Introduction
Janumet XR is a fixed-dose combination medication containing sitagliptin (a dipeptidyl peptidase-4 inhibitor) and metformin hydrochloride extended-release (a biguanide). This oral antihyperglycemic agent is designed for the management of type 2 diabetes mellitus, offering the complementary mechanisms of both components in a convenient once-daily formulation.
Mechanism of Action
Janumet XR combines two antihyperglycemic agents with distinct mechanisms:
- Sitagliptin: Inhibits dipeptidyl peptidase-4 (DPP-4), increasing concentrations of active incretin hormones (GLP-1 and GIP). This enhances glucose-dependent insulin secretion and reduces glucagon secretion
- Metformin XR: Decreases hepatic glucose production, reduces intestinal glucose absorption, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization
Indications
Janumet XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both sitagliptin and metformin is appropriate.
Dosage and Administration
Recommended dosing: Individualized based on current regimen, effectiveness, and tolerability- Maximum daily dose: Sitagliptin 100 mg/metformin 2000 mg
- Administration: Taken once daily with evening meal to reduce gastrointestinal effects
- Dose titration: Gradually increase to minimize gastrointestinal side effects
- Renal impairment: Not recommended when eGFR <30 mL/min/1.73 m²
- Hepatic impairment: Avoid use in patients with hepatic disease
- Elderly: Use with caution due to potential decreased renal function
- Pediatric: Safety and effectiveness not established
Pharmacokinetics
Absorption:- Sitagliptin: Rapid absorption, Tmax 1-4 hours
- Metformin XR: Extended-release formulation, Tmax 7 hours
- Sitagliptin: 38% protein bound
- Metformin: Negligible protein binding
- Sitagliptin: Minimal hepatic metabolism (CYP450 not involved)
- Metformin: Not metabolized
- Sitagliptin: Renal excretion (87% unchanged), half-life ~12.4 hours
- Metformin: Renal excretion unchanged, half-life ~6.2 hours
Contraindications
- Severe renal impairment (eGFR <30 mL/min/1.73 m²)
- Metabolic acidosis, including diabetic ketoacidosis
- History of hypersensitivity to sitagliptin, metformin, or any component
- Acute or chronic metabolic acidosis
Warnings and Precautions
Boxed Warning: Lactic acidosis - rare but serious metabolic complication with metformin- Risk factors: Renal impairment, concomitant drugs affecting renal function, advanced age, radiologic contrast studies, hypoxemia, dehydration, sepsis
- Symptoms: Myalgia, respiratory distress, abdominal pain, hypothermia, hypotension, bradyarrhythmia
- Vitamin B12 deficiency: Long-term metformin use may decrease absorption
- Hepatic impairment: Avoid use
- Hypoglycemia: Increased risk when used with insulin or insulin secretagogues
- Pancreatitis: Postmarketing reports; discontinue if suspected
- Heart failure: Monitor for worsening signs/symptoms
- Macrovascular outcomes: Not established for reducing macrovascular risk
Drug Interactions
Major interactions:- Carbonic anhydrase inhibitors (topiramate, zonisamide): Increased lactic acidosis risk
- Alcohol: Potentiates metformin's effect on lactate metabolism
- Drugs that reduce renal function (NSAIDs, diuretics): Increase metformin accumulation
- Cationic drugs (amiloride, digoxin, morphine): May increase metformin levels
- Insulin secretagogues: Increased hypoglycemia risk
- Beta-blockers: May mask hypoglycemia symptoms
Adverse Effects
Common (≥5%):- Diarrhea
- Nausea
- Upper respiratory infection
- Headache
- Lactic acidosis
- Pancreatitis
- Hypersensitivity reactions (anaphylaxis, angioedema)
- Severe joint pain
- Hepatic impairment
- Vitamin B12 deficiency
Monitoring Parameters
- Glycemic control: HbA1c every 3 months until stable
- Renal function: eGFR at baseline and annually (more frequently if impaired)
- Vitamin B12: Periodic assessment with long-term therapy
- Lactic acidosis signs: Regular assessment of metabolic status
- Hepatic function: Baseline and periodic monitoring
- Pancreatitis symptoms: Abdominal pain, nausea, vomiting
Patient Education
- Take with evening meal to reduce gastrointestinal upset
- Report unusual muscle pain, breathing difficulties, or abdominal discomfort immediately
- Understand hypoglycemia symptoms and management
- Avoid excessive alcohol consumption
- Inform all healthcare providers about Janumet XR use before procedures
- Do not crush or chew tablets; swallow whole
- Report signs of infection or illness that may affect glucose control
- Continue dietary restrictions, physical activity, and regular glucose monitoring
- Recognize and report symptoms of pancreatitis: severe abdominal pain that may radiate to the back
References
1. FDA Prescribing Information: Janumet XR (sitagliptin and metformin HCl extended-release) tablets 2. American Diabetes Association. Standards of Medical Care in Diabetes - 2023. Diabetes Care 2023;46(Suppl 1) 3. Inzucchi SE, et al. Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2022;45(11):2753-2786 4. Golightly LK, et al. Dipeptidyl peptidase-4 inhibitors in type 2 diabetes mellitus. Pharmacotherapy 2017;37(3):351-372 5. ClinicalTrials.gov: Studies of sitagliptin/metformin combination therapy 6. Nathan DM, et al. Medical management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2009;32(1):193-203