6 page paper on diabetes.

researchpaper4.pdf

Home >Applied Sciences homework help >6 page paper on diabetes.

INVITED REVIEW

Overview of clinically approved oral antidiabetic agents for the treatment of type 2 diabetes mellitus

Zhi-Xu He,* Zhi-Wei Zhou,† Yinxue Yang,‡ Tianxin Yang,§ Si-Yuan Pan,¶ Jia-Xuan Qiu** and Shu-Feng Zhou†

*Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center & Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, China, †Department of

Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA, ‡Department of Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan, China, §Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Center, Salt Lake City, UT, USA, ¶Department of Chinese Medicinal

Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, and **Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China

SUMMARY

Type 2 diabetes mellitus (T2DM) is caused by insulin resis- tance and characterized by progressive pancreatic b-cell dys- function. This articles reviews the application and limitations of currently approved oral drugs for the treatment of T2DM. Data were retrieved from the literature and well-recognized drug-related databases. Although lifestyle modifications and metformin are the cornerstones of the initial management of T2DM, there is an increasing array of second- and third-line pharmacological agents, including sulphonylureas, insulin, thia- zolidinediones and glitazones, a-glucosidase inhibitors, gluca- gon-like peptide-1 agonists, dipeptidyl peptidase 4 inhibitors and the amylin receptor agonist pramlintide. Current T2DM treatment focuses on reducing blood glucose levels via different mechanisms, including nuclear hormone receptors, nucleic acid binding proteins, transcription factors, voltage-gated K+ chan- nels, glucosidase, G-protein-coupled receptors and non-receptor serine/threonine protein kinase. Extensive efforts are needed to address the pathogenesis of T2DM, which may facilitate the development of new therapies and the identification of new therapeutic targets to overcome the shortcomings of currently available drugs for T2DM and to achieve therapeutic goals. Key words: biguanide, dipeptidyl peptidase 4, metformin,

sulphonylurea, type 2 diabetes mellitus.

INTRODUCTION

Diabetes mellitus (DM) is a major health problem around the world, with continued expansion of DM associated with

increased morbidity and mortality, reduced quality of life and increased healthcare costs. Diabetes places a considerable burden on individuals, family and society. Based on data from the 2014 National Diabetes Statistics Report in the US (http://www.cdc. gov//diabetes/pubs/statsreport14.htm, accessed 20 November 2014), 29.1 million children and adults (i.e. 9.3% of the popula- tion) have diabetes and 1.7 million new cases of diabetes were diagnosed in people aged 20 years and older in 2012. A total of 28.9 million or 12.3% of US people aged 20 years and older have diabetes. Notably, 8.1 million people (27.8% of the popula- tion) with diabetes are undiagnosed. In adults, type 2 DM (T2DM; previously called non-insulin-dependent diabetes mellitus or adult-onset diabetes) accounts for approximately 90–95% of all diagnosed cases of diabetes. Type 2 DM is a chronic meta- bolic disorder characterized by progressive hyperglycaemia sec- ondary to declining b-cell function and usually accompanied by reduced sensitivity to insulin in peripheral tissues, such as liver and muscle.1 If untreated or not managed well, long-term hyper- glycaemia can lead to increased risk of macrovascular (cardiovas- cular, cerebrovascular and peripheral vascular disease) and microvascular (nephropathy, neuropathy and retinopathy) compli- cations. The effectiveness of T2DM treatment therapy is often determined by indicators such as HbA1c levels.2 The American Diabetes Association recommends an HbA1c target of ≤ 7% in diabetic patients. Type 2 DM is often treated with insulin sensitisers (e.g. thiazo-

lidinediones; TZDs), insulin secretagogues (e.g. sulphonylureas (SUs) and meglitinides) and external insulin delivery (insulin ana- logues). A number of new compounds for the treatment of T2DM are currently at different stages of development. This article dis- cusses currently approved oral agents for the treatment of T2DM. Data on current clinically approved drugs for the treatment of T2DM were extracted from the US Food and Drugs Administration (FDA) website (http://www.fda.gov/), Drugbank (http://www.drug- bank.ca), the Therapeutic Target database (http://bidd.nus.edu. sg/group/cjttd/) and the Potential Drug Target database (http:// www.dddc.ac.cn/pdtd/; all from inception until September 2014).

Correspondence: Shu-Feng Zhou, Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, 12901 Bruce B. Downs Blvd, Tampa, FL 33612, USA. Email: szhou@health.usf.edu Received 4 December 2013; revision 22 September 2014; accepted 14

Clinical and Experimental Pharmacology and Physiology (2015) 42, 125–138 doi: 10.1111/1440-1681.12332

ALDOSE REDUCTASE INHIBITORS

Aldose reductase (i.e. aldehyde reductase) acts on the first step of the polyol metabolic pathway to catalyse the reduction of glu- cose to sorbitol with NADPH as a coenzyme.3 The second and last step in the pathway is catalysed by sorbitol dehydrogenase, that converts the NAD-linked oxidation of sorbitol to fructose. Aldose reductase inhibitors (ARIs) inhibit aldose reductase, resulting in decreased sorbitol production in cells (Table 1). Many ARIs (Fig. 1a) have been developed as drug candidates,

but the clinical outcomes are disappointing and the scattered clin- ical pharmacokinetics are given in Table 2. Tolrestat (AY-27773; Alredase; Wyeth-Ayerst Research, Philadelphia, PA, USA) is an oral ARI approved for the management of certain diabetic com- plications, such as neuropathy, retinopathy and nephropathy, however it was never approved by the US FDA.4 Tolrestat was discontinued by Wyeth-Ayerst Research in 1997 due to the risk of severe liver necrosis and death reported in Argentina, Canada and Italy.5 Epalrestat, another ARI, has been approved for use in Japan and India. Epalrestat has been reported to improve the sub- jective symptoms of neuropathy, abnormalities in the sense of vibration and abnormal changes in heart beat associated with dia- betic peripheral neuropathy.1,6 Epalrestat is well tolerated; the most frequently reported adverse effects include elevated liver enzyme levels and gastrointestinal-related events, such as nausea and vomiting.81 Other ARIs, such as fidarestat,7 ranirestat,8–10

ponalrestat,11 sorbinil and risarestat,12 are currently not being assessed in clinical trials.

AMYLIN RECEPTOR AGONISTS

Amylin inhibits postprandial glucagon secretion and delays gas- tric emptying, thereby modifying postprandial hyperglycaemia in diabetic patients, which presumably adds to overall glycaemic control without a concomitant increase in the risk of severe hypo- glycaemia.13 Therefore, amylin replacement may improve glycae- mic control in diabetes mellitus.6 However, human amylin exhibits physicochemical properties predisposing the peptide hor- mone to aggregate and form amyloid fibres, which makes it unsuitable for medical use. Pramlintide (Symlin; Amylin Pharma- ceuticals, San Diego, CA, USA) is a relatively new adjunct treat- ment for diabetes (both type 1 and T2DM).14 It is derived from amylin, a hormone that is released from pancreatic b-cells into the bloodstream. By mimicking the activity of amylin, pramlin- tide acts to improve glycaemic control by modifying the rate of gastric emptying, preventing the post-prandial rise in glucagon levels and increasing sensations of satiety, thereby reducing calo- ric intake and potentiating weight loss.15,16

ANORECTIC AGENT

Benfluorex (Fig. 1b; Mediator; Servier, Suresnes, France) is an anorectic and hypolipidaemic agent that is structurally related to fenfluramine, developed by the French pharmaceutical company Servier. Benfluorex inhibits gluconeogenesis and this is ascribed, at least in part, to a decrease in mitochondrial b-oxidation. Ben- fluorex decreases acetyl-CoA concentrations, reducing pyruvate carboxylase activity and thereby releases its inhibitory effect on pyruvate dehydrogenase. Benfluorex also decreases ATP/ADP

and NAD+/NADH ratios, leading to reduced gluconeogenic flux at the level of 3-phosphoglycerate kinase and GAPDH (Table 1).17 Two clinical studies have shown that benfluorex may improve glycaemic control and decrease insulin resistance in patients with poorly controlled T2DM. On 18 December 2009, the European Medicines Agency (EMA) recommended the with- drawal of all medicines containing benfluorex in the European Union due to the risk of heart valve disease.18

BIGUANIDES

Biguanides are oral agents used for the treatment of mild to mod- erately severe T2DM patients to overcome insulin resistance, especially in obese patients who fail diet and exercise therapy.1,19

