Expert Opinion on Pharmacotherapy

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Combination therapy for type 2 diabetes: dapagliflozin plus metformin Xueying Tan & Jingbo Hu To cite this article: Xueying Tan & Jingbo Hu (2015): Combination therapy for type 2 diabetes: dapagliflozin plus metformin, Expert Opinion on Pharmacotherapy, DOI: 10.1517/14656566.2016.1121235 To link to this article: http://dx.doi.org/10.1517/14656566.2016.1121235

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Drug Evaluation

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Combination therapy for type 2 diabetes: dapagliflozin plus metformin 1.

Introduction

2.

Body of review

3.

Conclusion

4.

Expert opinion

Xueying Tan† & Jingbo Hu† †

College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, China

Introduction: Type 2 diabetes (T2D) is a chronic and multifactorial metabolic disease, which brings great threats to public health. The morbidity of T2D keeps growing, and it is estimated that the population with T2D will rise to 552 million throughout the world by 2030. Effective glycemic control in patients is crucial for the treatment of T2D. However, with progressive deterioration of disease, most patients are usually unable to achieve glycemic targets receiving antidiabetic agent monotherapy. In such cases, combination therapy with different mechanisms of antidiabetic agents is highly desired. In addition, combination therapy can provide advantages beyond better glycemic improvement such as reduced incidence of hypoglycemia and cardiovascular events. Areas covered: We reviewed all the published data regarding the fixed-dose combination therapy of dapagliflozin combined with metformin, including complementary mechanism of action, pharmacodynamics, pharmacokinetics, clinical efficacy and safety. Expert opinion: The fixed-dose combination of dapagliflozin and metformin exerts synergistic effects based on two antidiabetic agents with complementary mechanisms of action. Rational co-administration of dapagliflozin and metformin provides better glycemic control with potential weight loss and the reduced incidence of hypoglycaemia. Keywords: combination therapy, dapagliflozin, metformin, sodium glucose co-transporter 2 (SGLT2) inhibitor, type 2 diabetes Expert Opin. Pharmacother. [Early Online]

1.

Introduction

Type 2 diabetes (T2D) is considered to be a chronic, progressive and multifactorial metabolic disease defined by the presence of chronic hyperglycemia.[1] The clinical pathological factors include decreased pancreatic insulin secretion, increased peripheral insulin resistance, impaired lipolysis, increased hepatic glucose production, gastrointestinal incretin deficiency/resistance, increased renal glucose reabsorption, α-cell hyperglucagonemia and neurotransmitter dysfunction.[2] Substantial increase in the number of type 2 diabetic patients is largely ascribed to obesity and irregular lifestyles, including drinking, smoking and irregular eating.[3] For patients with T2D, each 1% increase in glycosylated hemoglobin (HbA1c) is positively correlated with as much as 30% increased risk of all-cause mortality and 40% cardiovascular disease mortality.[4] Therefore, glycemic control is fundamental to the management of T2D, especially for diabetics with cardiovascular diseases.[5,6] Metformin, an oral antidiabetic agent, is recommended as the first-line therapy for patients with T2D, especially for overweight and obese people [7,8]. Metformin lowers glucose levels through suppressing hepatic glucose production.[9] In addition, it can reduce the absorption of glucose from the gastrointestinal tract (GIT), enhance peripheral glucose uptake and increase insulin sensitivity.[10] Thus, 10.1517/14656566.2016.1121235 © 2015 Taylor & Francis. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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Tan & Hu

combination medication of metformin with other antidiabetic agents has been considered. Dapagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, improves glycemic control by reducing glucose reabsorption from the glomerular filtrate to increase urinary glucose excretion (UGE) and reduce hyperglycemia in patients with T2D.[11] This pharmacological efficacy is independent of insulin action, both alone and together with other antidiabetic agents. Due to the complementary glucoselowering mechanisms of metformin and dapagliflozin, clinical trials with combination medication have presented significant reductions in HbA1c and fasting plasma glucose (FPG).[12–15] Besides earlier achievement of glycemic control than monotherapy, combination therapy with two or more drugs can appropriately reduce dosing frequency and dose of each agent, which contributes to minimizing doserelated side effects and improving patient’s adherence.[16] In addition, a fixed-dose tablet can improve pill burden and inadequate adherence to some extent. Cost factors should be considered in receiving combination therapy. One systematic review of 17 studies indicated reduced direct medical costs and better therapeutic outcomes with fixed-dose tablets versus multiple-pill regimens.[17] This review examines clinically relevant evidence for combining dapagliflozin with metformin, and comprehensively evaluates their clinical application value. 2. 2.1.

