ADA/EASD: General recommendations for choosing antihyperglycemic therapy in type 2 diabetes1

Individualization of treatment

  • Recommendations should be considered within the context of a patient's needs, preferences, and tolerances

Several patient-specific factors should be considered, including:

  • Patient attitude and expected treatment efforts
  • Risks potentially associated with hypoglycemia or other adverse events
  • Disease duration
  • Life expectancy
  • Comorbidities

ADA/EASD General Recommendations for Choosing Antihyperglycemic Therapy in Type 2 Diabetes

American Diabetes Association Diabetes Care, American Diabetes Association, 2015. Copyright and all rights reserved. Material from this publication has been used with the permission of American Diabetes Association.

Antihyperglycemic therapy in type 2 diabetes: general recommendations. Potential sequences of antihyperglycemic therapy for patients with type 2 diabetes are displayed, the usual transition being vertical, from top to bottom (although horizontal movement within therapy stages is also possible, depending on the circumstances). In most patients, begin with lifestyle changes; metformin monotherapy is added at, or soon after, diagnosis, unless there are contraindications. If the A1C target is not achieved after approximately 3 months, consider 1 of the 6 treatment options combined with metformin: an SU, TZD, DPP-4-i, SGLT2-i, GLP-1-RA, or basal insulin. (The order in the chart, not meant to denote any specific preference, was determined by the historical availability of the class and route of administration, with injectables to the right and insulin to the far right.) Drug choice is based on patient preferences as well as various patient, disease, and drug characteristics, with the goal being to reduce glucose concentrations while minimizing side effects, especially hypoglycemia. The figure emphasizes drugs in common use in the U.S. and/or Europe. Rapid-acting secretagogues (meglitinides) may be used in place of SUs in patients with irregular meal schedules or who develop late postprandial hypoglycemia on an SU. Other drugs not shown (α-glucosidase inhibitors, colesevelam, bromocriptine, pramlintide) may be tried in specific situations (where available), but are generally not favored because of their modest efficacy, the frequency of administration, and/or limiting side effects. In patients intolerant of, or with contraindications for, metformin, consider initial drug from other classes depicted under "Dual therapy" and proceed accordingly. In this circumstance, while published trials are generally lacking, it is reasonable to consider 3-drug combinations that do not include metformin. Consider initiating therapy with a dual combination when A1C is ≥9% (≥75 mmol/mol) to more expeditiously achieve target. Insulin has the advantage of being effective where other agents may not be and should be considered a part of any combination regimen when hyperglycemia is severe, especially if the patient is symptomatic or if any catabolic features (weight loss, any ketosis) are evident. Consider initiating combination injectable therapy with insulin when blood glucose is ≥300–350 mg/dL (≥16.7–19.4 mmol/L) and/or A1C ≥10%–12% (≥86–108 mmol/mol). Potentially, as the patient’s glucose toxicity resolves, the regimen can be subsequently simplified.

aConsider initial therapy at this stage when A1C is ≥9% (≥75 mmol/mol); bConsider initial therapy at this stage when blood glucose is ≥300–350 mg/dL (≥16.7–19.4 mmol/L) and/or A1C ≥10%–12% (≥86–108 mmol/mol), especially if patient is symptomatic or if catabolic features (weight loss, ketosis) are present, in which case basal insulin + mealtime insulin is the preferred initial regimen; cUsually a basal insulin (eg, NPH, glargine, detemir, degludec).

ADA = American Diabetes Association; EASD = European Association for the Study of Diabetes; SU = sulfonylurea; TZD = thiazolidinedione; DPP-4-i = dipeptidyl peptidase-4 inhibitor; SGLT2-i = sodium-glucose cotransporter 2 inhibitor; GLP-1-RA = glucagon-like peptide-1 receptor agonist; NPH = neutral protamine hagedorn.

Reference: 1. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140–149.

Selected Important Risk Information About JANUMET® (sitagliptin and metformin HCI) tablets

WARNING: LACTIC ACIDOSIS

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/Liter), 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 old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

If metformin-associated lactic acidosis is suspected, immediately discontinue JANUMET and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

JANUMET is contraindicated in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] below 30 mL/min/1.73 m2); hypersensitivity to metformin hydrochloride; acute or chronic metabolic acidosis, including diabetic ketoacidosis; or history of a serious hypersensitivity reaction to JANUMET or sitagliptin (one of the components of JANUMET), such as anaphylaxis or angioedema.

Postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney.