Biguanides have a twofold mechanism of action: (i) they enhance peripheral muscle glucose uptake and utilization by making mus- cle and fat cells more sensitive to available insulin; and (ii) they inhibit hepatic glucose output by preventing the liver from mak- ing excessive glucose.20 Biguanides are usually associated with a low risk of hypoglycemia, even in overdose, due to the fact that insulin secretion is not promoted. An earlier biguanide, namely phenformin (Fig. 2a), was intro-

duced in the US in 1957 to treat T2DM then removed from the market by the FDA in 1977 due to the high incidence of lactic acidosis. Buformin is an oral antidiabetic agent of the biguanide class, but was withdrawn from the market in some countries due to the risk of lactic acidosis. This drug has never been approved in the US. Buformin is still available and prescribed in Romania, Hungary, Taiwan and Japan. Metformin (Fig. 2a; Glucophage; Bristol-Myers Squibb, New York, NY, USA) was approved by the FDA in 1994 and has been used as first-line therapy for T2DM. Metformin suppresses hepatic glucose production, increases insulin sensitivity, enhances peripheral glucose uptake, decreases fatty acid oxidation and reduces the absorption of glu- cose from the gastrointestinal tract.21 The molecular mechanisms of action of metformin are not fully understood, but it may act via inhibition of the mitochondrial respiratory chain complex I, activation of AMP-activated protein kinase (AMPK), inhibition of glucagon-induced increases in cAMP and consequent activa- tion of protein kinase A and an effect on gut microbiota metabo- lism (Table 1; Fig. 2b).21,22 Metformin is not metabolized and is cleared from the body by tubular secretion mediated by organic cation transporters and is excreted unchanged in the urine.23 Met- formin has a low risk of causing hypoglycaemia and lactic acido- sis. However, metformin is contraindicated in people with any condition that could increase the risk of lactic acidosis, including kidney disorders, lung disease and liver disease. Metformin is often used in combination with other oral antidiabetic drugs. In the US, the most popular combination is metformin plus rosiglit- azone, sold as Avandamet by GlaxoSmithKline (Brentford, UK) since October 2002. In the US, metformin is also used in combi- nation with: (i) pioglitazone (Actoplus Met; Takeda Pharmaceuti- cals, Deerfield, IL, USA; approved by the FDA in August 2005); (ii) the SUs glipizide (Metaglip; Bristol-Myers Squibb; approved October 2002) and glibenclamide or glyburide (Glucovance; Bristol-Myers Squibb; approved September 2008); (iii) the dip- eptidyl peptidase (DPP)-4 inhibitors sitagliptin (Janumet; Merck, Whitehouse Station, NJ, USA; approved March 2007) and saxag- liptin (Kombiglyse XR; AstraZeneca, London, UK; approved

126 Z-X He et al.

Table 1 Mechanisms of action of oral antidiabetic drugs

Class Drug Mechanism of action

Aldose reductase inhibitors

Tolrestat Completely inhibits the production of sorbitol in cells Epalrestat Inhibits the reduction of glucose to sorbitol Fidarestat Blocks the production of sorbitol Ranirestat Reduces sorbitol accumulation in cells Ponalrestat Potent and specific inhibitor of aldose reductase; inhibits the production of sorbitol in cells Sorbinil Inhibits the first enzyme of the polyol pathway, which is activated when glucose levels are high and can damage

cells via multiple mechanisms Risarestat Reduces the production of sorbitol in cells

Anorectic Benfluorex Inhibits gluconeogenesis due, at least in part, to a decrease in mitochondrial b-oxidation Decreases acetyl-CoA concentrations, reducing pyruvate carboxylase activity and releasing its inhibitory effect on pyruvate dehydrogenase Decreases the ATP/ADP and NAD+/NADH ratios, leading to reduced gluconeogenic flux at the level of 3-phosphoglycerate kinase and GAPDH

Biguanides Buformin Activates AMPK, increasing insulin sensitivity Metformin Decreases blood glucose levels by reducing hepatic glucose production, decreasing intestinal absorption of

glucose and improving insulin sensitivity by increasing peripheral glucose uptake and utilization (effects mediated by AMPK activation)

Phenformin Binds to AMPK Decrease ion transport processes, affects cellular metabolism and activates AMPK Inhibits several varients of the KATP channel

DPP-4 inhibitors

Alogliptin Inhibits DPP-4, which increases active plasma incretins, aiding glycaemic control Gemigliptin Inhibits DPP-4, which increases active plasma incretins, aiding glycaemic control Linagliptin Competitive and reversible DPP-4 inhibitor that slows the breakdown of GLP-1, resulting in overall decrease in

glucose production in the liver and an increase in insulin in a glucose-dependent manner Saxagliptin Inhibits DPP-4

Forms a reversible, histidine-assisted covalent bond between its nitrile group and the S630 hydroxyl oxygen on DPP-4 DPP-4 inhibition increases levels active of GLP-1, which inhibits glucagon production from pancreatic a-cells and increases insulin production from pancreatic b-cells

Sitagliptin Highly selective DPP-4 inhibitor that is believed to act by slowing the inactivation of incretin hormones, including GLP-1 and GIP, thereby increasing their concentrations and prolonging their action

Vildagliptin Inhibits DPP-4, which inhibits the inactivation of GLP-1 by DPP-4, allowing GLP-1 to potentiate the secretion of insulin in b-cells

Dopamine D2 receptor agonist

Bromocriptine Stimulation of D2 receptors inhibits adenylyl cyclase, decreasing intracellular cAMP concentrations and blocking IP3-dependent release of Ca

2+ from intracellular stores

a-Glucosidase inhibitors

Acarbose Reversibly binds pancreatic a-amylase and membrane-bound intestinal a-glucoside hydrolases in the brush border of the small intestine

Miglitol Does not enhance insulin secretion Antihyperglycaemic action results from reversible inhibition of membrane-bound intestinal a-glucoside hydrolase

Voglibose Competitive inhibitor of a-glucosidases in the brush border of the small intestine Meglitinides Mitiglinide Thought to stimulate insulin secretion by binding to and blocking KATP channels in pancreatic b-cells

Nateglinide Activity depends on the presence functioning b-cells and glucose Has no effect on insulin release in the absence of glucose Potentiates the effect of extracellular glucose on KATP channels and has little effect on insulin levels between meals and overnight

Repaglinide Activity depends on the presence functioning b-cells and glucose Has no effect on insulin release in the absence of glucose Potentiates the effect of extracellular glucose on KATP channels and has little effect on insulin levels between meals and overnight

SGLT-2 inhibitors

Canagliflozin Inhibits SGLT-2 and so reduces reabsorption of filtered glucose and lowers the renal threshold for glucose, thereby increasing urinary glucose excretion

Dapagliflozin Competitive inhibitor of SGLT-2 Blocks glucose reabsorption into the kidney, resulting in elimination of blood glucose through the urine

Empagliflozin Inhibits SGLT-2, reducing the reabsorption of glucose in the kidney Remogliflozin Blocks SGLT-2, resulting in decreased reabsorption of glucose in the kidney Sergliflozin Blocks SGLT-2, resulting in decreased reabsorption of glucose in the kidney Tofogliflozin Binds to SGLT-2, inhibiting reabsorption of glucose in the kidney

Sulphonylureas Acetohexamide Binds to KATP channels on the cell membrane of pancreatic b-cells, inhibiting tonic hyperpolarizing outflux of potassium, causing membrane depolarization, which opens voltage-gated Ca2+ channels Increased intracellular calcium leads to increased fusion of insulin granules with the cell membrane and therefore increased secretion of (pro)insulin

Current drugs for treatment of T2DM 127

November 2010); and (iv) the meglitinide repaglinide (Prandi- Met; Sciele Pharma (Florham Park, NJ, USA) and Novo Nordisk (Plainsboro Township, NJ, USA); approved June 2008). In Eur- ope, the combined use of metformin and the DPP-4 inhibitor li- nagliptin was approved in May 2005 and this combination is

sold under the trade name Jentadueto (Eli Lilly, Indianapolis, IN, USA). This combination was also approved by the FDA in Feb- ruary 2012. The EMA also approved a new combination of met- formin and the DPP-4 inhibitor vildagliptin (Eucreas; Novartis, Basel, Switzerland) in February 2008. Furthermore, the FDA

Table 1 (continued)

Class Drug Mechanism of action

Carbutamide Block KATP channels on b-cells, resulting in membrane depolarization and calcium influx, calcium–calmodulin binding, kinase activation and release of insulin-containing granules by exocytosis (an effect similar to that of glucose)

Chlopropamide Binds to KATP channels on the pancreatic cell surface, reducing potassium conductance and causing membrane depolarization, which stimulates calcium ion influx through voltage-sensitive Ca2+ channels, increasing intracellular Ca2+ concentrations, which induces the secretion, or exocytosis, of insulin

Metahexamide Blocks KATP channels on b-cells, leading to membrane depolarization and calcium influx, calcium–calmodulin binding, kinase activation and release of insulin-containing granules by exocytosis (an effect similar to that of glucose)

Tolbutamide Inhibits KATP channels on b-cell membranes and potassium efflux, which results in membrane depolarization and calcium influx, calcium–calmodulin binding, kinase activation and release of insulin-containing granules by exocytosis (an effect similar to that of glucose)

Tolazamide Likely binds to KATP channels on the pancreatic cell surface, reducing potassium conductance and causing membrane depolarization, which stimulates calcium ion influx through voltage-sensitive Ca2+ channels, raising intracellular Ca2+ concentrations, which induces the secretion, or exocytosis of insulin

Glibenclamide Binds to KATP channels on the pancreatic cell surface, reducing potassium conductance and causing membrane depolarization, which stimulates calcium ion influx through voltage-sensitive Ca2+ channels, raising intracellular Ca2+ concentrations, which induces the secretion, or exocytosis of insulin

Glibornuride Blocks KATP channels, reducing potassium conductance and causing membrane depolarization Gliclazide Binds to b-cell SU receptor, which blocks KATP channels, leading to decreased potassium efflux and

depolarization of b-cells, which opens voltage-dependent Ca2+ channels, resulting in calmodulin activation, leading to exocytosis of insulin-containing secretorty granules

