Does this antihyperglycemic combination medication need to be added to a formulary?
Diabetes Mellitus (DM) is a heterogeneous group of metabolic disorders characterized by hyperglycemia, the presence of insulin resistance, and inadequate compensatory insulin secretion. Type 2 diabetes accounts for 90% of all cases of DM. Risk factors include family history, obesity, and a hemoglobin A1C 5.7% to 6.4%. In 2010, 26 million Americans 20 and older had DM, and it contributes to 65,000 lower-extremity amputations annually.
Dapagliflozin/saxagliptin is a combination sodium-glucose cotransporter 2 inhibitor and a dipeptidyl peptidase-4 inhibitor, approved by the FDA on February 28, 2017. It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 DM who have inadequate control with dapagliflozin or are already treated with dapagliflozin and saxagliptin. It is a fixed-dose combination of 10 mg dapagliflozin/5 mg saxagliptin by mouth every day, with or without food, and it is not to be cut/split. The limitations of use are that it is not indicated for type 1 DM or diabetic ketoacidosis and should only be used in patients who tolerate 10 mg dapagliflozin.
Mechanisms of Action:1
Dapagliflozin/saxagliptin combines 2 antihyperglycemic agents to improve glycemic control.
Dapagliflozin is a sodium glucose co-transporter 2 inhibitor. It reduces reabsorption of filtered glucose and lowers the renal threshold for glucose, resulting in increased urinary glucose excretion.
Saxagliptin is a dipeptidyl-peptidase-4 inhibitor. It slows the inactivation of the incretin hormones, causing a rise in incretin bloodstream concentrations, which leads to reduced fasting and postprandial glucose concentrations. It also causes an increase in insulin release from the pancreatic beta cells and a decrease in glucagon secretion from the pancreatic alpha cells.
Dapagliflozin has a time to max concentration of 2 hours, is 78% bioavailable, 91% protein-bound, and a high-fat diet reduces Cmax by up to 50%. It is metabolized via UGT1A1 to an inactive glucuronide metabolite and has a T1/2 = 12.9 hours.
Saxagliptin has a time to max concentration of 2 hours, 78% bioavailable, negligible protein binding, and a high-fat diet increases Tmax by 20 minutes and increases AUC by 27%. It is metabolized primarily by CYP P450 3A4/5, and a major metabolite is also a DPP-4 inhibitor, which is half as potent as saxagliptin. Saxagliptin has a T1/2 = 2.5 hours and has 24% urinary excretion.
Contraindications and Adverse Events:1
Dapagliflozin/saxagliptin is contraindicated in patients with a history of serious hypersensitivity reaction to dapagliflozin or saxagliptin and moderate to severe renal impairment (eGFR < 45 mL/min/1.73 m2), end-stage renal disease, or dialysis. Do not initiate if eGFR is below 60 mL/min/1.73 m2, and discontinue the medication if eGFR falls presistently below 60 mL/min/1.73 m2. Additionally, because saxagliptin is a CYP P450 3A4/5 substrate, it is important to not coadminister dapagliflozin/saxagliptin with strong CYP P450 3A4/5 inhibitors.
The most common adverse effects include: upper respiratory infections (13.6%), urinary tract infections (5.7%), and dyslipidemia (5.1%). This medication is not recommended in the second and third trimesters of pregnancy, and acute kidney injury may be caused by volume depletion. Bullous pemphigold has been reported with DPP-4 inhibitors, so patients must be counseled to reporting blisters or erosions.
The Savor trial was a multi-center, multi-national, randomized, double-blinded trial that looked at patients who had type 2 DM, were high risk for atherosclerotic cardiovascular disease, were at least 40 years of age, and had an HbA1c ≥ 6.5%. There were two intervention arms: Saxagliptin (N = 8280) and placebo (N = 8212). The primary endpoint of this trial was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal ischemic stroke. There were 269 deaths from cardiovascular causes (3.2%) in the saxagliptin group, versus 260 deaths (2.9%) in the placebo group, with a hazards ratio of 1.03 (95% CI [0.87, 1.22]; p-value 0.15).The risk of deaths from cardiovascular mortality was not statistically significant. However, more patients in the saxagliptin group than in the placebo group were hospitalized for heart failure (3.5% versus. 2.8%; hazard ratio, 1.27; 95% CI, 1.07 to 1.51; P=0.007).
