Fixed-Dose Combination of Dipeptidyl Peptidase-4 Inhibitors Plus Metformin in Patients with Type 2 Diabetes: A Review on Safety and Efficacy

There is a significant increase noted in the incidence and prevalence of Type 2 diabetes mellitus (T2DM). The global number of diabetic patients is projected by the International Diabetes Federation (IDF) to reach 552 million. T2DM disease has chronic and progressive nature. More than fifty percent of patients do not attain adequate glycemic control despite initial sufficient monotherapy. To maintain target glycated hemoglobin (HbA1c) levels (<7%), dose adjustment and adoption of several diabetes therapies become necessary in many cases. Compared to monotherapy, a fixed drug combination of oral agents and metformin has proven to be more efficacious to maintain levels of blood glucose and HbA1c. The combination of dipeptidyl peptidase-4 inhibitors (DDPIs) and metformin has been explicated to effectively decrease HbA1c to a relatively higher degree compared to the use of either agent individually. This combination addresses various pathophysiological processes involved in T2DM pathogenesis. Additionally, the Review Article Alshahrani et al.; JPRI, 33(53A): 53-59, 2021; Article no.JPRI.78289 54 concerned combination is safe and associated with a lower risk of hypoglycemia. Moreover, it is well-tolerated and prescribed as an easy-to-use single pill to improve patient compliance. This review provides an overview of the pharmacology, efficacy, and safety of fixed drug combinations of DDPIs and metformin according to current practice.


INTRODUCTION
An ideal glycemic control is the main objective in order to delay the advancement as well as complications of T2DM. A single antihyperglycemic agent fails in most cases in treatment to attain and/or maintain long term glycemic control among patients with type 2 diabetes (T2DM). Therefore, many patients need combinational therapeutic strategies that consisting of several antihyperglycemic medications with complementary action mechanisms [1]. When the glycemic goal is no longer attained by metformin as a monotherapy strategy, sulfonylurea and insulin are put to use [2][3][4]. Improper use of the combination therapy, likely linked to pill burden (higher amount of pills and frequency of dosage administration) and poor tolerability, can result in suboptimal clinical outcomes [5,6]. The use of fixed-dose combinations of antihyperglycemic agents simplifies regimen of treatment via decreasing the pill burden in contrast to the same combination used as individual pills [5].
The American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) have recommended important guidelines which constitute the traditional stepwise approach to manage T2DM. This approach involves a lifestyle change, medical nutritional therapy, and physical exercise. Additionally, in case the hemoglobin A1c (HbA1c) levels exceed the target level of 7.0%, metformin monotherapy is recommended [6]. However, fewer than 50% of T2DM patients achieve suggested HbA1c targets. This failure to attain sufficient glycaemic control has two reasons, the first is the progressive nature of T2DM, and the second is constraints present in present therapies, which involve poor adherence and tolerability [6][7][8]. To treat type 2 diabetes patients, monotherapy with metformin or sulphonylurea remains a common initial oral hypoglycaemic agent (OHA) regimen [9].
This narrative review aims to shed light on the up-to-date clinical utilization of the fixed-dose combination approach of DPP-4 inhibitors plus metformin in the treatment of type 2 diabetes.

