitagliptin 100mg (E5/S100), ertugliflozin 15mg plus sitagliptin 100mg (E15/S100), or placebo. The least-square mean change in HbA1c from baseline was taken at week 26 for all 291 patients included. HbA1c changes for placebo, E5/S100 and E15/S100 were -0.4% (-0.7, -0.2), -1.6% (-1.8, -1.4), and -1.7% (-1.9, -1.5) respectively. Surprisingly, a higher percentage of patients reached HbA1c <7% in the E5/S100 group than the E15/S100 group (35.7% vs. 31.3%). The SITA2 trial showed that ertugliflozin added to metformin and sitagliptin had greater glycemic control, body weight, blood pressure reductions versus metformin sitagliptin combination. Finally, the VERTIS FACTORIAL trial compared the Effect of combination DPP-4 and SGLT2 inhibitor therapy added to metformin with each agent’s individual agent. As expected, results showed a greater reduction in HbA1c with co-administration of ertugliflozin and sitagliptin and a higher percentage of patients reaching HbA1c < 7%. The VERTIS CV trial analyzed the effects of ertugliflozin on the cardiovascular system. Results indicated that empagliflozin did not increase the risk of heart attack, stroke, or cardiac death in patients with type 2 diabetes. All trials found a higher rate of mycotic infections in patients using SGLT2 therapy. Nevertheless, the relative frequency of adverse events was similar among all groups.  

Although the VERTIS trials’ results are mostly positive, CADTH notes that due to the frequency of rescue and early discontinuation in placebo and ertugliflozin groups, the actual treatment effects for ertugliflozin may be overestimated. Other limitations include a lack of comparative efficacies between these and other DPP-4 and SGLT2 inhibitors and other oral antidiabetic agents. No new safety concerns were raised concerning either drug; however, the short duration of the VERTIS trials may not detect rare side effects. When balancing the risks and benefits of glycemic control, a patient-centered approach requires numerous considerations. One of which is the consequence of adverse effects. Genitourinary tract infections, hypovolemia, fractures, lower extremity amputations, and euglycemic diabetic ketoacidosis have all been reported with SGLT2 inhibitors. Some reports for acute pancreatitis with DPP4 inhibitors also raise a concern. Per the package insert, Steglujan is not indicated for treating type 1 diabetes or diabetic ketoacidosis. It has not been studied in patients with a history of pancreatitis. Steglujan is also contradicted in patients with severe renal impairment or end-stage renal disease, patients on dialysis, or a history of severe hypersensitivity reactions to any of the components. 

Practice Pearls: 

  • Patients that took ertugliflozin/sitagliptin as an add-on to metformin had greater HbA1C control than metformin alone. 
  • Patients taking ertugliflozin/sitagliptin did have an increased risk of developing genital mycotic infections. 
  • There was no significant increase risk of any other adverse effects in patients taking ertugliflozin/sitagliptin combination therapy than monotherapy. 

 

Ertugliflozin and Sitagliptin. Lexi-Drugs. Hudson, OH: Lexi-Comp, Inc. [Updated June 20, 2020; AccessedJune 29.

 Rosenstock J, Frias J, Páll D, et al. Effect of ertugliflozin on glucose control, body weight, blood pressure, and bone density in type 2 diabetes mellitus inadequately controlled on metformin monotherapy (VERTIS MET) Diabetes Obes Metab 

 

Melinda Rodriguez, PharmD Candidate 2021, Lake Erie College of Osteopathic Medicine – L|E|C|O|M School of Pharmacy