Combination therapy of dipeptidyl peptidase-4 inhibitors and metformin in type 2 diabetes: rationale and evidence

Authors

  • Y. Liu,

    1. Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
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  • T. Hong

    Corresponding author
    1. Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
    • Correspondence to: Dr Tianpei Hong, Department of Endocrinology and Metabolism, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China. E-mail: tpho66@bjmu.edu.cn

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Abstract

The main pathogenesis of type 2 diabetes mellitus (T2DM) includes insulin resistance and pancreatic islet dysfunction. Metformin, which attenuates insulin resistance, has been recommended as the first-line antidiabetic medication. Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel oral hypoglycaemic agents that protect glucagon-like peptide-1 (GLP-1) from degradation, maintain the bioactivity of endogenous GLP-1, and thus improve islet dysfunction. Results from clinical trials have shown that the combination therapy of DPP-4 inhibitors and metformin [as an add-on, an initial combination or a fixed-dose combination (FDC)] provides excellent efficacy and safety in patients with T2DM. Moreover, recent studies have suggested that metformin enhances the biological effect of GLP-1 by increasing GLP-1 secretion, suppressing activity of DPP-4 and upregulating the expression of GLP-1 receptor in pancreatic β-cells. Conversely, DPP-4 inhibitors have a favourable effect on insulin sensitivity in patients with T2DM. Therefore, the combination of DPP-4 inhibitors and metformin provides an additive or even synergistic effect on metabolic control in patients with T2DM. This article provides an overview of clinical evidence and discusses the rationale for the combination therapy of DPP-4 inhibitors and metformin.

Introduction

Type 2 diabetes mellitus (T2DM) is one of the most common non-infectious chronic diseases that greatly threaten human health. Insulin resistance and pancreatic islet dysfunction are two major defects in the pathophysiological basis of T2DM. Various antidiabetic medications play important roles in the current management of T2DM. Metformin, which has been recommended as the first-line oral antidiabetic drug, improves glycaemic control mainly via attenuation of hepatic insulin resistance. Dipeptidyl peptidase-4 (DPP-4) inhibitors protect incretin hormones from degradation and, therefore, improve pancreatic islet dysfunction. Increasing evidence has shown that the combination therapy of DPP-4 inhibitors and metformin provides better glycaemic control than monotherapy in patients with T2DM. Moreover, recent studies have suggested some crosstalk between the two classes of antidiabetic agents, which may enhance their effects on metabolic control. In this review, the evidence and rationale of DPP-4 inhibitors plus metformin combination therapy are discussed.

Efficacy and Safety of DPP-4 Inhibitors and Metformin Combination Therapy

Multicentre, randomized, double-blinded, placebo-controlled trials have shown that adding DPP-4 inhibitors to metformin provides a greater reduction in glycated haemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) than adding placebo to metformin monotherapy-treated patients with inadequately controlled T2DM [1, 2]. Adding DPP-4 inhibitors to metformin was not worse than adding glimepiride or glipizide in lowering HbA1c in patients with T2DM [3-6]. Initial combination therapy with DPP-4 inhibitors and metformin also led to significantly better glycaemic control compared with the respective monotherapies [7-10]. On the basis of the ideal efficacy of DPP-4 inhibitors and metformin combination therapy, pharmaceutical companies have developed a fixed-dose combination (FDC) of the two classes of antidiabetic drugs. Bioequivalence studies have shown that the bioequivalence, safety and efficacy profile of co-administration of DPP-4 inhibitors and metformin can be extended to the FDC and extended-release FDC tablets [11, 12]. The changes from baseline HbA1c and FPG were greater in patients treated with the DPP-4 inhibitors/metformin FDC than in those treated with metformin monotherapy [13, 14].

The major randomized controlled trials involving the combination therapy of DPP-4 inhibitors and metformin are summarized in Table 1. All HbA1c values are shown as the National Glycohemoglobin Standardization Program (NGSP) levels, and they were also converted to the International Federation of Clinical Chemistry (IFCC) standard levels using the IFCC-NGSP master equation [15]. These results show an additive effect of the combination therapy on glycaemic control in patients with T2DM.