Glimepiride Blood glucose-lowering action appears to be dependent on stimulating insulin release from functioning pancreatic b-cells and increasing the sensitivity of peripheral tissues to insulin Likely binds KATP channels on pancreatic b-cells, reducing potassium conductance and causing membrane depolarization

Glipizide Likely binds KATP channels on pancreatic b-cells, reducing potassium conductance and causing membrane depolarization Depolarization stimulates calcium ion influx through voltage-sensitive Ca2+ channels, raising intracellular Ca2+

concentrations, which induces the secretion, or exocytosis, of insulin Gliquidone Blood glucose-lowering action appears to be dependent on stimulating insulin release from functioning pancreatic

b-cells and increasing the sensitivity of peripheral tissues to insulin Likely binds KATP channels on pancreatic b-cells, reducing potassium conductance and causing membrane depolarization

Glisoxepide Hypoglycemic SU Augments insulin secretion from pancreatic b-cells Non-selective KATP channel blocker Is thought to stimulate insulin secretion by closing KATP channels in pancreatic b-cells

Glyclopyramide Inhibits KATP channels in pancreatic b-cells, stimulating insulin secretion Thiazolidinedione Pioglitazone PPAR agonist in target tissues for insulin action (e.g. adipose tissue, skeletal muscle and liver)

Enhances tissue sensitivity to insulin and reduces hepatic gluconeogenesis Rivoglitazone PPAR-c agonist

Enhances tissue sensitivity to insulin and reduces hepatic gluconeogenesis Rosiglitazone Highly selective and potent agonist at PPAR in target tissues for insulin action (e.g. adipose tissue, skeletal

muscle and liver) Activation of PPAR-c regulates transcription of insulin-responsive genes involved in the control of glucose production, transport and utilization

Troglitazone Lowers blood glucose by improving target cell response to insulin Unique mechanism of action is dependent on the presence of insulin Decreases hepatic glucose output and increases insulin-dependent glucose disposal in skeletal muscle Mechanism of action thought to involve binding to PPAR that regulate the transcription of a number of insulin- responsive genes critical for the control of glucose and lipid metabolism

AMPK, AMP-activated protein kinase; DPP-4, dipeptidyl peptidase 4; GIP, gastric inhibitory polypeptide; GLP-1, glucagon-like peptide-1; KATP chan- nel, ATP-sensitive K+ channel; IP3, inositol 1,4,5-trisphosphate; PPAR, peroxisome proliferator-activated receptor; SGLT-2, sodium-glucose cotransport- er-2; SU, sulphonylurea.

128 Z-X He et al.

approved the combination of metformin and alogliptin under the trade name Kazano (Takeda Pharmaceuticals) in January 2013.

BILE ACID SEQUESTRANTS

Cholestyramine and colestipol are first-generation bile acid se- questrants and antihyperlipidaemic agents that currently have a limited use because of their relatively weak effect on lowering low-density lipoprotein cholesterol (LDL-C) and poor tolerabil- ity.24,25 The second-generation bile acid sequestrants, such as colesevelam and colestimide (also called colestilan; approved for treating T2DM in Japan in 1999) have a glucose-lowering effect and improved tolerance, which has led to re-evaluation of their application as oral antidiabetic agents. Colesevelam (Welchol; Daiichi Sankyo, Tokyo, Japan) is a bile

acid-binding resin sequestrant developed by Genzyme and mar- keted in the US since 2008 by Daiichi Sankyo. Colesevelam is indicated as an adjunct to diet and exercise to reduce elevated LDL-C in patients with primary hyperlipidaemia as monotherapy and to improve glycaemic control in T2DM, including in combi- nation with a statin.26,27 The mechanism by which colesevelam improves glycaemia has not been determined but may involve enhanced meal-induced incretin secretion and altered farnesoid X receptor (FXR) signalling.25,27

GLIPTINS (DPP-4 INHIBITORS)

Dipeptidyl peptidase-4 (also known as adenosine deaminase com- plexing protein 2 or CD26) cleaves the two N-terminal amino acids from peptides with a proline or alanine in the second posi- tion, inactivating both glucagon-like peptide-1 (GLP-1) and gas- tric inhibitory polypeptide (GIP).28,29 Endogenously released GLP-1 has a short biological half-life of 1.5–5 min, whereas the serum half-life of GIP is approximately 7 min.30 Upon secretion, GLP-1 and GIP are rapidly degraded and inactivated by DPP-4. Therefore, DPP-4 inhibitors (Fig. 3a) have been developed and used to prevent degradation of endogenously released GLP-1 and GIP and, consequently, to enhance plasma concentrations of

active incretin, prolonging the actions of the incretin and leading to increased insulin levels (Table 1).31

Sitagliptin (Januvia; Merck) was the first DPP-4 inhibitor launched and was approved for use in the US in October 2006 by the FDA. Sitagliptin was well tolerated and was not associated with hypoglycaemia.32 Further, a fixed-dose combination tablet containing 50 mg sitagliptin and 500 or 1000 mg metformin was approved by FDA in March 2007. Vildagliptin (Zomelis and Gal- vus; Novartis) gained approval from the EMA in February 2008. Aaxagliptin (Onglysa; AstraZeneca), another DPP-4 inhibitor, was approved by the FDA in July 2009. The new DPP-4 inhibi- tor linagliptin (Tradjenta; Eli Lilly) was approved by the FDA in May 2011. Gemigliptin (Zemiglo; LG Life Science, Seoul, South Korea; previously known as LC15-0444) gained approval in Korea in June 2012. Alogliptin (Nesina; Takeda Pharmaceuticals) obtained approval in Japan in April 2010. In January 2013, the FDA approved the drug in three formulations: (1) as a stand- alone; (ii) in combination with metformin (Kazano; Takeda Phar- maceuticals); and (iii) in combination with pioglitazone (Oseni; Takeda Pharmaceuticals). Alogliptin as monotherapy or added to metformin, pioglitazone, glibenclamide, voglibose or insulin ther- apy significantly improves glycaemic control compared with pla- cebo in adult or elderly patients with inadequately controlled T2DM.100 The clinical pharmacokinetics of alogliptin are given in Table 2. The National Institute for Health and Clinical Excel- lence (NICE) clinical guideline for T2DM (https://www.nice.org. uk/guidance/cg87, accessed 20 November 2014) suggests adding a DPP-4 inhibitor instead of an SU as second-line treatment to first-line metformin if there is a considerable risk of hypoglyca- emia or if an SU is contraindicated or not tolerated. The insulin-releasing effects of the incretins are glucose depen-

dent and the incretins have no insulinotropic activity at lower glucose concentrations (< 4 mmol/L), thus reducing the chance of hypoglycaemia, which is one of the major concerns with other antidiabetic drug classes. Furthermore, DPP-4 inhibitors are the first substances that have a glucose-dependent dual action on a- and b-cell functions, stimulating insulin secretion and sup- pressing glucagon secretion under hyperglycaemic conditions.

(a) (b)

Fig. 1 Chemical structure of (a) aldosse reductase inhibitors tolrestat, epalrestat, fidarestat, ranirestat, ponalrestat, sorbinil and risarestat and (b) benfluo- rex, an anorectic and hypolipidaemic agent.

Current drugs for treatment of T2DM 129

Table 2 Clinical pharmacokinetics of selected oral antidiabetic drugs

Drug Subjects Dose Cmax (mg/L) Tmax (h) AUC (mg/L per h) t½ (h) References

Alogliptin 13 patients 25 mg, q.d. (Day 1)

0.146 � 0.059 1.30 (0.80–6.20) 1.058 � 0.165 76

13 patients 25 mg, q.d. (Day 14)

0.153 � 0.039 1.10 (0.80–4.50) 1.474 � 0.214 21.10 � 8.80 76

14 patients 100 mg, q.d. (Day 1)

0.630 � 0.276 1.30 (0.50–6.40) 4.917 � 1.166 76

14 patients 100 mg, q.d. (Day 14)

0.742 � 0.578 1.00 (0.60–10.60) 6.804 � 2.866 20.00 � 14.90 76

15 patients 400 mg, q.d. (Day 1)

2.420 � 1.130 1.00 (0.50–2.50) 15.82 � 4.09 76

14 patients 400 mg, q.d. (Day 14)

2.560 � 0.791 1.10 (0.50–4.50) 20.68 � 5.70 12.50 � 2.20 76

Canagliflozin 9 patients 50 mg, q.d. (Day 1)

0.426 � 0.106 2.00 (1.00–4.00) 3.139 � 0.935 77

9 patients 50 mg, q.d. (Day 7)

0.536 � 0.174 2.00 (1.00–5.00) 4.059 � 1.105 16.30 � 4.80 77

8 patients 100 mg, q.d. (Day 1)

1.096 � 0.444 1.50 (1.00–5.00) 6.357 � 1.431 77

8 patients 100 mg, q.d. (Day 7)

1.227 � 0.481 1.50 (1.00–5.00) 8.225 � 1.947 13.70 � 2.10 77

10 patients 300 mg, q.d. (Day 1)

3.480 � 0.844 1.50 (1.00–6.00) 22.58 � 7.34 77

10 patients 300 mg, q.d. (Day 7)

