General Information

Trijardy XR is a combination of empagliflozin - a sodium-glucose cotransporter 2 (SGLT2) inhibitor, linagliptin- a dipeptidyl peptidase-4 (DPP-4) inhibitor and metformin hydrochloride (HCl) - a biguanide.

Trijardy XR is specifically indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Trijardy XR is supplied as an extended release table for oral administration. Prior to Initiation of Trijardy XR assess renal function and periodically thereafter. In patients with volume depletion, correct this condition prior to initiation of Trijardy XR. Recommended Dosage: Individualize the starting dose of Trijardy XR based on the patient’s current regimen:

• In patients on metformin HCl, with or without linagliptin, switch to Trijardy XR containing a similar total daily dose of metformin HCl and a total daily dose of empagliflozin 10 mg and linagliptin 5 mg;
• In patients on metformin HCl and any regimen containing empagliflozin, with or without linagliptin, switch to Trijardy XR containing a similar total daily dose of metformin HCl, the same total daily dose of empagliflozin and linagliptin 5 mg.

Monitor effectiveness and tolerability, and adjust dosing as appropriate, not to exceed the maximum recommended daily dose of empagliflozin 25 mg, linagliptin 5 mg and metformin HCl 2000 mg.

Take Trijardy XR orally, once daily with a meal in the morning.

• Take Trijardy XR 10 mg/5 mg/1000 mg or Trijardy XR 25 mg/5 mg/1000 mg as a single tablet once daily.
• Take Trijardy XR 5 mg/2.5 mg/1000 mg or Trijardy XR 12.5 mg/2.5 mg/1000 mg as two tablets together once daily.

Swallow Trijardy XR tablets whole. Do not split, crush, dissolve, or chew.

Mechanism of Action

Trijardy XR is a combination of empagliflozin, linagliptin and metformin. 

• Empagliflozin: Empagliflozin is a sodium-glucose co-transporter 2 (SGLT2) is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation.  Empagliflozin is an inhibitor of SGLT2.  By inhibiting SGLT2, empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.
• Linagliptin: Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).  Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the levels of glucagon in the circulation.  Both incretin hormones are involved in the physiological regulation of glucose homeostasis.  Incretin hormones are secreted at a low basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells in the presence of normal and elevated blood glucose levels.  Furthermore, GLP-1 also reduces glucagon secretion from pancreatic alpha cells, resulting in a reduction in hepatic glucose output.
• Metformin HCl: Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose.  Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.  With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

Side Effects

Adverse effects associated with the use of Trijardy XR may include, but are not limited to, the following:

• upper respiratory tract infection
• urinary tract infection
• nasopharyngitis
• diarrhea
• constipation
• headache
• gastroenteritis

Trijardy XR comes with the following Black Box warning: Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain.  Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL. Risk factors include renal impairment, concomitant use of certain drugs, age ≥65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information. If lactic acidosis is suspected, discontinue Trijardy XR and institute general supportive measures in a hospital setting.  Prompt hemodialysis is recommended.

Clinical Trial Results

The FDA approval of Trijardy XR was based on the following trials:

 Empagliflozin and Linagliptin Add-on Combination Therapy with Metformin for Glycemic Control

A total of 686 patients with type 2 diabetes participated in a double-blind, active-controlled study to evaluate the efficacy and safety of empagliflozin 10 mg or 25 mg in combination with linagliptin 5 mg, compared to the individual components. Patients with type 2 diabetes inadequately controlled on at least 1500 mg of metformin per day entered a single blind placebo run-in period for 2 weeks. At the end of the run-in period, patients who remained inadequately controlled and had an HbA1c between 7 and 10.5% were randomized 1:1:1:1:1 to one of 5 active-treatment arms of empagliflozin 10 mg or 25 mg, linagliptin 5 mg, or linagliptin 5 mg in combination with 10 mg or 25 mg empagliflozin as a fixed dose combination tablet.
 
At Week 24, empagliflozin 10 mg or 25 mg used in combination with linagliptin 5 mg provided statistically significant improvement in HbA1c and FPG compared to the individual components in patients who had been inadequately controlled on metformin. Treatment with empagliflozin 10 mg or 25 mg used in combination with linagliptin 5 mg also resulted in a statistically significant reduction in body weight compared to linagliptin 5 mg. There was no statistically significant difference compared to empagliflozin alone.

Empagliflozin Cardiovascular Outcome Study in Patients with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease

Empagliflozin is indicated to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease.  The effect of empagliflozin on cardiovascular risk in adult patients with type 2 diabetes and established, stable, atherosclerotic cardiovascular disease is presented below.
 
The EMPA-REG OUTCOME study, a multicenter, multi-national, randomized, double-blind parallel group trial compared the risk of experiencing a major adverse cardiovascular event (MACE) between empagliflozin and placebo when these were added to and used concomitantly with standard of care treatments for diabetes and atherosclerotic cardiovascular disease.  Coadministered antidiabetic medications were to be kept stable for the first 12 weeks of the trial.  Thereafter, antidiabetic and atherosclerotic therapies could be adjusted, at the discretion of investigators, to ensure participants were treated according to the standard care for these diseases.
 
A total of 7,020 patients were treated (empagliflozin 10 mg = 2345; empagliflozin 25 mg = 2342; placebo = 2333) and followed for a median of 3.1 years.

The primary endpoint in EMPA-REG OUTCOME was the time to first occurrence of a Major Adverse Cardiac Event (MACE).  A major adverse cardiac event was defined as occurrence of either a cardiovascular death or a nonfatal myocardial infarction (MI) or a nonfatal stroke.  The statistical analysis plan had pre-specified that the 10 and 25 mg doses would be combined. Empagliflozin significantly reduced the risk of first occurrence of primary composite endpoint of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke.  The treatment effect was due to a significant reduction in the risk of cardiovascular death in subjects randomized to empagliflozin, with no change in the risk of non-fatal myocardial infarction or non-fatal stroke.  Results for the 10 mg and 25 mg empagliflozin doses were consistent with results for the combined dose groups.

Linagliptin Cardiovascular Safety Trial

The cardiovascular risk of linagliptin was evaluated in CARMELINA, a multi-national, multicenter, placebo-controlled, double-blind, parallel group trial comparing linagliptin (N=3494) to placebo (N=3485) in adult patients with type 2 diabetes mellitus and a history of established macrovascular and/or renal disease. The trial compared the risk of major adverse cardiovascular events (MACE) between linagliptin and placebo when these were added to standard of care treatments for diabetes and other cardiovascular risk factors. The trial was event driven, the median duration of follow-up was 2.2 years and vital status was obtained for 99.7% of patients.
 
Patients were eligible to enter the trial if they were adults with type 2 diabetes, with HbA1c of 6.5% to 10%, and had either albuminuria and previous macrovascular disease (39% of enrolled population), or evidence of impaired renal function by eGFR and Urinary Albumin Creatinine Ratio (UACR) criteria (42% of enrolled population), or both (18% of enrolled population).

The primary endpoint, MACE, was the time to first occurrence of one of three composite outcomes which included cardiovascular death, nonfatal myocardial infarction or nonfatal stroke. The study was designed as a non-inferiority trial with a pre-specified risk margin of 1.3 for the hazard ratio of MACE. The incidence rate of MACE in both treatment arms: 56.3 MACE per 1000 patient-years on placebo vs. 57.7 MACE per 1000 patient years on linagliptin.