Fixed-Dose Combination of Metformin and Sitagliptin (JANUMET): A Bad Choice for Type 2 Diabetes

First approved by the Food and Drug Administration in 2007, the fixed-dose combination drug JANUMET is used in addition to diet and exercise to improve glycemic (blood sugar) control in adults with type 2 diabetes.[1] The tablets, composed of metformin (FORTAMET, GLUMETZA and generics) and sitagliptin (BRYNOVIN, JANUVIA, ZITUVIO), are taken orally twice daily with meals.

Janumet is one of 15 drugs in the current round of Medicare Part D price negotiations by the Centers for Medicare and Medicaid Services.[2] The negotiated prices will go into effect in 2027.

In 2022 the wholesale price for a one-month supply of Janumet was about $521, compared with $2.70 for generic metformin and about $521 for brand-name sitagliptin. In January 2026, because of prior price negotiations, the Part D price of a one-month supply of sitagliptin will decrease to $113 or less.[3] Between November 2023 and October 2024, Medicare spent about $1.08 billion on Janumet for 243,000 enrollees.[4] Public Citizen’s Health Research Group submitted comments to assist Medicare with the price negotiations.[5]

We have classified Janumet as a Do Not Use drug, metformin as a Limited Use[6] drug, and the gliptin class of medications, which includes sitagliptin, as Do Not Use[7] drugs. In general, we also recommend against the use of fixed-dose combination drugs, such as Janumet, when single-ingredient drugs are available and have similar effectiveness. In a fixed-dose combination drug, the amounts and proportions of each individual drug are set in advance.

Background on diabetes

About 1 in 10 Americans have diabetes, and 90-95% of these cases are classified as type 2, the form of the disease that typically emerges after age 45 years and can be mitigated or prevented by diet and exercise.[8] Persons with type 2 diabetes have inadequate cellular responses to insulin, the pancreatic hormone that metabolizes glucose, and develop hyperglycemia (high blood glucose), which correlates with serious health problems including heart and kidney disease and vision loss.

When medications are needed for newly diagnosed type 2 diabetes, metformin is a first-choice drug.[9] If metformin treatment is not successful, other classes of oral diabetes medications are available, as well as daily insulin injections.

Metformin

An important reason for our classification of metformin as Limited Use for type 2 diabetes[10] is that the drug label includes a boxed warning for lactic acidosis (buildup of lactic acid in the blood). Although metformin-associated lactic acidosis is a rare condition, it can lead to hypothermia, low blood pressure, heart rhythm abnormalities, and death.[11] Symptoms include malaise, muscle pains, trouble breathing, drowsiness and abdominal pain.

Metformin should be avoided in patients with severe kidney disease or liver disease and used cautiously in those with other risk factors, including concomitant use of certain drugs, age greater than 65 years, and radiologic studies with contrast. At least 5% of patients using metformin experience hypoglycemia (low blood sugar), diarrhea and nausea.[12]

Sitagliptin

In 2012 we classified sitagliptin and other gliptins as Do Not Use because their benefits do not outweigh their risks.[13] Those risks include severe joint pain, acute pancreatitis, heart failure, severe skin reactions, and vitamin B12 deficiency.[14] An advantage of gliptins is that they are one of several classes of oral drugs for controlling glycemia that have a lower risk of triggering hypoglycemia than other such drugs. Alternative treatments that also have relatively low risk of hypoglycemia include flozins (sodium-glucose cotransporter 2 inhibitors; for example, empagliflozin [JARDIANCE]).

In 2023 we reaffirmed the Do Not Use classification for gliptins after reviewing a 2022 study that found gliptin use, compared with use of other diabetes drugs, increased the risk of gallstones or gallbladder inflammation by approximately 11 cases per 10,000 person-years of exposure to such drugs.[15] That study also showed that, compared with flozins, gliptins had a 55% higher relative risk of gallbladder inflammation and a 31% higher risk of gallstones.