Metformin
Metformin is administered as a hydrochloride salt (IUPAC nomenclature: N, Ndimethylimidodicarbinimidic diamide hydrochloride). It is a derivative of guanidine and has a molecular formula of C 4 H 11 N 5 HCl ( Fig. 1. Chemical structure of metformin) [14]. Metformin is among biguanide class that work mainly by reducing glucose production from the liver and can also decrease insulin resistance [15]. Other probable effects of metformin involve increments in glucose uptake, insulin signalling, and fatty acid β-oxidation while a decrement in fatty acid and triglyceride synthesis. Metformin can also enhance glucose utilization in peripheral tissues and potentially reduce the meal intake and intestinal glucose absorption. Since metformin does not stimulate endogenous insulin secretion, it leads to no hypoglycemia or hyperinsulinemia, which are usually seen as side effects linked to other antidiabetic drugs [16].
Metformin undergoes saturable and partial oral bioavailability in the range of 40-60%. Food already present delays and reduces absorption.
The distribution of metformin occurs without binding to plasma proteins and mainly undergoes renal excretion without any change, with the remaining 20-30% obtained in the faeces. For patients with renal impairment, an appreciable increase in plasma half-life is noticed, and it is not indicated to treat patients with an approximated glomerular filtration rate of less than 30 mL/min/1.73 m. The mean plasma halflife has been projected to be in the range of 4-8.7 hours [12,14,17,18]. glucose-dependent insulinotropic polypeptide (GIP), which are produced as a result of food intake. GLP-1 and GIP enhancements result in insulin secretion by pancreatic β-cells, a decrease in glucagon secretion, and a decrease in glucose production by the liver. The excretion, as well as elimination, are primarily renal with 75% of an oral doses are presented in the urine as an unchanged drug and the remaining portion is metabolized by the cytochromes CYP 3A4 and CYP 2C8. Under sitagliptin therapy in clinical studies, the drugdrug interactions were not observed. In particular, no interactions of this nature were noticed with other antihyperglycemic agents in type 2 diabetic patients [19][20][21][22].

Vildagliptin
Vildagliptin, GLP-1 can stimulate insulin secretion from the pancreatic β-cells into the blood in response to the intake of glucose, reduce glucagon secretion from pancreatic α-cells, delay gastric emptying and suppress appetite. It can also guard pancreatic β-cells against apoptosis and enhance β-cell proliferation [23][24][25]. In addition, recent results suggest the anti-sclerotic, vasculoprotective, anti-inflammatory, and antihyperlipidemic effects of vildagliptin [26,27]. as an adjunct to diet and exercise to enhance glycemic control in adults suffering from T2DM. Saxagliptin appreciably boosts glycemic control, as shown by decreases in HbA1c, fasting plasma glucose (FPG), and postprandial glucose (PPG) [28,29]. Saxagliptin working as an add-on therapy to glyburide, a thiazolidinedione, or metformin, or in initial combination with metformin, is associated with a lower risk of hypoglycemia and higher reduction in HbA1c [30].

A FIXED-DOSE COMBINATION APPROACH IN THE TREATMENT OF DIABETES MELLITUS TYPE 2
T2DM patients, with concurrent hypertension, dyslipidemia and other comorbidities, face a frequent issue of polypharmacy. To attain optimal therapeutic benefits and decrease pill burden, the employment of FDCs is a rational approach. Pharmacotherapy with fixed-dose combination drugs is being more and more prevalent in the treatment of type 2 diabetes mellitus (T2DM) as evidence-based clinical guidelines have advocated the use of several therapeutic agents in complex regimens. Fixed-dose combination is understood as combinations of two or over active drugs within one dosage formulation (usually pills) [31][32][33].
Metformin is present as one of the component drugs in many fixed-dose combinations. But the standard immediate-release (IR) formulation of metformin may require two doses per day and may result in tolerability issues related to adverse gastrointestinal (GI) effects. Also, other formulations such as the XR formulations of metformin can be given as one dose per day and have been linked with a decrease in instances of GI effects frequently seen otherwise with metformin IR. As a result, they can possibly have compelling advantages to include in fixed-dose combinations. The long-term cost-effectiveness of a fixed-dose combinations needs to be thoroughly determined. As with all oral hypoglycemic agents (OHAs), monotherapy using a sulphonylurea may be not resulting in or maintaining adequate glycemic control. This necessitates novel, useful, and highly tolerable therapies that can be included in a sulphonylurea agent. In a similar manner, dual-combinational therapy with a sulphonylurea agent and metformin may not maintain or lead to glycemic control [5,34]. Even though insulin is often used as the next therapeutic approach and it needs parenteral administration found troublesome by a lot of patients, and the inclusion of a thiazolidinedione can result in edema and an increment in body weight, additional OHA options are required for inclusion in the dual combination of other OHAs and metformin to evade switching to insulin [35].