Before initiating JANUMET, obtain an eGFR. JANUMET is contraindicated in patients with an eGFR below 30 mL/min/1.73 m2. JANUMET is not recommended in patients with an eGFR between 30 and <45 mL/min/1.73 m2 because these patients require a lower dosage of sitagliptin than what is available in the fixed combination product JANUMET. Obtain an eGFR at least annually in all patients taking JANUMET. In patients at increased risk for the development of renal impairment (eg, the elderly), renal function should be assessed more frequently.

The concomitant use of JANUMET with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation. Consider more frequent monitoring of patients.

The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.

Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop JANUMET at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart JANUMET if renal function is stable.

Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment. JANUMET should be temporarily discontinued while patients have restricted food and fluid intake.

Postmarketing cases of metformin-associated lactic acidosis have occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. Discontinue JANUMET if this occurs.

Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving JANUMET.

Patients with hepatic impairment have developed metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Avoid using JANUMET in patients with clinical or laboratory evidence of hepatic disease.

There have been postmarketing reports of acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, in patients taking JANUMET. After initiating JANUMET, observe patients carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue JANUMET and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while taking JANUMET.

There have been postmarketing reports of worsening renal function, including acute renal failure, sometimes requiring dialysis. Before initiating JANUMET, and at least annually thereafter, renal function should be assessed. In patients in whom development of renal dysfunction is anticipated, particularly in elderly patients, renal function should be assessed more frequently and JANUMET discontinued if evidence of renal impairment is present.

Use With Medications Known to Cause Hypoglycemia
Sitagliptin

When sitagliptin was used in combination with a sulfonylurea or insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or insulin. Patients also receiving insulin or an insulin secretagogue (eg, sulfonylurea) may require a lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia.

The incidence (and rate) of hypoglycemia based on all reports of symptomatic hypoglycemia were: 16.4% (0.82 episodes/patient-year) for sitagliptin 100 mg in combination with metformin and glimepiride, 0.9% (0.02 episodes/patient-year) for placebo in combination with metformin and glimepiride, 8.2% (0.61 episodes/patient-year) for placebo in combination with metformin and insulin, and 15.3% (0.98 episodes/patient-year) for sitagliptin in combination with metformin and insulin.

Metformin hydrochloride

Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects.

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, one of the components of JANUMET, such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiating sitagliptin, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUMET, assess for other potential causes for the event, and institute alternative diabetes treatment.

Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with JANUMET.

There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from 1 day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause of severe joint pain and discontinue drug if appropriate.

Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving JANUMET. If bullous pemphigoid is suspected, JANUMET should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUMET or any other antidiabetic drug.

In clinical studies, the most common adverse reactions reported, regardless of investigator assessment of causality, in ≥5% of patients treated with either sitagliptin in combination with metformin or placebo were as follows: diarrhea (7.5% vs 4.0%), upper respiratory tract infection (6.2% vs 5.1%), and headache (5.9% vs 2.8%). In patients treated with sitagliptin in combination with metformin and sulfonylurea or placebo in combination with metformin and sulfonylurea: hypoglycemia (16.4% vs 0.9%) and headache (6.9% vs 2.7%). In patients treated with sitagliptin in combination with metformin and insulin or placebo in combination with metformin and insulin: hypoglycemia (15.3% vs 8.2%). Other adverse events with an incidence of ≥5% included nasopharyngitis for sitagliptin monotherapy and diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache for metformin therapy.

Adverse reactions with sitagliptin in combination with metformin and rosiglitazone through Week 18 were: upper respiratory tract infection (sitagliptin, 5.5%; placebo, 5.2%) and nasopharyngitis (6.1%, 4.1%). Through Week 54 they were: upper respiratory tract infection (sitagliptin, 15.5%; placebo, 6.2%), nasopharyngitis (11.0%, 9.3%), peripheral edema (8.3%, 5.2%), and headache (5.5%, 4.1%).

Before prescribing JANUMET® (sitagliptin and metformin HCl) tablets, please read the accompanying Prescribing Information, including the Boxed Warning about lactic acidosis. The Medication Guide also is available.

DIAB-1080640-0005 01/15

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Important Information

JANUMET 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.

JANUMET should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

JANUMET has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while taking JANUMET.