Table 1. Summary of randomized controlled trials of combination therapy with DPP-4 inhibitors and metformin
StudyDPP-4 inhibitorDuration and sizeTherapy regimentMean baseline HbA1c level in NSGP (IFCC)Change in HbA1c from baseline (unless otherwise indicated)
  1. DPP-4, dipeptidyl peptidase-4; NGSP, National Glycohemoglobin Standardization Program; IFCC, International Federation of Clinical Chemistry; HbA1c, haemoglobin A1c.
DPP-4 inhibitor as add-on therapy to metformin
Bosi et al. [1]Vildagliptin24 weeksMetformin (≥1.5 g/day) +8.4%Reduction versus placebo
544•Vildagliptin 50 mg/day(68 mmol/mol)•Vildagliptin 50 mg/day, −0.7% (8 mmol/mol)*
•Vildagliptin 100 mg/day•Vildagliptin 100 mg/day, −1.1% (12 mmol/mol)*
•Placebo(*p < 0.001, versus placebo)
Ferrannini et al [4]Vildagliptin52 weeksMetformin (mean 1.898 g/day) +7.3%•Vildagliptin, −0.4% (4 mmol/mol)
2789•Vildagliptin 100 mg/day(56 mmol/mol)•Glimepiride, −0.5% (5 mmol/mol)
•Glimepiride 4.5 mg/day (mean)(Non-inferiority, the between-group difference +0.1%, 97.5%CI +0.0% – +0.2%)
DeFronzo et al [2]Saxagliptin24 weeksMetformin (1.5 – 2.5 g/day) +8.0%•Saxagliptin 2.5 mg/day, −0.6% (7 mmol/mol)*
743•Saxagliptin 2.5 mg/day(64 mmol/mol)•Saxagliptin 5 mg/day, −0.7% (8 mmol/mol)*
•Saxagliptin 5 mg/day•Saxagliptin 10 mg/day, −0.6% (7 mmol/mol)*
•Saxagliptin 10 mg/day•Placebo, +0.1% (1 mmol/mol)
•Placebo(*p < 0.001, versus placebo)
Goke et al [6]Saxagliptin52 weeksMetformin (≥1.5 g/day) +7.7%•Saxagliptin, −0.7% (8 mmol/mol)
858•Saxagliptin 5 mg/day(61 mmol/mol)•Glipizide, −0.8% (9 mmol/mol)
•Glipizide 5 – 20 mg/day(Non-inferiority, the between-group difference +0.1%, 95% CI −0.1% to +0.2%)
Arechavaleta et al [3]Sitagliptin30 weeksMetformin (≥1.5 g/day) +7.5%•Sitagliptin, −0.5% (5 mmol/mol)
1035•Sitagliptin 100 mg/day(58 mmol/mol)•Glimepiride, −0.5% (5 mmol/mol)
•Glimepiride 1 – 6 mg/day(Non-inferiority, the between-group difference +0.1%, 95% CI −0.0% to +0.2%)
Gallwitz et al [5]Linagliptin2 yearsMetformin (stable dose) +7.7%•Linaglipitin, −0.2% (2 mmol/mol)
1552•Linagliptin 5 mg/day(61 mmol/mol)•Glimepiride, −0.4% (4 mmol/mol)
•G1imepiride 1 – 4 mg/day(Non-inferiority, the between-group difference +0.2%, 95% CI +0.1 – +0.3%)
Initial combination therapy with DPP-4 inhibitor and metformin
Goldstein et al [17]Sitagliptin24 weeks•Metformin 2 g/day + Sitagliptin 100 mg/day8.8%Reduction versus placebo
