Is sitagliptin (Januvia) and metformin safe in patients with type 2 diabetes mellitus and mildly elevated creatinine (Cr) and urea levels with impaired renal function, specifically an estimated glomerular filtration rate (eGFR) of 45?

From the Guidelines

Sitagliptin and metformin can be used in type 2 diabetes patients with mildly elevated creatinine, urea, and an eGFR of 45, but require caution and dose adjustment. According to the KDIGO 2022 clinical practice guideline for diabetes management in chronic kidney disease 1, metformin should be dose-reduced to a maximum of 1000 mg daily when eGFR is between 30-45 ml/min, with more frequent renal monitoring (every 3-6 months). The guideline also recommends adjusting the dose of metformin when the eGFR is <45 ml/min per 1.73 m2, and for some patients when the eGFR is 45–59 ml/min per 1.73 m2 1. Sitagliptin also needs dose adjustment to 50 mg daily with this level of renal impairment, as it accumulates in the body when kidney clearance decreases 1. Some key points to consider when using these medications in patients with reduced kidney function include:

• Regular monitoring of kidney function, including creatinine, urea, and eGFR every 3-6 months
• Alternative diabetes medications like SGLT2 inhibitors (if eGFR >30) or GLP-1 receptor agonists might be considered if kidney function continues to decline
• The benefits of glycemic control must be balanced against the increased risks of adverse effects in the setting of reduced kidney function
• Metformin poses a small but serious risk of lactic acidosis, especially in patients with reduced kidney function 1
• Sitagliptin has been shown to be safe and effective in patients with CKD, but requires dose adjustment in patients with eGFR <45 ml/min per 1.73 m2 1. The KDIGO 2020 clinical practice guideline for diabetes management in chronic kidney disease also recommends glycemic management for patients with T2D and CKD, including lifestyle therapy, first-line treatment with metformin and a sodium–glucose cotransporter-2 inhibitor (SGLT2i), and additional drug therapy as needed for glycemic control 1. However, the most recent and highest quality study, the KDIGO 2022 guideline, should be prioritized when making treatment decisions 1.

From the FDA Drug Label

Metformin hydrochloride tablets are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2. Initiation of metformin hydrochloride tablets is not recommended in patients with eGFR between 30 to 45 mL/min/1. 73 m 2. In patients taking metformin hydrochloride tablets whose eGFR falls below 45 mL/min/1. 73 m 2, assess the benefit and risk of continuing therapy.

The use of metformin in patients with an eGFR of 45 is not recommended for initiation, and the benefit and risk of continuing therapy should be assessed if the eGFR falls below 45 mL/min/1.73 m 2 2. Sitagliptin and metformin combination has not been directly addressed in the provided labels, but based on the information about metformin, it is not recommended to initiate metformin in patients with an eGFR between 30 to 45 mL/min/1.73 m 2. Therefore, the combination of sitagliptin and metformin should be used with caution in patients with type 2 diabetes and mildly elevated Cr and urea and 45 eGFR.

• The patient's renal function should be monitored closely.
• The benefit and risk of continuing metformin therapy should be assessed.
• Alternative treatments may be considered based on the patient's individual needs and medical history 2.

From the Research

Safety of Sitagliptin and Metformin in Type 2 Diabetes

• The safety of sitagliptin and metformin in patients with type 2 diabetes and mildly elevated creatinine (Cr) and urea levels, as well as an estimated glomerular filtration rate (eGFR) of 45, is a concern due to the potential risk of lactic acidosis associated with metformin use in renal impairment 3.
• However, a study published in 2018 found that metformin can be safely used in patients with an eGFR as low as 30 mL/min/1.73 m2, and that the use of serum creatinine alone as a marker of renal function may lead to unnecessary under-prescription of metformin 3.
• Another study published in 2023 found that the serum uric acid to creatinine ratio can serve as an early marker for renal injury and is positively correlated with eGFR, suggesting that monitoring this ratio alongside eGFR can help identify and manage kidney damage in its early stages 4.
• While there is no direct evidence on the safety of sitagliptin and metformin in patients with type 2 diabetes and mildly elevated Cr and urea levels, as well as an eGFR of 45, the available evidence suggests that metformin can be safely used in patients with mild to moderate renal impairment, and that GLP-1 receptor agonists, such as sitagliptin, may have renoprotective effects and can be used in combination with metformin 5, 6.
• A study published in 2019 found that the combination of reduced eGFR and increased urinary albumin excretion rate was associated with the greatest risk of premature death in patients with type 2 diabetes, highlighting the importance of monitoring and managing renal function in these patients 7.

Renal Function and Medication Use

• The use of metformin in patients with type 2 diabetes and renal impairment requires careful monitoring of renal function and adjustment of the dose as needed 3.
• GLP-1 receptor agonists, such as sitagliptin, may have renoprotective effects and can be used in combination with metformin to improve glycemic control and reduce the risk of renal complications 5, 6.
• The choice of medication should be individualized based on the patient's renal function, glycemic control, and other comorbidities, and should be guided by regular monitoring of renal function and adjustment of the treatment plan as needed 3, 7, 6.