Also in 2022, The Medical Letter concluded that gliptins failed in randomized trials to demonstrate efficacy to reduce the risk of major cardiovascular events, hospitalization for heart failure, or chronic kidney disease in patients with type 2 diabetes and cardiovascular disease or at increased risk of cardiovascular disease.[16] In 2023, Prescrire International similarly concluded that “(g)liptins have no proven efficacy against the complications of diabetes and have a burdensome adverse effect profile, making them drugs to avoid.”[17]

Combination drugs

Several randomized, placebo-controlled studies support the slight increase in efficacy of adding sitagliptin to metformin, effects that range from 0.4% to 0.9% reductions in HbA1c (the average level of blood glucose over the past several months).[18] However, the addition of sitagliptin to metformin is no more effective than the addition of other type 2 diabetes drugs, such as the sulfonylurea drug glipizide (GLUCOTROL XL and generics), to metformin.

What You Can Do

If you have type 2 diabetes, Public Citizen’s Health Research Group recommends that you not use gliptins, including combination drugs such as Janumet. If you have type 2 diabetes, and diet and exercise alone are insufficient for glycemic control, discuss with your clinician which medicine or medicines would be best for you, including metformin, other classes of diabetes drugs, and insulin.
 

References

[1] Merck & Company. Label: sitagliptin and metformin (JANUMET). June 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/022044s052lbl.pdf. Accessed May 6, 2025.

[2] Centers for Medicare & Medicaid Services. HHS announces 15 additional drugs selected for Medicare drug price negotiations in continued effort to lower prescription drug costs for seniors. January 17, 2025. https://www.cms.gov/newsroom/press-releases/hhs-announces-15-additional-drugs-selected-medicare-drug-price-negotiations-continued-effort-lower. Accessed May 6, 2025.

[3] Drugs for type 2 diabetes. Med Lett Drugs Ther. 2022;64(1663):177-184.

[4] Centers for Medicare & Medicaid Services. Medicare drug price negotiation program: selected drugs for initial price applicability year 2027. https://www.cms.gov/files/document/factsheet-medicare-negotiation-selected-drug-list-ipay-2027.pdf. Accessed May 6, 2025.

[5] Public Citizen. Comments to CMS regarding selected drugs for price negotiations (round 2). March 1, 2025. https://www.citizen.org/article/comments-to-cms-regarding-selected-drugs-for-price-negotiation-round-2/. Accessed May 6, 2025.

[6] Worst Pills, Best Pills News. Metformin: first-choice drug for type 2 diabetes. August 2018. https://www.worstpills.org/newsletters/view/1210. Accessed May 6, 2025.

[7] Worst Pills, Best Pills News. “Do Not Use” type 2 diabetes gliptin drugs also raise risk of gallbladder inflammation. March 2023. https://www.worstpills.org/newsletters/view/1521. May 6, 2025.

[8] Centers for Disease Control and Prevention. Diabetes. May 15, 2024. https://www.cdc.gov/diabetes/about/about-type-2-diabetes.html. Accessed May 6, 2025.

[9] Worst Pills, Best Pills News. Metformin: first-choice drug for type 2 diabetes. August 2018. https://www.worstpills.org/newsletters/view/1210. Accessed May 6, 2025.

[10] Ibid.

[11] ScieGen Pharmaceuticals Inc. Label: metformin. May 2021. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1452fbb1-e591-4a51-9f83-8a8a6a780b52&type=display. Accessed May 6, 2025.

[12] Merck & Company. Label: sitagliptin and metformin (JANUMET). June 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/022044s052lbl.pdf. Accessed May 6, 2025.

[13] Worst Pills, Best Pills News. A review of the ‘gliptin’ diabetes drugs. March 2012. https://www.worstpills.org/newsletters/view/784. Accessed May 6, 2025.

[14] Worst Pills, Best Pills News. “Do Not Use” type 2 diabetes gliptin drugs also raise risk of gallbladder inflammation. March 2023. https://www.worstpills.org/newsletters/view/1521. Accessed February 14, 2025.

[15] He L, Wang J, Ping F, et al. Dipeptidyl peptidase-4 inhibitors and gallbladder or biliary disease in type 2 diabetes: systematic review and pairwise and network meta-analysis of randomized controlled trials. BMJ. 2022;377:e068882.

[16] Drugs for type 2 diabetes. Med Lett Drugs Ther. 2022;64(1663):177-184.

[17] Prescrire International. Gliptins and GLP-1 agonists: gallstones and cholecystitis. Translated from Rev Prescrire May 2023 Volume 43, Number 475, page 354.

[18] Merck. Label: sitagliptin and metformin (JANUMET). June 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/022044s052lbl.pdf. Accessed May 6, 2022.