In a trial by Rosenstock, 2015, the efficacy and safety of triple therapy with the novel combination of dual add-on with saxagliptin plus dapagliflozin to metformin, compared with saxagliptin add-on alone or dapagliflozin add-on alone to metformin was assessed. This was a 24-week, multi-center, randomized, double-blind, active-controlled, parallel-group, phase 3 study. There were 3 study arms: Saxagliptin (SAXA) 5 mg/day Plus Dapagliflozin (DAPA) 10 mg/day [N = 179], SAXA 5 mg/day AND Placebo [N = 176], and DAPA 10 mg/day AND Placebo [N = 179]. The primary endpoint was the changes from baseline in HbA1c with SAXA+DAPA+MET versus SAXA+MET and DAPA+MET after 24 weeks. Adjusted mean change from baseline in the saxagliptin/dapagliflozin combination group was -1.47%, compared with -0.88% in the saxagliptin group and -1.20% in the dapagliflozin group. The results from the combination study showed that patients treated with saxagliptin/dapagliflozin plus metformin achieved significantly greater reductions in HbA1c, versus either agent alone, plus metformin after 24 weeks. However, the A1c reductions are not additive. Greater reductions were seen in patients with > 9% a1c and younger than 65. There were no events of major hypoglycemia. Urinary tract infections were more common in the SAXA+MET (5%) and DAPA+MET (4%) groups than in the SAXA+DAPA+MET (0.6%) group. The limitations of this study are that it was carried out for just 24 weeks, so the long-term benefits or safety concerns are unknown and there was a low representation of nonwhite people. The strengths include that it stratified results based on HbA1c levels, compared HbA1c reductions between study arms, and showed that triple therapy may result in fewer adverse effects than dual therapy.
One of the major benefits of marketing combination medications is the improvement to medication adherence. Switching a patient from individual dapagliflozin and saxagliptin would reduce the pill burden. However, it also raises concerns. It requires patients to discontinue the dapagliflozin component and continue individual metformin along with dapagliflozin/saxagliptin (Qtern). This would require diligence on the part of health care providers to ensure that the proper agents are continued and discontinued to ensure optimal therapy. The potential for heart failure or pancreatitis would require monitoring if started on Qtern without individual saxagliptin. In addition, cost is a concern. Per the pharmacy benefit manager of BlinkHealth, Kombiglyze XR 60 tablets 2.5 mg-1000mg is $403, Farxiga 10 mg 30 tablets is $450.81, Onglyza 5 mg 30 tablets is $403.42, and Xigduo XR 60 tablets 5 mg-1000mg is $450.81. The pricing information is not yet available for Qtern. Paying the increased cost of a new combination medication may not be clinically worth the slight reduction in A1c.
There are other antihyperglycemic combination medications on the market, such as metformin/dapagliflozin (Xigduo XR), metformin/saxagliptin (Kombiglyze XR), and metformin/sitagliptin (Janumet). From a cost perspective, Dapagliflozin/Saxagliptin (Qtern) does not need to be added to a formulary. Dapagliflozin/saxagliptin (Qtern) could potentially be used if a patent cannot tolerate the gastrointestinal adverse effects of metformin or lactic acidosis.
1. Qtern [prescribing information]. Wilmington, DE. AstraZeneca Pharmaceuticals, LP; 2017. accessdata.fda.gov/drugsatfda_docs/label/2017/209091s000lbl.pdf. Accessed October 12, 2017.
2. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317-26. doi: 10.1056/NEJMoa1307684.
3. Rosenstock J, Hansen L, Zee P, et al. Dual add-on therapy in type 2 diabetes poorly controlled with metformin monotherapy: a randomized double-blind trial of saxagliptin plus dapagliflozin addition versus single addition of saxagliptin or dapagliflozin to metformin. Diabetes Care. 2015;38(3):376-83. doi: 10.2337/dc14-1142.