1091•Metformin 1 g/day + Sitagliptin 100 mg/day(73 mmol/mol)•Metformin 2 g/day + Sitagliptin, −2.1% (23 mmol/mol)*
•Metformin 2 g/day•Metformin 1 g/day + Sitagliptin, −1.6% (17 mmol/mol)*
•Sitagliptin 100 mg/day•Metformin 2 g/day, −1.3% (14 mmol/mol)
•Placebo•Metformin 1 g/day, −1.0% (11 mmol/mol)
•Sitagliptin, −0.8% (9 mmol/mol)
(*p < 0.001, versus monotherapy)
Bosi et al [8]Vildagliptin24 weeks•Metformin 2 g/day + Viladaglpitin 100 mg/day8.8%•Metformin 2 g/day + Viladaglpitin, −1.8% (20 mmol/mol)*
1179•Metformin 1 g/day + Viladaglpitin 100 mg/day(73 mmol/mol)•Metformin 1 g/day + Viladaglpitin, −1.6% (17 mmol/mol)
•Viladaglpitin 100 mg/day•Viladaglpitin, −1.1% (12 mmol/mol)
•Metformin 2 g/day•Metformin, −1.4% (15 mmol/mol)
(*p < 0.001, p < 0.005, versus monotherapy)
Jadzinsky et al [16]Saxagliptin24 weeks•Metformin + Saxagliptin 5 mg/day9.4–9.6%•Metformin + Saxagliptin 5 mg/day, −2.5% (27 mmol/mol)*
1306•Metformin + Saxagliptin 10 mg/day(79 – 81 mmol/mol)•Metformin + Saxagliptin 10 mg/day, −2.5% (27 mmol/mol)*
•Saxagliptin 10 mg/day + Placebo•Saxagliptin 10 mg/day, −1.7% (19 mmol/mol)
•Metformin + Placebo•Metformin, −2.0% (22 mmol/mol)
(Metformin was uptitrated in 0.5 g/day increments to 2 g/day maximum in the first 5 weeks)(*p < 0.0001, versus monotherapy)
Pfutzner et al [45]Saxagliptin76 weeks•Same as aboveSame as above•Metformin + Saxagliptin 5 mg/day, −2.3% (25 mmol/mol)*
1306•No titration of metformin during the 52-week extension•Metformin + Saxagliptin 10 mg/day, −2.3% (25 mmol/mol)*
•Saxagliptin 10 mg/day, −1.6% (17 mmol/mol)
•Metformin, −1.8% (20 mmol/mol)
(*p < 0.0001, versus monotherapy)
Haak et al [10]Linagliptin24 weeks•Metformin 2 g/day + Linagliptin 5 mg/day8.7%Reduction versus placebo
791•Metformin 1 g/day + Linagliptin 5 mg/day(72 mmol/mol)•Metformin 2 g/d + Linagliptin, −1.7% (19 mmol/mol)*
•Metformin 2 g/day•Metformin 1 g/day + Linagliptin, −1.3% (14 mmol/mol)*
•Metformin 1 g/day•Metformin 2 g/day, −1.2% (13 mmol/mol)
•Linagliptin 5 mg/day•Metformin 1 g/day, −0.8% (9 mmol/mol)
•Placebo•Linagliptin, −0.6% (7 mmol/mol)
(*p < 0.0001, versus monotherapy)
DPP-4 inhibitor/metformin fixed-dose combination as initial therapy
Reasner et al [13]Sitagliptin/metformin18 weeks•Sitagliptin 50 mg/metformin 1 g twice-daily9.9%•Sitagliptin/metformin, −2.4% (26 mmol/mol)*
1250•Metformin 1 g twice-daily(85 mmol/mol)•Metformin, −1.8% (20 mmol/mol)
(*p < 0.0001, versus metformin)