Body of review Overview of the market

For people with new-onset diabetes, treatment with metformin and lifestyle interventions is recommended by the European Association for The Study of Diabetes and American Diabetes Association.[8] Subsequently, clinicians need to assess the benefits and risks of different antidiabetic agents, including the effects on HbA1c, FPG, body weight and safety profiles. Current therapeutic options include insulin, sulfonylureas, thiazolidinediones, SGLT2 inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors and GLP-1 receptor agonists. However, most patients with T2D are unable to achieve glycemic targets while receiving antidiabetic agent monotherapy.[2] Therefore, combination therapy with different mechanism of antidiabetic agents is of great importance to the management of T2D.[18] Compared with other antidiabetic agents, such as insulin, sulfonylureas and thiazolidinediones, dapagliflozin not only improves glycemic control but can induce weight loss and decreased blood pressure, [11] which can potentially enhance therapeutic effects in patients with obesity or cardiovascular risks. Metformin is always deemed to the cornerstone for the treatment of T2D because of its clinical superiorities, such as slight weight loss and low incidence of hypoglycemia. Accordingly, co-administration of dapagliflozin and metformin provides another good choice for patients. 2

2.2.

Introduction to the compound SGLT2 inhibitors

2.2.1.

Transporter protein SGLTs are a group of membrane proteins mediating the reabsorption of glucose and other substances in the gastrointestinal tract and the kidney.[15,19] Under normal physiological condition, the glucose filtered in the glomerulus is reabsorbed by the complex physiological process involving diversiform transport mechanisms. Sodium glucose co-transporter 1 (SGLT1) and SGLT2 are responsible for the transport of glucose across the proximal convoluted tubular cells.[20] Further, 10% of glucose is reabsorbed by SGLT1 in the gastrointestinal tract, and 90% of the filtered glucose is reabsorbed by SGLT2 in the S1 segment of the proximal tubule.[21] In individuals with T2D, the reabsorbing glucose increases and plasma glucose level in the body rises accordingly. The upregulated expression of SGLT2 transporter in the proximal tubule contributes to the increased renal threshold and capacity to reabsorb glucose, which results in increased glucose levels in patients with T2D. Therefore, correction of hyperglycemia can be achieved through inhibiting SGLT2 transport to lower glucose reabsorption and increase renal excretion of glucose. Preclinical and clinical studies have demonstrated that excretion of glucose induced by SGLT2 inhibitor is in proportion to the filtered glucose. The efficacy is dependent on the glomerular filtration rate and blood glucose concentration.[22] Under the effects of SGLT2 inhibitors, the glucose level gradually reduces through the increased glucose filtration and excretion of glucose. Moreover, the action of SGLT2 inhibitors does not rely on the secretion of insulin and diminishes following the decreased glucose levels. That is to say, SGLT2 inhibitors have a self-regulatory effect on glucose levels and low intrinsic risk to induce hypoglycemia.[11] Glucose excretion associated with a loss of calories contributes to the decreased body weight, and osmotic diuresis and natriuresis result in the modest reduction in blood pressure.[23] At present, various SGLT2 inhibitors have been developed or are being studied, including dapagliflozin, canagliflozin, ipragliflozin, empagliflozin and ertugliflozin. Therefore, dapagliflozin has been approved for T2D in the United States and in several European countries.[24,25] 2.2.2.

Dapagliflozin

The recommended initial dosage of dapagliflozin is 5 mg once daily and can be increased up to 10 mg when necessary.[26] Monotherapy with dapagliflozin in patients with T2D usually reduces HbA1c by 0.6–0.9% after 24–52 weeks. [11,13–15] Combination therapy with metformin can further decrease HbA1c and simultaneously reduce the administration dosage. In these trials,[12,27] FPG was reduced by 0.8–1.5 mmol/L, and postprandial blood glucose was decreased by 2.4–2.9 mmol/L. The reduction in body weight associated with dapagliflozin is observed in most of

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Combination therapy for type 2 diabetes

