What is the combination of oral anti-diabetic (antidiabetic) drugs?

From the Guidelines

Oral anti-diabetic drugs should be combined to improve glycemic control in type 2 diabetes when monotherapy is insufficient, with metformin as the first-line therapy and a second agent from a different class added as needed. The most common combination starts with metformin (500-2000 mg daily) as first-line therapy, then adds a second agent from a different class. Effective second-line options include sulfonylureas (like glimepiride 1-8 mg daily), DPP-4 inhibitors (such as sitagliptin 100 mg daily), SGLT-2 inhibitors (like empagliflozin 10-25 mg daily), or GLP-1 receptor agonists (such as semaglutide 3-14 mg weekly) 1. These combinations work through complementary mechanisms - metformin reduces hepatic glucose production and improves insulin sensitivity, while the second agent may enhance insulin secretion, reduce glucose reabsorption in kidneys, or slow gastric emptying.

Some key points to consider when combining oral anti-diabetic drugs include:

• The choice of medication added to metformin should be based on the clinical characteristics of the patient and their preferences 1
• Initial combination therapy should be considered in patients presenting with A1C levels 1.5–2.0% above target 1
• The combination of metformin and a DPP-4 inhibitor was associated with a lower risk for severe hypoglycemia than metformin plus a sulfonylurea 1
• Metformin plus an SGLT-2 inhibitor was associated with a lower risk for severe hypoglycemia than metformin plus a sulfonylurea 1

For patients with inadequate control on dual therapy, a third agent from another class can be added. The specific combination should be individualized based on efficacy, side effect profile, cost, comorbidities, and patient preferences. Regular monitoring of blood glucose, HbA1c, renal function, and potential side effects is essential when using combination therapy.

It's also important to note that the American Diabetes Association recommends a patient-centered approach to choosing appropriate pharmacologic treatment of blood glucose, considering factors such as efficacy, key patient factors, and patient preferences 1. Additionally, the American College of Physicians recommends that clinicians prescribe metformin to patients with type 2 diabetes when pharmacologic therapy is needed to improve glycemic control, and consider adding a second agent to metformin when the HbA1c target is not achieved with monotherapy alone 1.

From the FDA Drug Label

Combination Therapy Three 16-week, randomized, double-blind, placebo-controlled clinical studies and three 24-week, randomized, double-blind, dose-controlled clinical studies were conducted to evaluate the effects of ACTOS on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c ≥ 8%) despite current therapy with a sulfonylurea, metformin, or insulin ACTOS Plus Sulfonylurea Studies Two clinical studies were conducted with ACTOS in combination with a sulfonylurea. ACTOS Plus Metformin Studies Two clinical studies were conducted with ACTOS in combination with metformin ACTOS Plus Insulin Studies Two clinical studies were conducted with ACTOS in combination with insulin

The combination of oral anti-diabetic drugs with pioglitazone (ACTOS) is supported by the FDA drug label.

• Sulfonylurea: The addition of ACTOS to a sulfonylurea significantly reduced the mean HbA1c by 0.9% and 1.3% and mean FPG by 39 mg/dL and 58 mg/dL for the 15 mg and 30 mg doses, respectively 2.
• Metformin: The addition of ACTOS to metformin significantly reduced the mean HbA1c by 0.8% and decreased the mean FPG by 38 mg/dL 2.
• Insulin: The addition of ACTOS to insulin significantly reduced both HbA1c by 0.7% and 1.0% 2. Key points:
• The combination of ACTOS with other oral anti-diabetic drugs is effective in reducing HbA1c and FPG levels.
• The therapeutic effect of ACTOS in combination with other oral anti-diabetic drugs was observed in patients regardless of the dose of the other medication.

From the Research

Combination of Oral Anti-Diabetic Drugs

The combination of oral anti-diabetic drugs is a common approach in the management of type 2 diabetes mellitus. According to 3, the addition of a sulfonylurea or a DPP-4 inhibitor to metformin can improve glycemic control. The study found that the combination of glipizide and metformin resulted in a significant reduction in fasting plasma glucose, while the combination of saxagliptin and metformin had less significant changes.

Types of Combination Therapies

Different types of combination therapies are available, including:

• Metformin and sulfonylurea: This combination is commonly used and has been shown to be effective in improving glycemic control 3.
• Metformin and DPP-4 inhibitor: This combination has also been shown to be effective and may have a lower risk of hypoglycemia compared to sulfonylureas 3, 4.
• Insulin and oral anti-diabetic drugs: The addition of insulin to oral therapy can improve glycemic control and reduce the risk of microvascular complications 5.

Factors to Consider When Selecting a Combination Therapy

When selecting a combination therapy, several factors should be considered, including:

• Efficacy: The ability of the combination to improve glycemic control 3, 4.
• Safety: The risk of hypoglycemia and other adverse effects 3, 4.
• Cost: The cost of the combination therapy 6.
• Patient preferences: The patient's preferences and lifestyle should be taken into account when selecting a combination therapy 6.

Specific Combination Therapies

Specific combination therapies that have been studied include:

• Saxagliptin and metformin: This combination has been shown to be effective in improving glycemic control and has a low risk of hypoglycemia 4.
• Glipizide and metformin: This combination has been shown to be effective in improving glycemic control, but may have a higher risk of hypoglycemia compared to saxagliptin and metformin 3.
• Sulfonylureas and metformin: This combination is commonly used and has been shown to be effective in improving glycemic control, but may have a higher risk of hypoglycemia compared to DPP-4 inhibitors and metformin 3, 7.