With regard to safety issues, the incidence of overall adverse events (AEs) was similar between metformin monotherapy and combination therapy of DPP-4 inhibitors plus metformin [1, 16]. Particularly, the combination therapy was well tolerated with a low and similar incidence of hypoglycaemia as metformin monotherapy [2, 10, 17]. As metformin and DPP-4 inhibitors both have gastrointestinal AEs, respectively, it was of concern whether co-administration of the two drugs would trigger more gastrointestinal events. In a randomized trial, fewer patients reported gastrointestinal AEs in the group with vildagliptin added to metformin than in the group with placebo addition [1]. In another trial, abdominal pain and diarrhoea occurred significantly less with sitagliptin/metformin FDC versus an equivalent dose of metformin monotherapy, and the incidence of nausea and vomiting was similar in both groups [13].

Besides DPP-4 inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists are another option for incretin-based therapy. DPP-4 inhibitors primarily potentiate endogenous GLP-1 without reaching its pharmacological levels, whereas GLP-1 receptor agonists lead to pharmacological activation of GLP-1 signalling. Thus, GLP-1 receptor agonists show more significant improvement in glycaemic control in both monotherapy and in combination with metformin [18]. However, GLP-1 receptor agonists should be administered by injection and produce more gastrointestinal AEs compared with DPP-4 inhibitors [18], which contribute to substantial treatment interruption [19]. DPP-4 inhibitors are oral agents and are better tolerated, making them easier and more acceptable for patients to use, especially for those who are on their first years of treatment. Moreover, DPP-4 inhibitors can be co-administered with metformin in FDC, thus enhancing medication adherence as other FDCs because of its convenience [20].

Rationale for the Combination Therapy

Complementary Action between DPP-4 Inhibitors and Metformin

The major mechanisms of metformin and DPP-4 inhibitors in controlling plasma glucose are different. Metformin acts as an antihyperglycaemic agent primarily by improving hepatic insulin resistance to reduce hepatic glucose output. DPP-4 inhibitors protect incretins, including GLP-1, from degradation. In both clinical and preclinical studies, GLP-1 improves pancreatic islet function through several actions including amplifying glucose-dependent insulin secretion of pancreatic β-cells and inhibiting glucagon secretion from pancreatic α-cells. GLP-1 also upregulates gene transcription and biosynthesis of insulin, promotes β-cell proliferation and neogenesis and inhibits β-cell apoptosis in preclinical studies [21]. However, plasma GLP-1 is rapidly inactivated by the enzyme DPP-4. DPP-4 inhibitors selectively block DPP-4 activity and increase the level of intact GLP-1 in circulation, thus enhancing the bioactivity of endogenous GLP-1 in regulating β-cell function. DPP-4 inhibitors and metformin target different defects in T2DM. Therefore, an additive or synergistic action of these two drugs when used in combination would be expected. In fact, randomized, placebo-controlled trials showed that initial combination therapy with metformin and sitagliptin decreased homeostasis model assessment-insulin resistance (HOMA-IR) and improved parameters of pancreatic β-cell function from baseline levels in drug-naive patients with T2DM. In addition, the combination therapy provided greater reduction in both fasting glucose and HbA1c versus their respective monotherapy [7, 16], suggesting an additive effect of the combination of metformin and DPP-4 inhibitors.

Interestingly, recent studies have suggested some crosstalk in their pharmacological effects between metformin and DPP-4 inhibitors.

Evidence for the Direct Effects of Metformin on GLP-1 Level and Bioactivity

Metformin used to be considered as having no essential influence on pancreatic β-cell function, which is the major target of GLP-1-based therapy. However, clinical trials showed that co-administration of metformin with DPP-4 inhibitors improved the homeostasis model assessment of β-cell function (HOMA-β), fasting proinsulin level and proinsulin/insulin ratio more significantly than the same dose of DPP-4 inhibitors alone [7, 16, 22]. The increase of insulinogenic index of the combination therapy was even greater than the sum of their separate effects at the same doses [16]. In agreement with the above data, administration of either sitagliptin (100 mg daily) or metformin (1 g daily) alone increased postprandial active GLP-1 concentrations 1.76- and 1.95-fold, respectively; while co-administration of the two drugs with the same doses increased the GLP-1 concentration 4.12-fold [23]. These results suggest that there is an additive and even synergistic action of DPP-4 inhibitors and metformin combination therapy on the incretin effects resulted from GLP-1.