4.678 � 1.685 1.50 (1.00–2.00) 31.00 � 11.15 14.90 � 4.80 77

Dapagliflozin 6 HV 2.5 mg, q.d. 0.029 1.00 (1.00–2.00) 0.103 8.10 � 4.80 78 6 HV 10 mg, q.d. 0.124 1.30 (1.00–1.50) 0.489 12.10 � 7.80 78 6 HV 20 mg, q.d. 0.265 1.00 (0.50–2.00) 0.939 12.20 � 4.70 78 6 HV 50 mg, q.d. 0.610 1.30 (1.00–1.50) 2.093 12.10 � 7.00 78

Empagliflozin 16 HV 50 mg, q.d. 0.532 2.50 (1.00–4.00) 3.801 8.50 79 16 patients 10 mg, b.i.d. 0.139 1.50 (1.00–2.50) 0.699 8.80 80 16 patients 25 mg, b.i.d. 0.326 1.50 (0.80–2.00) 1.772 8.20 80 30 patients 100 mg, b.i.d. 1.186 1.50 (0.80–3.00) 7.169 8.70 80

Epalrestat HV 50 mg, q.d. 3.900 1.00 6.400 81 Glibenclamide 110 patients 20 mg, q.d.* 0.354 � 0.033 3.20 � 0.86 2.968 � 0.283 10.40 � 1.80 82

110 patients 20 mg, q.d.‡ 0.360 � 0.049 3.50 � 0.45 2.810 � 0.405 9.00 � 1.30 82 Gliclazide 9 Caucasian

patients 160 mg, q.d.† 15.000 � 3.700 2.80 � 1.60 171.1 � 59.9 12.50 � 2.30 83

10 aboriginal patients

160 mg, q.d.† 14.100 � 5.100 2.10 � 0.70 143.3 � 84.7 14.20 � 4.10 83

Glimepiride 8 patients 2 mg, q.d. 1.88 � 0.21 0.706 � 0.063 3.28 � 0.21 84 Glipizide 6 patients 10 mg, q.d. 1.800–2.300 4.70 � 0.40 85

10 HV (≤ 25 years)

10 mg, q.d.* 0.465 � 0.146 2.10 � 1.00 2.584 � 1.305 4.20 � 2.70 86

10 HV (≥ 65 years)

10 mg, q.d.* 0.399 � 0.101 2.50 � 2.50 2.325 � 0.639 4.00 � 0.90 86

15 patients (≥ 65 years)

10 mg, q.d.* 0.385 � 0.150 2.30 � 1.70 1.898 � 0.664 4.20 � 1.50 86

Gliquidone 32 patients 30 mg, q.d. 0.650 (0.120–2.140) 2.25 (1.25–4.75) 5.100 (1.500–10.100) 8.00 (5.70–9.40) 87 Linagliptin 184 HV 0.5–600 mg, q.d. 0.002–2.050 0.73–6.00 0.030–15.599 55.40–184.00 88

41 patients 5 mg, q.d. 0.050 � 0.030 1.50 0.065 � 0.015 89 Metformin 13 patients 500 mg, b.i.d. 1.018 4.00 (1.00–6.00 7.141 (4.000–8.700) 90 Mitiglinide 8 HV 5 mg, q.d.* 0.565 � 0.110 0.36 � 0.16 0.762 � 0.141 1.19 � 0.22 91

8 HV 5 mg, q.d.† 0.224 � 0.065 1.75 � 0.92 0.746 � 0.193 1.21 � 0.18 91 8 HV 10 mg, q.d.* 1.874 � 0.628 0.29 � 0.19 2.440 � 0.184 1.58 � 0.36 91 8 HV 10 mg, q.d.† 0.657 � 0.269 1.97 � 0.81 2.200 � 0.573 1.60 � 0.65 91 8 HV 20 mg, q.d.* 2.635 � 0.901 0.30 � 0.10 3.610 � 0.873 1.43 � 0.19 91 8 HV 20 mg, q.d.† 0.913 � 0.345 1.18 � 0.68 3.773 � 1.075 2.03 � 1.90 91

Nateglinide 6 HV 120 mg, q.d. 5.690 ≤ 1.00 11.800 1.50 92 Pioglitazone 6 HV 45 mg, q.d. 1.329 � 0.667 2.00 (1.00–4.00) 17.387 13.70 � 5.70 93

6 patients with moderate renal impairment

45 mg, q.d. 1.337 � 0.363 1.00 (1.00–4.00) 14.466 9.70 � 3.60 93

6 patients with severe renal impairment

45 mg, q.d. 1.123 � 0.295 2.00 (1.00–4.00) 13.476 8.00 � 3.00 93

130 Z-X He et al.

This dual action leads to an improved time-course of islet hor- mone secretion after a meal and hyperglycaemia. The discovery of and advances in incretin therapy may help overcome the limi- tations of the classical treatment options for T2DM.

DOPAMINE D2 RECEPTOR AGONIST (BROMOCRIPTINE)

Bromocriptine (Fig. 3b; Cycloset; Salix Pharmaceuticals, Raleigh, NC, USA), a central-acting dopamine D2 receptor ago- nist, was approved by the FDA for the treatment of T2DM in May 2009.33 This drug has been previously widely used to treat hyperprolactinaemia and galactorrhoea caused by pituitary tumours, Parkinson’s disease, hyperprolactinaemia and neurolep- tic malignant syndrome.33 The mechanism of action underlying how bromocriptine regulates glycaemic control is unclear, but data indicate that bromocriptine improves insulin sensitivity and other metabolic abnormalities and this is likely a result of its effect on dopamine and serotonin oscillation.34 Bromocriptine is a potent agonist at dopamine D2 receptors, serotonin (5-HT1, 5-HT2 and 5-HT6) receptors and a1- and a2-adrenoceptors. In addition, it is a moderate agonist for dopamine D1 receptors and 1- and 2-adrenoceptors (Table 1).

33,34 Bromocriptine inhibits glucose-stimulated insulin secretion by direct activation of

a2-adrenoceptors on b-cells. 35 Clinical studies have shown that

quick release (QR) bromocriptine lowers HbA1c by 0.6%–1.2% (7–13 mmol/mol) either as monotherapy or in combination with other antidiabetic drugs.33

a-GLUCOSIDASE INHIBITORS

a-Glucosidase inhibitors (AGIs; Fig. 3c) are oral antidiabetic agents that delay the breakdown of complex carbohydrates in the small intestine and slow glucose absorption, which leads to a slower rise in blood glucose concentrations (Table 1).36 The AGIs are the most effective antidiabetic agents primarily target- ing post-prandial hyperglycaemia.36 Compared with metformin or the SUs, AGIs are less effective in lowering hyperglycaemia, reducing HbA1c levels by 0.5%–0.8%.36 Hypoglycaemia is not often observed with AGIs because they do not increase insulin secretion; however, increased delivery of carbohydrate to the colon is commonly observed, which results in increased gas pro- duction and gastrointestinal symptoms, such as flatulence and diarrhoea.36,37 The AGIs may be used as monotherapy or in com- bination with an appropriate diabetic diet and exercise, or they may be used in conjunction with other antidiabetic drugs. Clinically used AGIs include acarbose (first AGI approved;

Precose in North America, Glucobay in China and Europe and

Table 2 (continued)

Drug Subjects Dose Cmax (mg/L) Tmax (h) AUC (mg/L per h) t½ (h) References

Ranirestat 33 patients 5 mg, q.d. 0.50–11.00 22.00–80.00 94 34 patients 20 mg, q.d. 0.50–11.00 22.00–80.00 94

Remogliflozin 13 patients 500 mg, b.i.d. 2.689 3.00 (1.00–4.00) 6.814 90 Rosiglitazone 32 HV 1 mg, q.d.* 0.076 � 0.013 0.358 � 0.112 3.16 � 0.72 95

32 HV 2 mg, q.d.* 0.156 � 0.042 0.733 � 0.184 3.15 � 0.39 95 32 HV 8 mg, q.d.* 0.598 � 0.117 2.971 � 0.730 3.37 � 0.63 95 32 HV 8 mg, q.d.† 0.432 � 0.092 2.890 � 0.795 3.59 � 0.70 95

Sergliflozin 7 HV 5 mg, q.d. 0.007 (0.005–0.010) 0.50 (0.35–1.00) 0.003 (0.001–0.006) 52 8 HV 15 mg, q.d. 0.021 (0.016–0.026) 0.75 (0.35–3.00) 0.018 (0.013–0.025) 0.44 (0.24–0.83) 52 8 HV 50 mg, q.d. 0.084 (0.057–0.122) 0.75 (0.50–2.50) 0.095 (0.080–0.113) 1.09 (0.96–1.23) 52 8 patients 50 mg, q.d. 0.096 (0.073–0.125) 0.75 (0.25–2.00) 0.152 (0.012–0.193) 1.39 (1.07–1.81) 52 8 HV 100 mg, q.d. 0.128 (0.093–0.177) 0.75 (0.80–2.0) 0.169 (0.124–0.231) 1.06 (0.88–1.26) 52 7 patients 150 mg, q.d. 0.363 (0.221–0.595) 0.50 (0.25–1.50) 0.452 (0.321–0.636) 1.37 (1.18–1.60) 52 8 HV 200 mg, q.d. 0.350 (0.295–0.414) 1.10 (0.35–2.00) 0.502 (0.392–0.642) 1.32 (1.12–1.54 52 7 HV 500 mg, q.d. 0.845 (0.602–1.185) 0.75 (0.75–2.00) 1.154 (0.922–1.444) 1.26 (1.18–1.34) 52 7 patients 500 mg, q.d. 0.912 (0.527–1.579) 0.75 (0.5–1.25) 1.681 (1.215–2.326) 1.33 (1.14–1.56) 52

