What is the rationale for using fixed-dose drug combinations, such as metformin (biguanide) and a sulfonylurea (e.g. gliclazide) or metformin and a DPP-4 (dipeptidyl peptidase-4) inhibitor (e.g. sitagliptin), in the treatment of diabetes?

From the Guidelines

Fixed-dose drug combinations, such as metformin and a DPP-4 inhibitor, are recommended for patients with type 2 diabetes who require dual-combination therapy to achieve and maintain individualized glycemic goals, as they offer improved treatment efficacy and medication adherence. The primary rationale for using these combinations is the complementary mechanisms of action of the individual medications. Metformin reduces hepatic glucose production and improves insulin sensitivity, while DPP-4 inhibitors increase incretin levels to enhance glucose-dependent insulin secretion. This approach leads to better glycemic control than either medication alone, as supported by the 2025 standards of care in diabetes, which suggest that higher-efficacy approaches, including combination therapy, have a greater likelihood of achieving treatment goals 1.

The use of fixed-dose combinations can also improve medication adherence by reducing pill burden and simplifying dosing regimens, which is particularly beneficial for patients on multiple medications. For example, combining metformin with a DPP-4 inhibitor can provide effective glucose control with less hypoglycemia risk than metformin-sulfonylurea combinations. Additionally, these combinations can be cost-effective compared to taking the medications separately. However, fixed-dose combinations limit dosing flexibility, so they're typically introduced after optimal doses of individual medications have been established. According to the 2018 consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), fixed-dose formulations can improve medication adherence when combination therapy is used, and may help achieve glycemic targets more rapidly 1.

Some key considerations when using fixed-dose combinations include:

• The potential benefits of combination therapy need to be weighed against the exposure of patients to multiple medications and potential side effects, increased cost, and less flexibility in dosing.
• Metformin is a commonly used medication that historically has been the first-line treatment for type 2 diabetes, and is effective and safe, inexpensive, and widely available, and reduces risks of microvascular complications, cardiovascular events, and death 1.
• The principal side effects of metformin are gastrointestinal intolerance, and the drug is cleared by kidney filtration, and may be safely used in people with estimated glomerular filtration rate ≥30 mL/min/1.73 m² 1.

Overall, the use of fixed-dose drug combinations in diabetes treatment offers several therapeutic advantages, including improved treatment efficacy and medication adherence, and can be a valuable treatment option for patients with type 2 diabetes who require dual-combination therapy to achieve and maintain individualized glycemic goals.

From the FDA Drug Label

A 29-week, double-blind, placebo-controlled study of metformin hydrochloride tablets and glyburide, alone and in combination, was conducted in obese patients with type 2 diabetes mellitus who had failed to achieve adequate glycemic control while on maximum doses of glyburide (baseline FPG of approximately 250 mg/dL) Patients randomized to the combination arm started therapy with metformin hydrochloride tablets 500 mg and glyburide 20 mg.

The rationale for using fixed-dose drug combinations, such as metformin and a sulfonylurea, in the treatment of diabetes is to achieve better glycemic control by combining two agents with different mechanisms of action.

• Improved efficacy: The combination of metformin and glyburide has been shown to be more effective in reducing fasting plasma glucose and HbA1c levels compared to either agent alone 2.
• Convenience: Fixed-dose combinations can simplify treatment regimens and improve patient adherence. However, the provided drug label does not directly address the rationale for using fixed-dose combinations with a DPP-4 inhibitor, such as sitagliptin.

From the Research

Rationale for Using Fixed-Dose Drug Combinations in Diabetes

The use of fixed-dose drug combinations in the treatment of diabetes is supported by several studies that highlight their advantages over monotherapy or loose-dose combinations. Some of the key benefits include:

• Improved efficacy: Fixed-dose combinations have been shown to be more effective than higher dose monotherapy in achieving glycaemic control 3.
• Reduced risk of adverse reactions: Fixed-dose combinations may reduce the risk of adverse reactions compared to higher dose monotherapy 3.
• Lower overall costs: Fixed-dose combinations can be more cost-effective than loose-dose combinations, which can lead to lower overall costs for patients 3.
• Improved medication concordance: Simplifying treatment regimens with fixed-dose combinations can improve patient compliance and adherence to medication 3, 4, 5.

Specific Combinations

Some specific fixed-dose combinations that have been studied include:

• Metformin and a sulfonylurea (e.g. gliclazide): This combination has been shown to be effective in achieving glycaemic control 3.
• Metformin and a DPP-4 inhibitor (e.g. sitagliptin): This combination has been shown to be effective in improving metabolic control in type 2 diabetes, with a low risk of adverse events 6, 7.
• Other combinations, such as metformin and a thiazolidinedione, or metformin and an incretin-based drug, have also been studied and may offer advantages over other combinations 6.

Patient Outcomes

Studies have shown that fixed-dose combinations can lead to improved patient outcomes, including:

• Better glycaemic control: Fixed-dose combinations have been shown to be effective in achieving glycaemic control, which can reduce the risk of complications associated with diabetes 3, 4.
• Improved patient satisfaction: Patients who are prescribed fixed-dose combinations may be more satisfied with their treatment, which can improve adherence and outcomes 4.
• Reduced pill burden: Fixed-dose combinations can reduce the number of pills that patients need to take, which can improve adherence and reduce the risk of medication errors 5.