The Stimulatory Effect of Metformin on GLP-1 Secretion

Metformin monotherapy has been associated with increased postprandial plasma active GLP-1 levels in obese patients with T2DM [24]. A similar metformin treatment-associated effect has also been found in both diabetic and non-diabetic obese patients [25]. Furthermore, metformin increased the fasting active GLP-1 level in patients who had already received the DPP-4 inhibitor vildagliptin, and the level of active GLP-1 was positively related to the level of total GLP-1 [26]. On the basis of these findings, it has been suggested that the upregulation of bioactive GLP-1 level by metformin is achieved via its simulating effect on total GLP-1 secretion [27]. In addition, it has been reported that metformin acutely and specifically increased plasma levels of GLP-1 in mice, even in the absence of concomitant enteral glucose administration, but did not increase plasma levels of glucose-dependent insulinotropic peptide (GIP) secreted by K cells or peptide YY co-localized with GLP-1 in L cells [28]. Therefore, the stimulatory action of metformin on the gut endocrine system may be L cell-specific and, more precisely, GLP-1-specific.

Up to now, the signalling pathway by which metformin acts on L cells is far from clear. In a preliminary study, metformin did not enhance GLP-1 secretion in L cells in vivo [29]. Other studies have reported that metformin facilitated intestinal glucose utilization [30] and restored normal glucose uptake in the small intestine, which is disturbed by insulin resistance [31], and this might be coupled to GLP-1 production. Additionally, metformin inhibited the apical sodium-dependent bile acid transporter [32] and thus might be able to increase the concentration of bile acid in the intestine, which could stimulate GLP-1 secretion from L cells through the G-protein-coupled receptor TGR5 [33]. In a recent study, metformin increased plasma levels of total GLP-1 in rats. Chronic bilateral subdiaphragmatic vagotomy suppressed basal GLP-1 secretion but did not alter the GLP-1 response to metformin. Pretreatment with either non-specific muscarinic (M) receptor antagonist or M3 receptor antagonist decreased metformin-induced GLP-1 secretion, whereas M1 and M2 receptor antagonists had no effect. These results suggest that metformin-induced GLP-1 secretion is independent of the vagus nerve but dependent on M3 receptor [27].

The Inhibitory Effect of Metformin on DPP-4 Activity

Metformin might also be able to inhibit plasma DPP-4 activity, resulting in an increase of bioactive GLP-1 in circulation. Indeed, DPP-4 activity was reduced in patients with T2DM receiving metformin therapy [34, 35]. Metformin inhibited the degradation of active GLP-1 in the pooled plasma of obese patients without diabetes, and similar results were obtained in a buffer solution containing DPP-4 [36]. Metformin lowered plasma DPP-4 activity in healthy and ob/ob diabetic mice, and improved the insulin-releasing and glucose-lowing effects of exogenous GLP-1 administration [37]. However, several other studies have reported that metformin did not directly inhibit DPP-4 activity both in vitro [38] and in vivo [28]. It is noteworthy that metformin upregulated plasma-active GLP-1 levels in DPP-4-deficient rats [39]. These results imply that the elevation of plasma GLP-1 levels by metformin cannot be fully explained by its inhibitory effect on DPP-4 activity.