Sorbinil 16 HV 250 mg, q.d. 5.810 � 0.280 5.90 � 1.30 0.538 � 0.038 67.70 � 4.60 96 Tolbutamide 10 HV 500 mg, q.d. 63.00 � 11.00 3.30 (1.60–6.00) 798.0 � 102.0 9.10 97 Troglitazone 20 HV 400 mg, q.d.* 1.050 (0.280–1.920) 1.75 (1.00–4.00) 8.500 (1.300–16.000) 98

20 HV 400 mg, q.d.† 1.380 (0.570–4.060) 3.41 (1.00–12.00) 11.400 (4.500–20.700) 98 12 HV 400 mg, q.d.* 1.100 (0.300–3.900) 1.50 (0.75–4.00) 7.200 (1.300–24.600) 98 12 HV 400 mg, q.d.† 2.200 (0.900–3.800) 1.50 (0.50–2.00) 11.400 (4.000–21.200) 98 12 HV 400 mg, q.d.‡ 2.000 (0.800–3.700) 2.00 (1.50–4.00) 11.500 (4.000–25.200) 98 20 HV 400 mg, q.d.* 1.060 (0.440–1.810) 1.60 (0.50–4.00) 9.300 (4.700–16.400) 98 20 HV 400 mg, q.d.† 1.960 (0.450–4.010) 3.70 (2.00–12.00 17.100 (7.800–27.900) 98 6 HV 400 mg, q.d.† 0.770 (0.380–1.650) 4.20 (2.00–6.00) 13.200 (3.400–42.200) 15.90 (4.30–53.70) 98 8 HV 400 mg, q.d.† 0.730 (0.380–1.200) 3.70 (1.00–8.00) 13.600 (3.600–23.100) 24.00 (6.60–70.40) 98 8 HV 400 mg, q.d.† 0.370 (0.160–0.790) 5.50 (2.00–16.00) 5.990 (2.100–17.800) 9.90 (3.80–22.90) 98

Vildagliptin 58–151 HV 50 mg, q.d. 0.119 3.00 1.334 13.10 99

Values show the mean � SD or median values with the interquartile range in parentheses. *Administered to fasted participants. †Administered with food. ‡Administered 30 min after a meal. AUC, area under the plasma concentration–time curve; Cmax, maximum plasma concentration observed; HV, healthy volunteer; t½, half-life of

elimination, Tmax, time to reach Cmax.

Current drugs for treatment of T2DM 131

Prandase in Canada (Bayer HealthCare Pharmaceuticals, Mont- ville, NJ, USA), emiglitate, miglitol (Glycet; Pfizer, New York, NY, USAand voglibose. Only acarbose and miglitol are available in the US. Acarbose is an adjunct to diet and exercise in T2DM patients in whom glycaemic control is not achieved. All AGIs act on a-glucosidases. However, acarbose is most effective in inhibit- ing glucoamylase, whereas miglitol is a more potent inhibitor of disaccharide-digesting enzymes.36 Acarbose inhibits a-glucosidas- es in the brush border of the small intestines and pancreatic a- amylase. Moreover, new AGIs are being developed to improve the efficacy and safety of this class of drugs.38 Interestingly, AGIs are frequently prescribed as first-line agents in Asian coun- tries with a diet rich in complex carbohydrates, but they are sel- dom prescribed in the US and Europe, where the diet is rich in protein and fat. Generally, AGIs are well tolerated.

GLUCAGON-LIKE PEPTIDE-1 AGONISTS

So far, there are at least five GLP-1 agonists approved for the treatment of T2DM worldwide. Exenatide (Byetta; AstraZeneca) was the first GLP-1 analogue launched and was approved by the FDA in April 2005 and the EMA in September 2006. It was developed from exendin-4, found in the saliva of the Gila mon- ster lizard and has approximately 50% homology with human GLP-1. Liraglutide (Fig. 4; Victoza; Novo Nordisk, Bagsværd, Denmark) has 97% homology with GLP-1 and was approved by the FDA in January 2010. Two more GLP-1 analogues, namely albiglutide (GlaxoSmithKline) and taspoglutide (Roche) have been developed. However, the Phase III clinical trial of taspoglu- tide has been halted due to serious hypersensitivity reactions and gastrointestinal side-effects.39

MEGLITINIDES OR GLINIDES (POTASSIUM CHANNEL MODULATORS)

Meglitinides (Fig. 5) stimulate rapid insulin secretion from b- cells by inhibiting ATP-sensitive K+ channels and activating volt- age-dependent Ca2+ channels (Table 1). The extent of insulin release stimulated by meglitinides is glucose dependent and diminishes at low glucose levels.40 Unlike SUs, meglitinides act on a non-SU binding site on pancreatic b-cells. Meglitinides are indicated as adjuncts to diet and exercise to improve glycaemic control in adults with T2DM. Meglitinides are not recommended as monotherapy; however, they may be added to metformin ther- apy for those patients with continued post-prandial hyperglyca- emia. Repaglinide (Prandin; Novo Nordisk), a benzoic acid deriva-

tive, was the first meglitinide analogue and has been available since December 1997 in the US.41 The rapid onset of action and glucose-dependent insulin secretory effect of repaglinide makes this agent suitable for preprandial administration. In addition, repaglinide causes early phase insulin secretion, which allows patients to have flexible meal times without increasing the risk of hypoglycaemia or compromising glycaemic control.41 As with SUs, the major side-effect for repaglinide is hypoglycaemia. Nateglinide (Starlix; Novartis) was approved by the FDA in December 2000. Nateglinide is used with diet and exercise to control blood glucose levels in patients with T2DM.42,43 Nategli- nide promotes a more rapid but less sustained secretion of insu- lin than other available oral antidiabetic agents. It is most effective when administered in a dose of 120 mg, 1–10 min before a meal. Combination studies with metformin (Gluco- phage) have shown it to be effective in controlling hyperglyca- emia.42 Whereas metformin reduces basal plasma glucose levels, nateglinide helps to control post-prandial peaks. It can also be used in combination with pioglitazone (Actos; Takeda Pharma- ceuticals) or rosiglitazone (Avandia; GlaxoSmithKline). Mitigli- nide is the third meglitinide mainly targeting post-prandial hyperglycaemia.44 However, it has not gained approval from the FDA. Mitiglinide exhibits a rapid onset and short duration of action, mimicking a physiological pattern of insulin release in non-diabetic people.44 This drug modestly decreases HbA1c, post-prandial hyperglycaemia, oxidative stress and inflammatory markers associated with post-prandial hyperglycaemia. Mitiglinide is well tolerated.

(a)

(b)

Fig. 2 (a) Chemical structure of buformin, metformin and phenformin. (b) Proposed mechanisms of action of metformin. Metformin activates AMP-activated protein kinase (AMPK) in the liver and skeletal muscle and modulates microbiota metabolism, resulting in decreased gluconeo- genesis, glycogenesis and fatty acid oxidation, eventually leading to a reduction in blood glucose levels. p-AMPK, phosphorylated AMPK; ACC, acetyl-CoA carboxylase; SREPB1, sterol regulatory element bind- ing transcription factor 1.

132 Z-X He et al.

SODIUM–GLUCOSE COTRANSPORTER 2 INHIBITORS

Sodium–glucose cotransporter 2 (SGLT-2) inhibitors (Fig. 6) function by lowering the threshold for glycosuria and correcting hyperglycaemia.45,46 Inhibition of SGLT-2 results in normaliza-

tion of blood glucose levels and amelioration of insulin resistance by augmenting insulin signalling and increasing glucose trans- porter GLUT-4 and glycogen synthase activity in muscle.45,46 In the liver, correction of hyperglycaemia decreases the activity of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, which, in turn, results in a reduction in gluconeogenesis, total hepatic glucose production and fasting plasma glucose (FPG) concentrations.45,46 Furthermore, correction of the hyperglyca- emia improves b-cell function (Table 1).45,46

Clinical trials of SGLT-2 inhibitors in patients with T2DM demonstrate a significant clinical effect in decreasing serum glu- cose, HbA1c, bodyweight and systolic blood pressure, improving b-cell function and minimizing the risk of hypoglycaemia.47

Canagliflozin (Invokana; Johnson & Johnson, New Brunswick, NJ, USA) was the first SGLT-2 inhibitor48 to gain FDA approval in March 2013 and from the EMA in September 2013. Canagli- flozin is indicated as an adjunct to diet and exercise to improve glycaemic control in adults with T2DM.49,50 It corrects hyper- glycaemia, has an insulin-independent action, reduces HbA1c by 0.5–1.1%, promotes weight loss, is associated with a low incidence of hypoglycaemia, complements the action of other antidiabetic agents, can be used at any stage of diabetes and appears to be safe in patients with impaired renal function. Due to its side-effects, such as urinary tract and genital infections and hypotension, proper patient selection for drug initiation and close monitoring are important.50 Dapagliflozin (Foxiga; Bristol-Myers Squibb) has been approved by the EMA and is already on the market in several European countries, but the FDA rejected dapa- gliflozin based on a lack of clinical data to effectively assess the benefit : risk profile. Dapagliflozin can be used in combination with other antihyperglycaemic agents and at all stages of the disease. Several other SGLT-2 inhibitors are currently in Phase I, II or

III clinical trials; including ISIS388626, GW869682, EGT0001442, ertugliflozin, sergliflozin, ipragliflozin, empagliflo- zin, tofogliflozin and luseogliflozin (Table 2). In healthy volun- teers and T2DM patients, oral administration of sergliflozin produces rapid and sustained suppression of renal glucose

(a) (b)

(c)

Fig. 3 Chemical structure of (a) the dipeptidyl peptidase 4 inhibitors alogliptin, gemigliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin, (b) bro- mocriptine, a centrally acting dopamine D2 receptor agonist, and (c) the a-glucosidase inhibitors acarbose, miglitol and voglibose.

