Sitagliptin and metformin

Also see individual agents.

1% to 10%:

Central nervous system: Headache (6%)

Gastrointestinal: Diarrhea (8%), nausea (5%), abdominal pain (3%), vomiting (2%)

Respiratory: Upper respiratory tract infection (6%)

<1% (Limited to important or life-threatening): Hypersensitivity reaction (including anaphylaxis, angioedema, skin rash, urticaria, hypersensitivity angiitis, exfoliative skin conditions [including Stevens-Johnson syndrome]), lactic acidosis, pancreatitis (including hemorrhagic or necrotizing), pemphigoid, renal failure, renal insufficiency, severe arthralgia (FDA Safety Alert, Aug 28, 2015)

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio, and metformin plasma levels generally >5 mcg/mL.

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), age ≥65 years, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), 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 metformin-associated lactic acidosis is suspected, immediately discontinue sitagliptin/metformin and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

Concerns related to adverse effects:

• Arthralgia: Severe and disabling arthralgia has been reported with DPP-IV inhibitor use; onset may occur within one day to years after treatment initiation and may resolve with discontinuation of therapy. Some patients may experience a recurrence of symptoms if DPP-IV inhibitor therapy resumed.

• Bullous pemphigoid: DPP-4 inhibitor use has been associated with development of bullous pemphigoid; cases have typically resolved with topical or systemic immunosuppressive therapy and discontinuation of DPP-4 inhibitor therapy. Advise patients to report development of blisters or erosions. Discontinue therapy if bullous pemphigoid is suspected and consider referral to a dermatologist.

• Hypersensitivity reactions: Rare hypersensitivity reactions (including anaphylaxis, angioedema and/or severe dermatologic reactions, such as Stevens-Johnson syndrome) have been reported in postmarketing surveillance; discontinue if signs/symptoms of hypersensitivity reactions occur. Events have generally been noted within the first 3 months of therapy, and may occur with the initial dose. Use with caution if patient has experienced angioedema with other DPP-IV inhibitor use.

• Lactic acidosis: [US Boxed Warning]: Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset is often subtle, accompanied by nonspecific symptoms (eg, malaise, myalgias, respiratory distress, somnolence, abdominal pain); elevated blood lactate levels (>5 mmol/L); anion gap acidosis (without evidence of ketonuria or ketonemia); increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Risk factors for lactic acidosis include patients with renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), ≥65 years, having a radiologic study with contrast, surgery and other procedures, hypoxic states (eg, acute heart failure), excessive alcohol intake, and hepatic impairment. Discontinue immediately if acidosis is suspected; prompt hemodialysis is recommended. Lactic acidosis should be suspected in any patient with diabetes receiving metformin with evidence of acidosis but without evidence of ketoacidosis. Discontinue metformin in patients with conditions associated with dehydration, hypoperfusion, sepsis, or hypoxemia. Temporarily discontinue therapy in patients with restricted food and fluid intake. The risk of accumulation and lactic acidosis increases with the degree of impairment of renal function.

• Pancreatitis: Cases of acute pancreatitis (including hemorrhagic and necrotizing with some fatalities) have been reported with use. Monitor for signs/symptoms of pancreatitis; discontinue use immediately if pancreatitis is suspected and initiate appropriate management. Use with caution in patients with a history of pancreatitis as it is not known if this population is at greater risk.

• Vitamin B12 concentrations: Long-term metformin use is associated with vitamin B12 deficiency; monitor vitamin B12 serum concentrations periodically with long-term therapy. Monitoring of B12 serum concentrations should be considered in all patients receiving metformin and in particular those with peripheral neuropathy or anemia (ADA 2017c).

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with congestive heart failure requiring pharmacologic management, particularly in patients with unstable acute heart failure; risk of lactic acidosis may be increased secondary to hypoperfusion. In one large randomized, double-blinded trial in patients with type 2 diabetes and established cardiovascular disease (history of major CAD, ischemic cerebrovascular disease, or atherosclerotic peripheral arterial disease), the occurrence of the primary composite cardiovascular outcome (cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina) with sitagliptin was found to be noninferior to placebo. In addition, the rate of hospitalization for heart failure did not differ between the two groups (Green 2015). In a scientific statement from the American Heart Association, sitagliptin has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: major) (AHA [Page 2016]).

• Hepatic impairment: Use is not recommended in patients with hepatic impairment due to potential for lactic acidosis.

• Renal impairment: Metformin is substantially excreted by the kidney; use is contraindicated in patients with eGFR <30 mL/minute/1.73 m2. Use of concomitant medications that may affect renal function (ie, affect tubular secretion) may also affect metformin disposition. Metformin should be withheld in patients with dehydration and/or prerenal azotemia.

• Stress-related states: It may be necessary to discontinue metformin and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage forms specific issues:

• Extended release tablet: Incompletely dissolved tablets passed in stool have been reported; assess the adequacy of glycemic control in patients who repeatedly observe tablets in their stool.

Special populations:

• Elderly: Use with caution; risk of metformin associated lactic acidosis increases with age.

Other warnings/precautions:

• Appropriate use: Not indicated for use in patients with insulin-dependent diabetes mellitus (IDDM) (type 1) or in patients with diabetic ketoacidosis (DKA).

• Ethanol use: Instruct patients to avoid excessive acute or chronic ethanol use; ethanol may potentiate metformin's effect on lactate metabolism.

• Iodinated contrast: Discontinue metformin at the time of or before iodinated contrast imaging procedures in patients with an eGFR 30 to 60 mL/minute/1.73 m2; or with a history of hepatic disease, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast. Reevaluate eGFR 48 hours after imaging procedure; restart if renal function is stable. Alternatively, the American College of Radiology (ACR) guidelines recommend that metformin may be used prior to or following administration of iodinated contrast media in patients with no evidence of acute kidney injury (AKI) and with an eGFR ≥30 mL/minute/1.73 m2; ACR guidelines recommend temporary discontinuation of metformin in patients with known AKI or severe chronic kidney disease (stage IV or V [ie, eGFR <30 mL/minute/1.73 m2]) or who are undergoing arterial catheter studies (ACR 2015).

• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.

• Surgical procedures: Metformin should be withheld 24 hours before surgery (all other oral hypoglycemic agents should be withheld the morning of surgery or procedure) (ADA 2017d). Resume only after normal intake resumed and normal renal function is verified.

Animal reproduction studies have not been conducted with this combination. See individual agents.

Health professionals are encouraged to report any prenatal exposure to sitagliptin/metformin combination by contacting Merck’s pregnancy registry (1-800-986-8999).