Upregulation of GLP-1 Receptor Expression by Metformin in Pancreatic Islet β-Cells

In a recent study, metformin directly increased GLP-1 receptor and GIP receptor expression in the mouse insulinoma cell line INS-1. The levels of mRNA transcripts for the incretin receptors were significantly increased in the islets from metformin-treated mice; therefore, the incretin effect of glucose-induced insulin secretion from pancreatic β cells was enhanced by metformin. Interestingly, metformin upregulated GLP-1 receptor transcription through a peroxisome proliferator-activated receptor-α (PPAR-α)-dependent and an AMP-activated protein kinase (AMPK)-independent mechanisms [28]. Hence, metformin can be regarded as an enhancer of GLP-1 secretion and possibly as a GLP-1 sensitizer. It is notable that acute metformin administration improved oral glucose tolerance despite loss of incretin action in GLP-1 receptor and GIP receptor single or double knockout mice, indicating that incretin receptors do not represent the dominant mechanism for the action of metformin on oral glucose tolerance in acute settings [28].

Improvement of Insulin Resistance by DPP-4 Inhibitors

Increased output of glucose from the liver is one of the characteristics of insulin resistance in T2DM. Pancreatic α-cell glucagon secretion, which accelerates hepatic glucose delivery, is suppressed by DPP-4 inhibitors [40]. Therefore, DPP-4 inhibitors might be able to improve the insulin resistance in patients with T2DM. In a double-blinded, placebo-controlled randomized-order, crossover study in patients with T2DM, vildaliptin (50 mg, twice daily) significantly increased the level of active GLP-1 and lowered the plasma levels of postprandial glucagon and endogenous glucose. The reduction in plasma glucagon level correlated with the reduction in plasma endogenous glucose level. The glucose clearance and insulin-stimulated systemic glucose utilization, as measured with a two-step glucose clamp, were significantly improved after vildagliptin treatment [41]. Another randomized, double-blinded, placebo-controlled study evaluated the effect of vildagliptin on insulin sensitivity in patients who had already received steady metformin treatment (1.5–3.0 g/day). Patients who were treated with vildagliptin (50 mg daily) in addition to metformin achieved significantly greater insulin sensitivity improvement than patients who had placebo in addition to metformin [42]. In a parallel-group, non-inferiority, double-blind trial patients inadequately controlled on a stable dose of metformin alone were randomly assigned to linagliptin or glimepiride once daily for 2 years. Although similar HbA1c reduction was obtained in both groups, HOMA-IR decreased with linagliptin treatment but increased with glimepiride treatment [5]. Moreover, chronically elevated GLP-1 in DPP-4 deficient rats showed reduced hepatic fat accumulation via activation of the AMPK pathway in hepatocytes [43]. One-week treatment with a weight-neutral dose of liraglutide, a GLP-1 receptor agonist, has been shown to improve cardiac insulin sensitivity and cardiac function in mice on a high-fat diet by an AMPK-dependent mechanism [44]. Therefore, it is conceivable that DPP-4 inhibitors might be able to potentiate the insulin-sensitizing and glucose-lowering effects of metformin based on the facts that metformin exerts its antihyperglycaemic effects mainly through activation of the AMPK pathway and that GLP-1 can also activate this signal pathway.

Conclusion

Metformin mainly improves insulin resistance and DPP-4 inhibitors enhance pancreatic islet function through maintaining the bioactivity of endogenous GLP-1. Additionally, metformin increases plasma GLP-1 levels and upregulates GLP-1 receptor expression in pancreatic β-cells, and DPP-4 inhibitors might improve insulin resistance. Therefore, co-administration of these two classes of antidiabetic drugs might have an additive or even synergistic effect for the treatment of T2DM. Indeed, clinical trials have shown the optimal efficacy and safety of this co-administration treatment, suggesting that the combination therapy of DPP-4 inhibitors and metformin is a promising strategy in the treatment of T2DM.

Acknowledgements

This work was supported by the National Natural Sciences Foundation of China (81000315 and 81270858), the Chinese National 973 Program (2012CB517502) and The Research Fund for the Doctoral Program of Higher Education of China (20120001120069).

Conflict of Interest

Y. L. collected the data and wrote the manuscript. T. H. designed the work and supervised the data collection and writing of the manuscript. There is no potential conflict of interest with any company whose products are discussed in this review. The authors have nothing else to disclose.

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