Introduction
Fixed-dose metformin + dipeptidyl peptidase-4 (DPP-4) inhibitor combinations are used to treat type 2 diabetes. Individually, both agents have a distinct blood glucose-lowering mechanism of action, and thus complement each other as a combination.
Metformin has been in use for over 60 years and, in this time, has established itself as a safe and effective medication, as well as the primary agent of choice for type 2 diabetes across the majority of global guidelines. On the other hand, DPP‑4 inhibitors are one of the safest glucose-lowering agents with proven cardiac and renal safety.
The versatile applicability of metformin and DPP‑4 inhibitors makes their combination a valuable tool for the treatment of type 2 diabetes. This article discusses the indications, advantages, and limitations of this combination.
Relevance
For the majority of people with type 2 diabetes, metformin is the recommended first-line pharmacotherapy [1]. However, most patients will ultimately require additional therapies to help sustain glycemic control as their condition advances.
Ensuring intensive glucose control early on in the disease process is imperative, and may eventually lead to benefits that continue beyond the period of treatment [2]. Consequently, when metformin fails to attain glycemic control, combination therapy is required.
Given their complementary mechanisms of action, a fixed-dose metformin + DPP‑4 inhibitor combination offers good glycemic control. without the hypoglycemia and weight gain commonly associated with insulins and sulfonylureas [3,4,5]. An added advantage includes improvement in kidney function [3].
Advantages
The fixed-dose metformin + DPP‑4 inhibitor combination is useful in a broad range of type 2 diabetes patient profiles, but particularly in people who are on a high dose of metformin.
The fixed-dose combination is well tolerated with safety profiles comparable to the individual agents, with certain caveats for its use in pregnant/breastfeeding patients, and in patients with severe renal impairment (chronic kidney disease stage 5 [metformin contraindicated due to increased risk of lactic acidosis]) [6,7].
It may be helpful to remember the advantages of this combination using the six “E” mnemonic shown in Table 1 below
Table 1. Advantages of DPP‑4 inhibitor + metformin fixed-dose combination |
Efficacy |
- Effective reduction of HbA1c
- No/minimal glycemic variability
|
Ease of use |
- Minimal dose required
- Flexibility in timing of administration
|
Error free |
|
Extra-glycemic effect |
- Renal (reduction in progression of albuminuria)
- Cardiac (safety as seen with both the agents individually)
|
Elementary investigations |
- Minimum investigations required at screening
- Minimum investigations needed for monitoring
|
Elasticity |
- Can be prescribed once or twice daily
- Can be prescribed with all insulins/oral anti-diabetic agents except oral semaglutide
|
The advantages of the fixed-dose combination translate into robust indications, as listed in Table 2.
Table 2. Indications of DPP‑4 inhibitor + metformin fixed-dose combination |
Glycemia based:
- As initiation therapy at HbA1c >7.5% (58 mmol/mol)
- As intensification therapy if metformin proves inadequate
|
Complication based:
- In people with diabetes at high risk of hypoglycemia/with hypoglycemia unawareness
- In people with diabetes with/at high risk of renal impairment
|
Psychosocial:
- In people with diabetes who may not be able/willing to undergo regular follow up
- In people with diabetes who may struggle with the complex self-care required with other regimens
|
My personal experience
The advantages of the DPP‑4 inhibitor + metformin fixed-dose combination include a robust HbA1c reduction, good tolerability profile, flexible dosing, and greater convenience for the patient.
These characteristics may translate into improved medication taking, better glycemic control, and greater cost-effectiveness.
The combination also reflects some of the advantages of DPP‑4 inhibitor monotherapy, such as usefulness in patients with renal impairment. However, it is critical to remember that metformin is contraindicated in people with chronic kidney disease stage 5. Therefore, the DPP‑4 inhibitor + metformin fixed-dose combination cannot be used in this subset of people.
One the greatest benefits of the DPP‑4 inhibitor + metformin fixed-dose combination is the simplicity of its use. This is a very useful and versatile combination, which adds great value to our clinical practice. The combination of safety and efficacy, coupled with flexibility and versatility, encourages its extensive use in adults with type 2 diabetes.
Availability of this fixed-dose combination allows for timely initiation and intensification of oral anti-diabetic therapy, facilitates achievement of glycemic targets, and prevents occurrence of unwanted complications.
References
- Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2018; 61: 2461–2498.
- Ceriello A. The emerging challenge in diabetes: the “metabolic memory”. Vascul Pharmacol 2012; 57: 133–138.
- Koliaki C, Doupis J. Linagliptin/Metformin fixed-dose combination treatment: a dual attack to type 2 diabetes pathophysiology. Adv Ther 2012; 29: 993–1004.
- Gallwitz B. Sitagliptin with metformin: profile of a combination for the treatment of type 2 diabetes. Drugs Today (Barc) 2007 43: 681–689.
- Halimi S, Schweizer A, Minic B, Foley J, Dejager S. Combination treatment in the management of type 2 diabetes: focus on vildagliptin and metformin as a single tablet. Vasc Health Risk Manag 2008; 4:481–492.
- Lipska KJ. Metformin use in patients with historical contraindications. Ann Int Med 2017; 166: 225–226.
- DeFronzo R, Fleming GA, Chen K, Bicsak TA. Metformin-associated lactic acidosis: Current perspectives on causes and risk. Metabolism 2016; 65: 20–29.