Fig. 4 Chemical structure of liraglutide, a glucagon-like peptide-1 agonist.

Current drugs for treatment of T2DM 133

reabsorption and dose-dependent glucosuria.51,52 Ipragliflozin (ASP1941) is an SGLT-2 inhibitor in Phase III clinical devel- opment for the treatment of T2DM.53–55 Ipragliflozin signifi- cantly reduces HbA1c, FPG and the amplitude of glucose excursions, with good safety profiles.56,57 Empagliflozin is a newly developed selective SGLT-2 inhibitor for the treatment of T2DM as monotherapy or in combination therapy with other antidiabetic agents.58,59 Empagliflozin is well tolerated in T2DM patients.60

SULPHONYLUREAS

Sulphonylureas have long been established in the treatment of T2DM, since the 1950s, and were the first oral antidiabetic medi- cations to be introduced into clinical practice. They are still widely used and are the second-line recommended choice of oral hypoglycaemic treatment after metformin.61 Sulphonylureas are insulin secretagogues that bind to SU receptors (SUR1) on func- tional b-cells, causing closure of ATP-sensitive K+ channels, which leads to depolarization, an influx of Ca2+ and insulin secretion (Table 1).62,63 Tolbutamide and gliclazide block chan- nels containing SUR1 (b-cell type; encoded by the ABCC8 gene), but not SUR2A (cardiac and skeletal muscle type; encoded by the ABCC9 gene) or SUR2B (smooth muscle and adipose tissue; encoded by the ABCC9 gene), whereas glibenclamide, glimepi- ride, repaglinide and meglitinide block both types of chan- nels.62,64 Sulphonylureas used as monotherapy can reduce HbA1c levels by approximately 1.51% (corresponding to a decrease of 17 mmol/mol glucose), which is comparable to that of metformin.65 Sulphonylureas added to oral diabetes treatment reduce HbA1c levels by 1.62% (18 mmol/mol) compared with other treatments and SU added to insulin lowers HbA1c by 0.46% (6 mmol/mol) and lowers the insulin dose.65 Sulphonylu- reas may also reduce hepatic clearance of insulin, further increas- ing plasma insulin levels. The first-generation SUs include tolbutamide, acetohexamide,

carbutamide, metahexamide, tolazamide and chlorpropamide (Fig. 7a) and they are rarely used nowadays due to their severe side-effects. The major side-effects induced by SUs include hypo- glycaemia or even coma and binding to cardiac receptors, result- ing in failure of coronary vasodilatation and subsequent deleterious cardiac effects due to low specificity of the biological action, delayed time of onset and the long duration of the effect.66 Second-generation SUs exhibit a safer and better biologi-

cal profile, which is achieved by selective binding and a rapid onset of action. These improvements address the issues of SU- induced hypoglycaemia and cardiovascular side-effects. The sec- ond-generation SUs include glibenclamide (glyburide, Diabeta, Glynase and Micronase; Pfizer), glibornuride, glipizide (Glucotrol; Pfizer), gliquidone, glisoxepide, glyclopyramide (Dea- melin-S; KYORIN Pharmaceutical, Tokyo, Japan), glimepiride (Amaryl; Hoechst Marion Roussel, Kansas City, MO, USA) and gliclazide (not marketed in US; Fig. 7b).

THIAZOLIDINEDIONES AND/OR GLITAZONES AND DUAL PEROXISOME PROLIFERATOR- ACTIVATED RECEPTOR a AND c AGONISTS

(GLITAZARS)

Thiazolidinediones (Fig. 8) act as peroxisome proliferator-acti- vated receptor (PPAR) agonists, lowering plasma glucose, triglyc- eride and fatty acid levels in patients with T2DM (Table 1). There are three distinct PPARs that have been identified, namely PPARa, PPARd (also called PPARb, nuclear hormone receptor 1 (NUC-1) or fatty acid-activated receptor (FAAR)) and PPARc, with substantial differences in tissue distribution, ligand binding and metabolic regulation.67,68 Peroxisome proliferator-activated receptor a is the most abundant in brown adipose tissue and liver and is present to a lesser extent in the kidney, heart and skeletal muscle.67 Peroxisome proliferator-activated receptor d is widely distributed, but is mainly expressed in the gut, kidney and heart.69 Peroxisome proliferator-activated receptor c is mainly expressed in adipose tissue, followed by the enteric system, immune system and retina.67

An older TZD troglitazone was withdrawn from the market in March 2000 due to fatal idiosyncratic hepatotoxicity. Other TZDs, including rosiglitazone, pioglitazone and rivoglitazone, have not shown the same problems, but patients should be clo- sely monitored for possible liver problems.70,71 Hypoglycaemia associated with TZDs (rosiglitazone) is low (≤ 2%) because they do not stimulate insulin secretion, which is similar to biguanides. Thiazolidinediones are contraindicated in patients with severe

Fig. 5 Chemical structure of the meglitinides mitiglinide, nateglinide and repaglinide.

Fig. 6 Chemical structure of the sodium–glucose cotransporter 2 inhibi- tors canagliflozin, dapagliflozin, empagliflozin, remogliflozin, sergliflozin and tofogliflozin.

134 Z-X He et al.

heart failure or liver disease. Glitazones have only a modest effect on dyslipidaemia and increase fat mass and plasma vol- ume; fibrate PPARa activators decrease plasma triglycerides and increase high-density lipoprotein (HDL) cholesterol levels and PPARd activators increase the capacity for fat oxidation in skele- tal muscle.72 These observations have encouraged attempts to develop single molecules that activate two or all three PPARs. Many dual PPARa and PPARc agonists, such as aleglitazar, mu- raglitazar, saroglitazar and tesaglitazar, are under development and reduce both hyperglycaemia and dyslipidaemia.72 However, their development has been hampered by issues such as increased weight gain, oedema, plasma creatinine and myocardial infarction or stroke and cancer risk. In June 2013, saroglitazar, developed by Zydus Cadila (Ahmedabad, India), was the first glitazar to be approved by the Drug Controller General of India for the treat- ment of T2DM. It is marketed under the trade name Lipaglyn. The average terminal half-life of saroglitazar is 5.6 h and it is not eliminated via the renal route.73 Single oral doses of sarog-

litazar up to 128 mg are well tolerated.73 Bezafibrate (marketed as Bezalip (Roche) and various other brand names) is a fibrate drug used for the treatment of hyperlipidaemia. It helps lower LDL-C and triglyceride and increase HDL in the blood. Like the other fibrates, bezafibrate is a PPARa agonist; some studies suggest it may also have modulating effects on PPARc and PPARd.74,75

CONCLUSIONS AND FUTURE DIRECTIONS

Despite the fact that a variety of antidiabetic agents are available for the treatment T2DM patients, there are shortcomings in diabetes treatment at present and the search for optimal therapy is ongoing. Putting aside common side-effects, such as weight gain and hypo- glycaemia, current diabetes therapies do not address the key driver of this condition, namely b-cell dysfunction, and do not alter the progressive nature of the insulin secretory deficit. In addition, the pathophysiology of the disease is only partially understood and there are currently no antidiabetic agents that can effectively reduce excessive cardiovascular risk associated with T2DM. Therefore, development of new antidiabetic drugs should not only address blood glucose levels, but also aim to halt disease progression, restore b-cell function and, in the long run, reduce T2DM-associ- ated complications, such as cardiovascular risks.

ACKNOWLEDGEMENTS

The authors’ work reported herein was supported by Startup Funds from the College of Pharmacy, University of South Florida (Tampa, FL, USA) and Guizhou Medical University (Guiyang, China). Z-WZ holds a postdoctoral scholarship from the College of Pharmacy, University of South Florida. The authors that Mr Jeffrey L Edelman (University of South Florida) for help with English language expression.

(a) (b)

Fig. 7 Chemical structure of (a) first- and (b) second-generation sulphonylureas.

Fig. 8 Chemical structures of the thiazolidinediones pioglitazone, rivog- litazone, rosiglitazone and troglitazone.

Current drugs for treatment of T2DM 135

DISCLOSURE

The authors declare no conflicts of interest.

REFERENCES

1. Holman RR. Type 2 diabetes mellitus in 2012. Optimal manage- ment of T2DM remains elusive. Nat. Rev. Endocrinol. 2013; 9: 67–8.

2. Stein SA, Lamos EM, Davis SN. A review of the efficacy and safety of oral antidiabetic drugs. Expert Opin. Drug Saf. 2013; 12: 153–75.

3. Oka M, Kato N. Aldose reductase inhibitors. J. Enzyme Inhib. 2001; 16: 465–73.

4. Sestanj K, Bellini F, Fung S et al. N-[5-(Trifluoromethyl)-6-meth- oxy-1-naphthalenyl]thioxomethyl]-N-methylglycine (tolrestat), a potent, orally active aldose reductase inhibitor. J. Med. Chem. 1984; 27: 255–6.

