Type 2 diabetes (T2DM) is a complex disease with multiple physiological causes, including impaired insulin secretion, peripheral and hepatic insulin resistance, and gut hormone dysfunction. Consequently, therapies have been developed to target each of these defects, which has increased the number of available treatment choices over the years for patients with T2DM. Despite this progress, attaining good glycemic control for the millions of adults with diabetes remains a challenge, in part due to the progressive failure of beta cells, insulin resistance, ineffective lifestyle, weight gain, and cost-related poor adherence to treatment. As a result, almost half of U.S. adults with diabetes do not meet the guidelines for diabetes care.1 Therefore, improving the treatment of T2DM and its delivery to patients remains a high priority.
With an increasing number of medications available to treat T2DM, selecting the optimal therapeutic regimen for each patient is becoming less straightforward. Patients with T2DM often have other comorbidities requiring medication that contribute to overall pill burden. Fixed-dose combinations (FDC), also known as single-pill combinations, have the potential to reduce this pill burden and simplify the medication regimen, thus facilitating adherence and better glycemic control.
In addition, emerging evidence suggests that FDCs may work even more efficiently to lower blood glucose levels compared to their respective individual components ("syngergy"), while having similar safety and tolerability profiles, as well as possibly reducing health care costs. The FDCs for T2DM are largely divided into two groups: those containing metformin versus those that do not. Compared to metformin monotherapy, metformin-containing FDCs have been shown to lead to a greater reduction in hemoglobin HbA1C among users.
Metformin extended-release (XR) may offer additional benefits given once-daily dosing and milder gastrointestinal side effects. The article by Blonde et al specifically reviews the FDCs containing metformin XR, which include saxagliptin/metformin XR, pioglitazone/metformin XR, and sitagliptin/metformin XR. For patients who are unable to tolerate metformin, there are alternative FDCs, such as TZD plus sulfonylurea, TZD plus DPP4 inhibitor (eg, alogliptin and pioglitazone), SGLT2 inhibitor and DPP4 inhibitor (eg, dapagliflozin plus saxagliptin, empagliflozin plus linagliptin), SGLT2 inhibitor plus sulfonylurea, and SGLT2 inhibitor plus TZD.
For obvious reasons, FDCs have the potential to improve long-term patient adherence. In the article by Lokhandwala et al, patients in the FDC cohort reported a higher rate of adherence and lower rate of hypoglycemia than those prescribed multiple loose pills. Although prescription costs were higher in the FDC cohort, the all-cause monthly costs were lower in this group compared to the LDC group – suggesting possible economic benefits beyond monthly prescription costs.
One of the newest FDCs approved is empagliflozin/linagliptin, discussed in detail in the reviewed article by Kim et al. The efficacy of empagliflozin/linagliptin 10 mg/5 mg was shown to be better than the individual components while, surprisingly, empagliflozin/linagliptin 25 mg/5 mg did not show superior efficacy to its individual components. The side effects of empagliflozin/linagliptin were similar to the individual components and included urinary tract infection, upper respiratory tract infections, and nasopharyngitis.
The FDC of metformin and a DPP-4 inhibitor, commonly used in the US, is reviewed in detail in the article by Liu et al. In addition to convenience and tolerability, FDCs may be more efficient than their respective individual components due to additive effect of the combined medications, an effect that is explained through several mechanisms discussed in the article.
Altogether, FDCs may help improve glycemic control in patients with T2DM by facilitating adherence, reducing health care costs, and reducing side effects by avoiding maximum doses of each component medication. Consequently, there is a growing interest in their use as initial combination therapy. Indeed, a systematic review suggested a potential benefit of using a metformin-containing FDC as initial treatment compared to metformin monotherapy in patients with T2DM at varying HbA1C levels.2 Many of the studies examining the role of FDCs were limited by the fact that they were largely sponsored by the pharmaceutical companies, and the effects of FDCs were often compared to those with monotherapy using one of the individual components.
While the FDCs appear promising in improving the treatment of T2DM, whether we need to shift the paradigm in the step-wise management of T2DM remains to be determined.
1. Ali MK, Bullard KM, Saaddine JB, Cowie CC, Imperatore G, Gregg EW. Achievement of goals in U.S. diabetes care, 1999-2010. N Engl J Med. 2013;368(17):1613-1624.
2. Phung OJ, Sobieraj DM, Engel SS, Rajpathak SN. Early combination therapy for the treatment of type 2 diabetes mellitus: Systematic review and meta-analysis. Diabetes Obes Metab. 2014;16(5):410-417.