Janumet XR
Janumet XR
Generic Name
Janumet XR
Mechanism
Sitagliptin
• Inhibits dipeptidyl peptidase‑4 (DPP‑4), prolonging the action of incretin hormones GLP‑1 and GIP.
• ↑ insulin secretion in a glucose‑dependent manner; ↓ glucagon release → reduced hepatic gluconeogenesis.
Metformin XR
• Inhibits hepatic gluconeogenesis via AMPK activation.
• ↓ intestinal glucose absorption and post‑prandial hyperglycemia.
• Enhances insulin sensitivity in peripheral tissues.
The two agents act synergistically: sitagliptin optimizes post‑prandial insulin secretion while XR metformin maintains basal glucose control.
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Pharmacokinetics
| Parameter | Sitagliptin | Metformin XR |
| Absorption | Rapid; oral bioavailability ≈ 87 % | Slow, extended release; Tmax 2–4 h |
| Tmax | ~0.5–1 h | 2–4 h |
| Protein binding | < 10 % | < 5 % |
| Half‑life | 8–12 h | 4–8 h |
| Metabolism | Minimal; mostly unchanged | None (renal elimination) |
| Excretion | Renal (≈ 80 %) | Renal (≈ 90 %) |
Renal function: both drugs are renally cleared; dose adjustments are required for creatinine clearance (CrCl) < 50 mL/min.
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Indications
- Type 2 Diabetes Mellitus: as monotherapy or add‑on to metformin, sulfonylurea, insulin, or other glucose‑lowering agents.
- T1DM: not indicated.
- HbA1c target: individualized, typically < 7 % (ADA/ADA guidelines).
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Contraindications
- Contraindications:
- Known hypersensitivity to sitagliptin, metformin, or excipients.
- Severe renal impairment (CrCl < 30 mL/min).
- Metabolic acidosis, including diabetic ketoacidosis.
- Warnings:
- Lactic acidosis risk: use caution in renal/hepatic dysfunction, heart failure, uncontrolled alcoholism, or sepsis.
- Hypoglycemia: occurs mainly when co‑administered with sulfonylureas or insulin; discontinue or reduce those agents.
- Renal adverse events: monitor for worsening renal function; avoid iodinated contrast in ≤ 30 mL/min.
- Pregnancy: category‑B; not recommended during lactation.
- Pancreatitis: rare but serious; discontinue if abdominal pain with lipase elevation.
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Dosing
1. Initiation – 50 mg sitagliptin + 1000 mg metformin XR once daily (typically in the morning).
2. Titration – if HbA1c not achieved after 3 months, increase metformin component to 2000 mg XR (still 50 mg sitagliptin).
3. Renal adjustment
• CrCl 30–50 mL/min: maintain 25 mg sitagliptin + 500/1000 mg metformin XR.
• CrCl < 30 mL/min: hold; consider alternative therapy.
4. Administration – with a meal; avoid alcohol.
5. No dose splitting – tablets must be taken whole.
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Adverse Effects
- Common
- Gastrointestinal: diarrhea, nausea, abdominal discomfort (≈ 10 %).
- Headache, nasopharyngitis.
- Weight neutral or modest loss.
- Serious
- Lactic acidosis: rare (< 1 in 10,000; fatal if untreated).
- Hypoglycemia: < 5 % when combined with sulfonylureas/insulin.
- Allergic reactions: rash, pruritus, anaphylaxis (rare).
- Pancreatitis: monitor lipase if abdominal pain.
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Monitoring
| Parameter | Frequency | Rationale |
| HbA1c | Every 3 months | Glycemic control |
| Fasting glucose | Every 2–3 weeks during titration | Dose adjustment |
| Serum creatinine/CrCl | Baseline, every 3 months (or more if renal disease) | Renal clearance |
| Liver function tests | Baseline, then annually | Metformin safe in mild hepatic dysfunction |
| Weight, BMI | Every visit | Monitor adiposity trends |
| Signs of lactic acidosis | At each visit; patient education on symptoms (myalgia, tachypnea, abdominal pain) | Early detection |
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Clinical Pearls
- Extended‑Release Advantage – XR metformin improves patient adherence by reducing dosing frequency and minimizing gastrointestinal side effects compared with immediate‑release formulations.
- Renal‑Safe Pairing – Sitagliptin’s minimal hepatic metabolism and low risk of hypoglycemia make Janumet XR attractive for patients with biventricular heart failure, where other agents might worsen fluid status.
- Dose Harmonization – Start with 1000 mg XR; only increase to 2000 mg if HbA1c remains > 7 % after 3 months to avoid excessive weight loss or GI upset.
- Pancreatitis Vigilance – Any persistent epigastric pain warrants pancreatitis work‑up; discontinue Janumet XR if lipase > 3× upper limit.
- Pregnancy Check – Although category B, maintain a pre‑conception counseling plan; transfer to alternative agents if conception is planned or occurs.
- Contrast‑Exposure Precaution – In patients with borderline CrCl, avoid iodinated contrast or delay Janumet XR dosing > 24 h post‑contrast to reduce lactic acidosis risk.
- Patient Education – Emphasize that sitagliptin alone has negligible hypoglycemia risk; extra caution only when added to insulin or sulfonylureas.
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• Key Takeaway: Janumet XR provides a convenient, once‑daily regimen that combines the proven glycemic benefits of metformin XR with the insulin‑secretagogue and glucagon‑reducing properties of sitagliptin. Proper renal monitoring and cautious use with other hypoglycemic agents mitigate most safety concerns, making it a cornerstone therapy for many adults with T2DM.