these trials,[15,27,28] and the effect is significantly better than that with placebo.[11] In addition to the induced weight loss, dapagliflozin can also be beneficial to the reduction in blood pressure, especially systolic blood pressure. In older patients with T2D and cardiovascular diseases, changes compared with placebo in HbA1c from baseline (−0.3% vs 0.1%, P < 0.001), in body weight (−2.5 vs −0.6 kg, P < 0.001) and in systolic blood pressure (−2.7 vs 0.3 mmHg, P < 0.001).[29] But it is important to note that the kidney function must be assessed before use, and dapagliflozin needs to be discontinued if the estimated glomerular filtration rate (eGFR) remains persistently below 60 mL/min/ 1.73 m2.[26] The most common adverse reactions of dapagliflozin were genital or urinary tract infections, nasopharyngitis, diarrhea, back pain and constipation. [11–14] Therefore, genital or urinary tract infections appear to be related to the mechanism of action of dapagliflozin. Urogenital infections were reported more frequently in patients receiving dapagliflozin plus metformin than those receiving glipizide plus metformin.[13] The low incidence of hypoglycemia is detected in the monotherapy and combination therapy with other antidiabetic agents.[12,27] In addition, plasma lipids can also be affected by dapagliflozin, such as changes from baseline in total (3.4–1.4%), LDL (4.8–0.9%), and triglycerides (−8.0% to 2.9%) versus placebo.[30] 2.2.3.

Metformin

Metformin has been used in the clinic for many years and is still recommended as the first-line therapy for patients with T2D, especially in obese patients.[7,8] Metformin lowers hepatic glucose production through stimulating AMP-activated protein kinase, which is primary glucoselowering efficacy.[7] In addition, metformin can increase insulin sensitivity, enhance peripheral glucose uptake and reduce the absorption of glucose from the gastrointestinal tract.[10] Compared with insulin and sulfonylureas, metformin can induce weight loss, which can further improve glycemic control.[32]

Rationale of co-administration

With progressive deterioration of disease, metformin gradually loses glucose-lowering efficacy. Sulfonylurea or insulin added-on to existing therapy is required to regain glucose targets.[1] However, sulfonylureas and thiazolidinediones are usually associated with weight gain, insulin resistance and increased incidence of hypoglycemia. [12,13] Combination therapy with antidiabetic agents based on the non-insulin hypoglycemic mechanism contributes to metformin to enhance therapeutic outcome and reduces incidence risk of hypoglycemia in the meantime. Xigduo XR (dapagliflozin/metformin hydrochloride extended-release) contains two fixed-dose antidiabetic agents (5 mg/500 mg, 5 mg/1000 mg, 10 mg/500 mg and 10 mg/ 1000 mg) with complementary mechanisms of action to achieve glucose homeostasis in patients with T2D. Dapagliflozin suppresses glucose reabsorption in the kidney through selectively and potently inhibiting SGLT2 and increasing urinary glucose excretion, which is independent of insulin.[33] Meanwhile, metformin plays antidiabetic roles through inhibiting hepatic gluconeogenesis and improving peripheral insulin sensitivity.[34,35] Thus, combination therapy with dapagliflozin and metformin can better improve therapeutic outcome and patient’s treatment adherence.[12,14,15] 2.3.

Biguanide

Biguanides, a class of antidiabetic drugs, were gradually used in clinical practice for the management of T2D in the late 1950s. They can significantly improve peripheral glucose level, impair oxidative phosphorylation and gluconeogenesis as well as increase glycolysis.[31] Different from other antidiabetic agents such as sulfonylureas, biguanides have no effects on the output of insulin. They can be used as monotherapy or in combination with other antidiabetic agents. However, a few of derivatives, such as phenformin and buformin, were withdrawn from the market due to their potentially fatal lactic acidosis. Only metformin, with good safety profile, is still widely used in pharmacotherapy. 2.2.4.

2.2.5.

Chemistry

Chemical structures of dapagliflozin and metformin are given in Box 1. 2.4.

Pharmacodynamics

Dapagliflozin and metformin have different and complementary mechanisms of action in improving glycemic control. Dapagliflozin improves glycemic control by reducing glucose reabsorption from the glomerular filtrate to increase urinary glucose excretion (UGE) and reduce hyperglycemia in patients with T2D,[11] whereas metformin lowers serum glucose levels through suppressing hepatic glucose production.[18] Combination therapy with dapagliflozin based on the non-insulin hypoglycemic mechanism contributes to metformin to enhance therapeutic outcome and reduces the incidence of risk of hypoglycemia in the meantime. 2.5.

