What is the onset time of metformin (biguanide) compared to sitagliptin (dipeptidyl peptidase-4 inhibitor)?

From the Guidelines

Metformin has a faster onset of action compared to sitagliptin, with significant effects seen within 24-48 hours, while sitagliptin requires approximately 1-2 weeks for full therapeutic effect. The difference in onset time relates to their distinct mechanisms of action. Metformin works primarily by reducing hepatic glucose production and improving peripheral insulin sensitivity, which can produce relatively rapid effects on blood glucose levels 1. In contrast, sitagliptin inhibits the DPP-4 enzyme, which prolongs the action of incretin hormones that stimulate insulin release in response to meals, a mechanism that takes somewhat longer to fully manifest its glucose-lowering effects.

Some key points to consider when initiating either medication include:

• Metformin is effective and safe, is inexpensive and widely available, and reduces risks of microvascular complications, cardiovascular events, and death 1
• Metformin is available in an immediate-release form for twice-daily dosing or as an extended-release form that can be given once daily 1
• The principal side effects of metformin are gastrointestinal intolerance due to bloating, abdominal discomfort, and diarrhea; these can be mitigated by gradual dose titration and/or using extended-release formulation 1
• Sitagliptin, as a DPP-4 inhibitor, has a slower onset of action compared to metformin, but is still an effective option for glycemic control 1

When initiating either medication, patients should be advised that while some effects may be seen quickly, optimal glycemic control will develop over 1-2 weeks of consistent use. It is essential to consider the patient's individualized glycemic goals, comorbidities, and potential side effects when choosing between metformin and sitagliptin 1.

From the FDA Drug Label

At usual clinical doses and dosing schedules of metformin hydrochloride tablets, steady state plasma concentrations of metformin are reached within 24 to 48 hours Following a single oral dose of metformin hydrochloride extended-release tablets, C max is achieved with a median value of 7 hours and a range of 4 to 8 hours

The onset time of metformin is reached within 24 to 48 hours for steady state plasma concentrations, and C max is achieved in a median of 7 hours. There is no information in the provided drug label about sitagliptin to compare the onset time. 2

From the Research

Onset Time of Metformin and Sitagliptin

• The onset time of metformin and sitagliptin can be compared based on their efficacy in reducing HbA1c levels and improving glycaemic control in patients with type 2 diabetes.
• A study published in 2010 3 compared the efficacy and safety of monotherapy with sitagliptin and metformin in treatment-naïve patients with type 2 diabetes, and found that metformin had a greater reduction in HbA1c levels (-0.57% vs -0.43%) after 24 weeks of treatment.
• Another study published in 2012 4 evaluated the efficacy and safety of initial therapy with a fixed-dose combination of sitagliptin and metformin compared with pioglitazone in drug-naïve patients with type 2 diabetes, and found that the combination of sitagliptin and metformin had a greater reduction in HbA1c levels (-1.9% vs -1.4%) after 32 weeks of treatment.
• A study published in 2008 5 evaluated the efficacy and safety of sitagliptin as an add-on to metformin therapy in patients with moderately severe type 2 diabetes, and found that sitagliptin significantly reduced HbA1c levels (-1.0% vs -0.1%) after 18 weeks of treatment.
• A meta-analysis published in 2013 6 compared the therapeutic efficacy of sitagliptin and metformin in the treatment of type 2 diabetes, and found that the two treatments had comparable efficacy in reducing HbA1c levels (P = 0.148).

Time to Achieve Significant Reduction in HbA1c Levels

• A study published in 2011 7 evaluated the efficacy and safety of sitagliptin and the fixed-dose combination of sitagliptin and metformin vs. pioglitazone in drug-naïve patients with type 2 diabetes, and found that sitagliptin had a significant reduction in HbA1c levels (-1.0%) after 12 weeks of treatment.
• The same study found that the combination of sitagliptin and metformin had a greater reduction in HbA1c levels (-1.7% vs -1.4%) after 28 weeks of treatment compared with pioglitazone.
• The study published in 2012 4 found that the combination of sitagliptin and metformin had a significant reduction in fasting plasma glucose (-40.5 mg/dl) after 1 week of treatment, and a greater reduction in HbA1c levels (-1.9% vs -1.4%) after 32 weeks of treatment compared with pioglitazone.

Comparison of Onset Time

• Based on the available evidence, metformin appears to have a faster onset of action compared with sitagliptin, with significant reductions in HbA1c levels observed after 12-24 weeks of treatment 3, 7.
• The combination of sitagliptin and metformin has been shown to have a faster onset of action compared with pioglitazone, with significant reductions in HbA1c levels observed after 1-12 weeks of treatment 4, 7.
• However, the onset time of sitagliptin as monotherapy is less clear, with some studies suggesting that it may take longer to achieve significant reductions in HbA1c levels 5, 6.