5. Foppiano M, Lombardo G. Worldwide pharmacovigilance systems and tolrestat withdrawal. Lancet 1997; 349: 399–400.

6. Nyholm B, Brock B, Orskov L, Schmitz O. Amylin receptor agon- ists: A novel pharmacological approach in the management of insulin-treated diabetes mellitus. Expert Opin. Investig. Drugs 2001; 10: 1641–52.

7. Scheen AJ. DPP-4 inhibitors in the management of type 2 diabe- tes: A critical review of head-to-head trials. Diabetes Metab. 2012; 38: 89–101.

8. Plosker GL. Dapagliflozin: A review of its use in type 2 diabetes mellitus. Drugs 2012; 72: 2289–312.

9. Deeks ED. Linagliptin. A review of its use in the management of type 2 diabetes mellitus. Drugs 2012; 72: 1793–824.

10. Gong L, Goswami S, Giacomini KM, Altman RB, Klein TE. Met- formin pathways: Pharmacokinetics and pharmacodynamics. Phar- macogenet. Genomics 2012; 22: 820–7.

11. Inkster B, Zammitt NN, Frier BM. Drug-induced hypoglycaemia in type 2 diabetes. Expert Opin. Drug Saf. 2012; 11: 597–614.

12. Gough SC. Liraglutide: From clinical trials to clinical practice. Diabetes Obes. Metab. 2012; 14 (Suppl. 2): 33–40.

13. Pillay K, Govender P. Amylin uncovered: A review on the poly- peptide responsible for type II diabetes. Biomed. Res. Int. 2013; 2013: 826706.

14. Lebovitz HE. Adjunct therapy for type 1 diabetes mellitus. Nat. Rev. Endocrinol. 2010; 6: 326–34.

15. Kleppinger EL, Vivian EM. Pramlintide for the treatment of diabe- tes mellitus. Ann. Pharmacother. 2003; 37: 1082–9.

16. Younk LM, Mikeladze M, Davis SN. Pramlintide and the treat- ment of diabetes: A review of the data since its introduction. Expert Opin. Pharmacother. 2011; 12: 1439–51.

17. Kohl C, Ravel D, Girard J, Pegorier JP. Effects of benfluorex on fatty acid and glucose metabolism in isolated rat hepatocytes: From metabolic fluxes to gene expression. Diabetes 2002; 51: 2363–8.

18. UK Prospective Diabetes Study (UKPDS) Group. Effect of inten- sive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352: 854–65.

19. Mehanna A. Antidiabetic agents: Past, present and future. Future Med. Chem. 2013; 5: 411–30.

20. Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 2013; 494: 256–60.

21. Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: An overview. Clin. Sci. 2012; 122: 253–70.

22. Cabreiro F, Au C, Leung KY et al. Metformin retards aging in C. elegans by altering microbial folate and methionine metabo- lism. Cell 2013; 153: 228–39.

23. Robert F, Fendri S, Hary L, Lacroix C, Andrejak M, Lalau JD. Kinetics of plasma and erythrocyte metformin after acute adminis- tration in healthy subjects. Diabetes Metab. 2003; 29: 279–83.

24. Out C, Groen AK, Brufau G. Bile acid sequestrants: More than simple resins. Curr. Opin. Lipidol. 2012; 23: 43–55.

25. Takebayashi K, Aso Y, Inukai T. Role of bile acid sequestrants in the treatment of type 2 diabetes. World J. Diabetes 2010; 1: 146–52.

26. Emami Riedmaier A, Fisel P, Nies AT, Schaeffeler E, Schwab M. Metformin and cancer. From the old medicine cabinet to pharma- cological pitfalls and prospects. Trends Pharmacol. Sci. 2013; 34: 126–35.

27. Hemmingsen B, Christensen LL, Wetterslev J et al. Comparison of metformin and insulin versus insulin alone for type 2 diabetes. Systematic review of randomised clinical trials with meta-analyses and trial sequential analyses. BMJ 2012; 344: e1771.

28. Edwards KL, Stapleton M, Weis J, Irons BK. An update in incre- tin-based therapy. A focus on glucagon-like peptide-1 receptor ag- onists. Diabetes Technol. Ther. 2012; 14: 951–67.

29. Stonehouse AH, Darsow T, Maggs DG. Incretin-based therapies. J. Diabetes 2012; 4: 55–67.

30. Dailey MJ, Moran TH. Glucagon-like peptide 1 and appetite. Trends Endocrinol. Metab. 2013; 24: 85–91.

31. Russell S. Incretin-based therapies for type 2 diabetes mellitus: A review of direct comparisons of efficacy, safety and patient satis- faction. Int. J. Clin. Pharm. 2013; 35: 159–72.

32. Subbarayan S, Kipnes M. Sitagliptin: A review. Expert Opin. Pharmacother. 2011; 12: 1613–22.

33. Holt RI, Barnett AH, Bailey CJ. Bromocriptine: Old drug, new formulation and new indication. Diabetes Obes. Metab. 2010; 12: 1048–57.

34. Pijl H, Edo AM. Modulation of monoaminergic neural circuits. Potential for the treatment of type 2 diabetes mellitus. Treat. Endocrinol. 2002; 1: 71–8.

35. de Leeuw van Weenen JE, Parlevliet ET, Maechler P et al. The dopamine receptor D2 agonist bromocriptine inhibits glucose-stim- ulated insulin secretion by direct activation of the a2-adrenergic receptors in b-cells. Biochem. Pharmacol. 2010; 79: 1827–36.

36. Derosa G, Maffioli P. a-Glucosidase inhibitors and their use in clinical practice. Arch. Med. Sci. 2012; 8: 899–906.

37. Nathan DM, Buse JB, Davidson MB et al. Medical management of hyperglycaemia in type 2 diabetes mellitus. A consensus algo- rithm for the initiation and adjustment of therapy: A consensus statement from the American Diabetes Association and the Euro- pean Association for the Study of Diabetes. Diabetologia 2009; 52: 17–30.

38. Narender T, Madhur G, Jaiswal N et al. Synthesis of novel triter- pene and N-allylated/N-alkylated niacin hybrids as alpha-glucosi- dase inhibitors. Eur. J. Med. Chem. 2013; 63: 162–9.

39. Nauck M, Horton E, Andjelkovic M et al. Taspoglutide, a once- weekly glucagon-like peptide 1 analogue, vs. insulin glargine titrated to target in patients with Type 2 diabetes: An open-label randomized trial. Diabet. Med. 2013; 30: 109–13.

40. Black C, Donnelly P, McIntyre L, Royle PL, Shepherd JP, Tho- mas S. Meglitinide analogues for type 2 diabetes mellitus. Cochra- ne Database Syst. Rev. 2007; 2: CD004654.

41. Scott LJ. Repaglinide: A review of its use in type 2 diabetes mell- itus. Drugs 2012; 72: 249–72.

42. Tentolouris N, Voulgari C, Katsilambros N. A review of nategli- nide in the management of patients with type 2 diabetes. Vasc. Health Risk Manag. 2007; 3: 797–807.

43. Hanif W, Kumar S. Nateglinide: A new rapid-acting insulinotropic agent. Expert Opin. Pharmacother. 2001; 2: 1027–31.

44. Phillippe HM, Wargo KA. Mitiglinide for type 2 diabetes treat- ment. Expert Opin. Pharmacother. 2013; 14: 2133–44.

45. Rosenwasser RF, Sultan S, Sutton D, Choksi R, Epstein BJ. SGLT-2 inhibitors and their potential in the treatment of diabetes. Diabetes Metab. Syndr. Obes. 2013; 6: 453–67.

136 Z-X He et al.

46. Tahrani AA. SGLT-2 inhibitors as second-line therapy in type 2 diabetes. Lancet Diabetes Endocrinol. 2014; 2: 678–9.

47. Diamant M, Morsink LM. SGLT2 inhibitors for diabetes: Turning symptoms into therapy. Lancet 2013; 382: 917–8.

48. Nomura S, Sakamaki S, Hongu M et al. Discovery of canagliflo- zin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabe- tes mellitus. J. Med. Chem. 2010; 53: 6355–60.

49. Elkinson S, Scott LJ. Canagliflozin: First global approval. Drugs 2013; 73: 979–88.

50. Babu A. Canagliflozin for the treatment of type 2 diabetes. Drugs Today 2013; 49: 363–76.

51. Hussey EK, Dobbins RL, Stoltz RR et al. Multiple-dose pharma- cokinetics and pharmacodynamics of sergliflozin etabonate, a novel inhibitor of glucose reabsorption, in healthy overweight and obese subjects: A randomized double-blind study. J. Clin. Phar- macol. 2010; 50: 636–46.

52. Hussey EK, Clark RV, Amin DM et al. Single-dose pharmacoki- netics and pharmacodynamics of sergliflozin etabonate, a novel inhibitor of glucose reabsorption, in healthy volunteers and patients with type 2 diabetes mellitus. J. Clin. Pharmacol. 2010; 50: 623–35.

53. Kurosaki E, Ogasawara H. Ipragliflozin and other sodium-glucose cotransporter-2 (SGLT2) inhibitors in the treatment of type 2 dia- betes: Preclinical and clinical data. Pharmacol. Ther. 2013; 139: 51–9.