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Selected Important Risk Information About JANUMET® (sitagliptin and metformin HCI) tablets

WARNING: LACTIC ACIDOSIS

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/Liter), 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 old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

If metformin-associated lactic acidosis is suspected, immediately discontinue JANUMET and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

JANUMET is contraindicated in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] below 30 mL/min/1.73 m2); hypersensitivity to metformin hydrochloride; acute or chronic metabolic acidosis, including diabetic ketoacidosis; or history of a serious hypersensitivity reaction to JANUMET or sitagliptin (one of the components of JANUMET), such as anaphylaxis or angioedema.

Postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney.

Before initiating JANUMET, obtain an eGFR. JANUMET is contraindicated in patients with an eGFR below 30 mL/min/1.73 m2. JANUMET is not recommended in patients with an eGFR between 30 and <45 mL/min/1.73 m2 because these patients require a lower dosage of sitagliptin than what is available in the fixed combination product JANUMET. Obtain an eGFR at least annually in all patients taking JANUMET. In patients at increased risk for the development of renal impairment (eg, the elderly), renal function should be assessed more frequently.

The concomitant use of JANUMET with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation. Consider more frequent monitoring of patients.

The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.

Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop JANUMET at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart JANUMET if renal function is stable.

Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment. JANUMET should be temporarily discontinued while patients have restricted food and fluid intake.

Postmarketing cases of metformin-associated lactic acidosis have occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. Discontinue JANUMET if this occurs.

Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving JANUMET.

Patients with hepatic impairment have developed metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Avoid using JANUMET in patients with clinical or laboratory evidence of hepatic disease.

There have been postmarketing reports of acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, in patients taking JANUMET. After initiating JANUMET, observe patients carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue JANUMET and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while taking JANUMET.

There have been postmarketing reports of worsening renal function, including acute renal failure, sometimes requiring dialysis. Before initiating JANUMET, and at least annually thereafter, renal function should be assessed. In patients in whom development of renal dysfunction is anticipated, particularly in elderly patients, renal function should be assessed more frequently and JANUMET discontinued if evidence of renal impairment is present.

Use With Medications Known to Cause Hypoglycemia
Sitagliptin

When sitagliptin was used in combination with a sulfonylurea or insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or insulin. Patients also receiving insulin or an insulin secretagogue (eg, sulfonylurea) may require a lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia.

The incidence (and rate) of hypoglycemia based on all reports of symptomatic hypoglycemia were: 16.4% (0.82 episodes/patient-year) for sitagliptin 100 mg in combination with metformin and glimepiride, 0.9% (0.02 episodes/patient-year) for placebo in combination with metformin and glimepiride, 8.2% (0.61 episodes/patient-year) for placebo in combination with metformin and insulin, and 15.3% (0.98 episodes/patient-year) for sitagliptin in combination with metformin and insulin.

Metformin hydrochloride

Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects.

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, one of the components of JANUMET, such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiating sitagliptin, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUMET, assess for other potential causes for the event, and institute alternative diabetes treatment.

Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with JANUMET.

There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from 1 day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause of severe joint pain and discontinue drug if appropriate.

Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving JANUMET. If bullous pemphigoid is suspected, JANUMET should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUMET or any other antidiabetic drug.

In clinical studies, the most common adverse reactions reported, regardless of investigator assessment of causality, in ≥5% of patients treated with either sitagliptin in combination with metformin or placebo were as follows: diarrhea (7.5% vs 4.0%), upper respiratory tract infection (6.2% vs 5.1%), and headache (5.9% vs 2.8%). In patients treated with sitagliptin in combination with metformin and sulfonylurea or placebo in combination with metformin and sulfonylurea: hypoglycemia (16.4% vs 0.9%) and headache (6.9% vs 2.7%). In patients treated with sitagliptin in combination with metformin and insulin or placebo in combination with metformin and insulin: hypoglycemia (15.3% vs 8.2%). Other adverse events with an incidence of ≥5% included nasopharyngitis for sitagliptin monotherapy and diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache for metformin therapy.

Adverse reactions with sitagliptin in combination with metformin and rosiglitazone through Week 18 were: upper respiratory tract infection (sitagliptin, 5.5%; placebo, 5.2%) and nasopharyngitis (6.1%, 4.1%). Through Week 54 they were: upper respiratory tract infection (sitagliptin, 15.5%; placebo, 6.2%), nasopharyngitis (11.0%, 9.3%), peripheral edema (8.3%, 5.2%), and headache (5.5%, 4.1%).

Before prescribing JANUMET® (sitagliptin and metformin HCl) tablets, please read the accompanying Prescribing Information, including the Boxed Warning about lactic acidosis. The Medication Guide also is available.