Pharmacokinetics and metabolism

This section aims at summarizing the pharmacokinetic (PK) properties of co-administration of dapagliflozin and metformin, which is bioequivalent to the corresponding doses of individual component tablets.[36] Compared with dapagliflozin alone, the co-administration of dapagliflozin with metformin is not affected in PK properties, such as maximum plasma concentration and area under the plasma concentration. Furthermore, dapagliflozin has

Expert Opin. Pharmacother. (2015) 17(1)

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Tan & Hu

Box 1. Drug summary. Drug name Indication Route of administration Mechanism of action Chemical structures

Dapagliflozin + metformin hydrochloride Type 2 diabetes Oral Inhibiting SGLT2 transport; Suppressing hepatic glucose production

Dapagliflozin

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Metformin

Pivotal trial

Long-term glycemic response and tolerability of dapagliflozin versus a sulfonylurea as add-on therapy to metformin in patients with type 2 diabetes: 4-year data. [44]

no effect on the PK behavior of co-administered drugs. [37] Some PK parameters are described in Table 1. Studies in healthy individuals and patients with T2D show that dapagliflozin reaches the maximum plasma concentration with an oral absolute bioavailability of −78% within 2 hours in the fasting state.[38] The Cmax and AUC values increase in a dose-proportional manner. Although co-administration with food will affect the drug’s pharmacokinetic profile, such as Cmax and Tmax, these changes are identified as being of no clinical significance.[36] Similarly, absorption rate of metformin will be reduced during co-administration with food and absorptive amount is almost unchanged.[38] Protein binding rate of dapagliflozin is approximately 91%,

and does not change in individuals with hepatic or renal impairment.[38] Dapagliflozin is metabolized by UGT1A9 and its predominant metabolite is dapagliflozin 3-O-glucuronide, which is mainly excreted through the urine.[38] Although dapagliflozin is metabolized by the cytochrome P450 (CYP) enzyme system, it has no clinically significant interaction with other drugs, namely no inhibition or induction on CYP isoenzymes. Following oral administration, the elimination halflife of dapagliflozin and metformin hydrochloride is approximately 12.9 and 17.6 h, respectively.[38] The fixed-dose tablets thus have PK properties that recommend a oncedaily dosage regimen. 2.6.

Table 1. Pharmacokinetic features of dapagliflozin and metformin. Dose

Dapagliflozin10 mg/d

Metformin 500, 850 mg

Absorption

~78% absorbed Cmax 158 ng/ml AUC 628 ng h/ml

50 ~ 60% absorbed Cmax < 5 ug/ml Steady state plasma concentration 400 ml/min T1/2 6.5 h

4

Clinical efficacy

To date, the efficacy of dapagliflozin combined with metformin therapy in patients with T2D has been evaluated in multiple clinical trials (Table 2). The efficacies of combination therapy (dapagliflozin plus metformin) versus placebo on glycemic control and weight loss are shown in Figures 1–3. 2.6.1.

Glycemic control

A total of 598 eligible patients were enrolled in the study and randomly assigned to receive dapagliflozin (5 or 10 mg) plus metformin, dapagliflozin alone, or metformin.[39] The combination in reducing HbA1c and FPG was more effective than either monotherapy. The proportion of patients achieving HbA1c 8.5%, combination therapy should be initiated.[54] In the USA, more than 25% of the population aged 65 and older has diabetes,[55] and diabetes in the aged is associated with higher mortality, progressively reduced physical function as well as increased risk of institutionalization. Older adults with T2D more easily suffer from cardiovascular disease. Accordingly, for patients aged 65 and older, rational selection of antidiabetic agents is of great importance to the management of T2D.[56] Successful management of T2D will necessitate facing several challenges, including combination therapy in clinical practice and the associated possible risks.[55] With the progress of T2D, treatment intensification will become necessary to maintain glycemic control.[1] For

older adults with T2D, persistent hyperglycemia will induce dehydration, urinary incontinence, falls, and hyperglycemic hyperosmolar syndrome.[57] Therefore, combination therayp with dapagliflozin and metformin, both with high safety profiles, probably is a good choice for the old people with T2D. In addition, previous studies found that dapagliflozin probably has an effect on calcium and phosphate homeostasis and bone mineral density (BMD),[13] which drew the attention of many researchers. Ljunggren et al. [41] evaluated bone formation and resorption and bone mineral density in patients receiving dapagliflozin treatment. The evaluation index included serum markers of bone formation (procollagen type 1 N-terminal propeptide), bone resorption (C-terminal cross-linking telopeptides of type I collagen) and bone mineral density. After 50 weeks of dapagliflozin treatment, no significant changes from the baseline were detected in dapagliflozin treatment compared with placebo. Based on these findings, we recommend combination therapy with dapagliflozin and metformin for patients with T2D, especially in those aged 65 and older.

Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Affiliation Xueying Tan1 & Jingbo Hu†2 † Author for correspondence 1 Department of endocrinology, Yuyao People’s Hospital, Yuyao 315400, China 2 College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, China Tel: +86-13884432106 E-mail: [email protected]

Combination therapy for type 2 diabetes: dapagliflozin plus metformin.

Type 2 diabetes (T2D) is a chronic and multifactorial metabolic disease, which brings great threats to public health. The morbidity of T2D keeps growi...
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