EFFICACY AND SAFETY OF DDP-4 INHIBITORS AND METFORMIN AS FIXED-DOSE COMBINATION
Previous studies presented that the DPP-4 inhibitors with metformin as the initial combination therapy were linked with a higher reduction in HbA1c level, higher reduction in FPG level, and lower weight loss compared to metformin monotherapy. Furthermore, DPP-4 inhibitors with metformin acting as initial combinational therapy were not linked with a further decrease in adverse cardiovascular events nor the higher risk of hypoglycemia, nor the prolonged risk of gastrointestinal AEs when compared with metformin monotherapy [36,37]. On the other hand, an increased risk of hypoglycemia and weight gain is present with the sulfonylurea combinations. FDCs with thiazohdinedione bear warnings of an appreciably higher risk of edema and heart failure relative to placebo and also a higher risk of bone loss and fracture [38][39][40].
As with DPP-4 monotherapy, the fixed-dose combinations coupling a DPP-4 inhibitor with metformin XR (saxagliptin with metformin XR and sitagliptin with metformin XR) or with metformin immediate-release (sitagliptin with metformin immediate-release and alogliptin with metformin immediate-release) bear caution for pancreatitis and major hypersensitivity reactions. Likewise, in other metformin-containing fixed-dose combinations, tolerability considerations include gastrointestinal effects as possible adverse effects. For the reduction of GI side effects, patients should take fixed-dose combination therapy with a meal, and in most cases, with a progressive escalation of doses. Moreover, fixeddose combinations of metformin with DDPI-4 inhibitors were found to promote patient adherence by decreasing the number of pills required, making the dosing regimen less complex, and reducing dosing frequency [40][41][42][43].

COST-EFFECTIVENESS OF FIXED-DOSE COMBINATION THERAPY
The price of a fixed-dose combination formulation, in most cases, matches or is lesser when compared with the overall price of the separate components. The data mainly dealing with the effects of antihyperglycemic single-pill fixed-dose combinations in relation to costs of healthcare are limited. Some of the costeffectiveness analyses have ascertained the clinical benefits of fixed-dose combinations in terms of a smaller number of healthcare resources and reduced direct monthly healthcare costs related to clinical trials, translating into cost reduction and higher life expectancy. A previous retrospective study revealed that fixed-dose combination therapies present a compliance benefit compared to loose-pill therapies, that can possibly lead to decreases in utilization of healthcare and expenditures [44].

CONCLUSION
Polypharmacy is considered a serious issue for diabetic patients. The use of fixed-dose combination formulations is a sound approach to obtain excellent clinical outcomes meanwhile reducing the heavy pill burden for the patients.
Due to the difficulty of providing complete bioavailability and bioequivalence profiles for fixed-dose combination formulations, there is a dearth of prospective, randomized controlled trials mainly comparing fixed-dose combination formulations with their component drugs given as individual pills. This should not be taken as a constraint to their use. The treatment with DDP-4 inhibitors as a fixed-dose combination with metformin leads to clinically relevant decrease in HbA 1c , fasting glucose, and PPG than monotherapy with metformin alone. Overall, treatment with DDP-4 inhibitors as a fixed-dose combination is well tolerated and results in fewer adverse events.

DISCLAIMER
The products used for this research are commonly and predominantly use products in our area of research and country. There is absolutely no conflict of interest between the authors and producers of the products because we do not intend to use these products as an avenue for any litigation but for the advancement of knowledge. Also, the research was not funded by the producing company rather it was funded by personal efforts of the authors.

CONSENT AND ETHICAL APPROVAL
It is not applicable.