54. Imamura M, Nakanishi K, Suzuki T et al. Discovery of ipragliflo- zin (ASP1941): A novel C-glucoside with benzothiophene struc- ture as a potent and selective sodium glucose co-transporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes mellitus. Bioorg. Med. Chem. 2012; 20: 3263–79.

55. Veltkamp SA, Kadokura T, Krauwinkel WJ, Smulders RA. Effect of ipragliflozin (ASP1941), a novel selective sodium-dependent glucose co-transporter 2 inhibitor, on urinary glucose excretion in healthy subjects. Clin. Drug Invest. 2011; 31: 839–51.

56. Schwartz SL, Akinlade B, Klasen S, Kowalski D, Zhang W, Wil- pshaar W. Safety, pharmacokinetic, and pharmacodynamic profiles of ipragliflozin (ASP1941), a novel and selective inhibitor of sodium-dependent glucose co-transporter 2, in patients with type 2 diabetes mellitus. Diabetes Technol. Ther. 2011; 13: 1219–27.

57. Fonseca VA, Ferrannini E, Wilding JP et al. Active- and placebo- controlled dose-finding study to assess the efficacy, safety, and tol- erability of multiple doses of ipragliflozin in patients with type 2 diabetes mellitus. J. Diabetes Complicat. 2013; 27: 268–73.

58. Macha S, Rose P, Mattheus M et al. Pharmacokinetics, safety and tolerability of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with hepatic impairment. Diabetes Obes. Metab. 2013; 16: 118–23.

59. Kovacs CS, Seshiah V, Swallow R et al. Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: A 24-week, randomized, placebo-controlled trial. Diabetes Obes. Metab. 2013; 16: 147–58.

60. Ferrannini E, Seman L, Seewaldt-Becker E, Hantel S, Pinnetti S, Woerle HJ. A Phase IIb, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabe- tes. Diabetes Obes. Metab. 2013; 15: 721–8.

61. Green JB, Feinglos MN. Are sulfonylureas passe? Curr. Diab. Rep. 2006; 6: 373–7.

62. Aguilar-Bryan L, Bryan J. Molecular biology of adenosine tri- phosphate-sensitive potassium channels. Endocr. Rev. 1999; 20: 101–35.

63. Proks P, Reimann F, Green N, Gribble F, Ashcroft F. Sulfonyl- urea stimulation of insulin secretion. Diabetes 2002; 51 (Suppl. 3): S368–76.

64. Nichols CG. KATP channels as molecular sensors of cellular metabolism. Nature 2006; 440: 470–6.

65. Hirst JA, Farmer AJ, Dyar A, Lung TW, Stevens RJ. Estimating the effect of sulfonylurea on HbA1c in diabetes: A systematic review and meta-analysis. Diabetologia 2013; 56: 973–84.

66. Singh S, Bhat J, Wang PH. Cardiovascular effects of anti-diabetic medications in type 2 diabetes mellitus. Curr. Cardiol. Rep. 2013; 15: 327.

67. Cronet P, Petersen JF, Folmer R et al. Structure of the PPARalpha and -gamma ligand binding domain in complex with AZ 242: Ligand selectivity and agonist activation in the PPAR family. Structure 2001; 9: 699–706.

68. Ahmadian M, Suh JM, Hah N et al. PPARgamma signaling and metabolism: The good, the bad and the future. Nat. Med. 2013; 19: 557–66.

69. Lee CH, Olson P, Hevener A et al. PPARdelta regulates glucose metabolism and insulin sensitivity. Proc. Natl Acad. Sci. USA 2006; 103: 3444–9.

70. Koffarnus RL, Wargo KA, Phillippe HM. Rivoglitazone. A new thiazolidinedione for the treatment of type 2 diabetes mellitus. Ann. Pharmacother. 2013; 47: 877–85.

71. Kung J, Henry RR. Thiazolidinedione safety. Expert Opin. Drug Saf. 2012; 11: 565–79.

72. Heald M, Cawthorne MA. Dual acting and pan-PPAR activators as potential anti-diabetic therapies. Handb. Exp. Pharmacol. 2011; 203: 35–51.

73. Jani RH, Kansagra K, Jain MR, Patel H. Pharmacokinetics, safety, and tolerability of saroglitazar (ZYH1), a predominantly PPARa agonist with moderate PPARc agonist activity in healthy human subjects. Clin. Drug Invest. 2013; 33: 809–16.

74. Bezafibrate Infarction Prevention (BIP) Study. Secondary preven- tion by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Circulation 2000; 102: 21–7.

75. Chikahisa S, Tominaga K, Kawai T et al. Bezafibrate, a peroxi- some proliferator-activated receptors agonist, decreases body tem- perature and enhances electroencephalogram delta-oscillation during sleep in mice. Endocrinology 2008; 149: 5262–71.

76. Covington P, Christopher R, Davenport M et al. Pharmacokinetic, pharmacodynamic, and tolerability profiles of the dipeptidyl peptidase-4 inhibitor alogliptin: A randomized, double-blind, placebo-controlled, multiple-dose study in adult patients with type 2 diabetes. Clin. Ther. 2008; 30: 499–512.

77. Devineni D, Curtin CR, Polidori D et al. Pharmacokinetics and pharmacodynamics of canagliflozin, a sodium glucose co-trans- porter 2 inhibitor, in subjects with type 2 diabetes mellitus. J. Clin. Pharmacol. 2013; 53: 601–10.

78. Kasichayanula S, Liu X, Griffen SC, Lacreta FP, Boulton DW. Effects of rifampin and mefenamic acid on the pharmacokinetics and pharmacodynamics of dapagliflozin. Diabetes Obes. Metab. 2013; 15: 280–3.

79. Brand T, Macha S, Mattheus M, Pinnetti S, Woerle HJ. Pharma- cokinetics of empagliflozin, a sodium glucose cotransporter-2 (SGLT-2) inhibitor, coadministered with sitagliptin in healthy vol- unteers. Adv. Ther. 2012; 29: 889–99.

80. Heise T, Seewaldt-Becker E, Macha S et al. Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks’ treatment with empagliflozin once daily in patients with type 2 diabetes. Diabetes Obes. Metab. 2013; 15: 613–21.

81. Ramirez MA, Borja NL. Epalrestat. An aldose reductase inhibitor for the treatment of diabetic neuropathy. Pharmacotherapy 2008; 28: 646–55.

82. Coppack SW, Lant AF, McIntosh CS, Rodgers AV. Pharmacoki- netic and pharmacodynamic studies of glibenclamide in non-insu- lin dependent diabetes mellitus. Br. J. Clin. Pharmacol. 1990; 29: 673–84.

83. Davis TM, Daly F, Walsh JP et al. Pharmacokinetics and phar- macodynamics of gliclazide in Caucasians and Australian Aborig- ines with type 2 diabetes. Br. J. Clin. Pharmacol. 2000; 49: 223–30.

Current drugs for treatment of T2DM 137

84. Matsuki M, Matsuda M, Kohara K et al. Pharmacokinetics and pharmacodynamics of glimepiride in type 2 diabetic patients. Compared effects of once- versus twice-daily dosing. Endocr. J. 2007; 54: 571–6.

85. Huupponen R, Seppala P, Iisalo E. Glipizide pharmacokinetics and response in diabetics. Int. J. Clin. Pharmacol. Ther. Toxicol. 1982; 20: 417–22.

86. Kradjan WA, Kobayashi KA, Bauer LA, Horn JR, Opheim KE, Wood FJ Jr. Glipizide pharmacokinetics: Effects of age, diabetes, and multiple dosing. J. Clin. Pharmacol. 1989; 29: 1121–7.

87. von Nicolai H, Brickl R, Eschey H et al. Duration of action and pharmacokinetics of the oral antidiabetic drug gliquidone in patients with non-insulin-dependent (type 2) diabetes mellitus. Arzneimittelforschung 1997; 47: 247–52.

88. Graefe-Mody U, Retlich S, Friedrich C. Clinical pharmacokinetics and pharmacodynamics of linagliptin. Clin. Pharmacokinet. 2012; 51: 411–27.

89. Friedrich C, Glund S, Lionetti D et al. Pharmacokinetic and phar- macodynamic evaluation of linagliptin in African American patients with type 2 diabetes mellitus. Br. J. Clin. Pharmacol. 2013; 76: 445–54.

90. Hussey EK, Kapur A, O’Connor-Semmes R et al. Safety, pharma- cokinetics and pharmacodynamics of remogliflozin etabonate, a novel SGLT2 inhibitor, and metformin when co-administered in subjects with type 2 diabetes mellitus. BMC Pharmacol. Toxicol. 2013; 14: 25.

91. Zhang J, Cai LJ, Peng WX, Zhu RH, Yang J, Zhang QZ. The effects of food on the pharmacokinetics of mitiglinide tablets in healthy volunteers and a novel mass-spectrometric (UPLC-MS/

MS) method for such studies. J. Clin. Pharm. Ther. 2012; 37: 95–9.

92. Weaver ML, Orwig BA, Rodriguez LC et al. Pharmacokinetics and metabolism of nateglinide in humans. Drug Metab. Dispos. 2001; 29: 415–21.

93. Budde K, Neumayer HH, Fritsche L, Sulowicz W, Stompor T, Eck- land D. The pharmacokinetics of pioglitazone in patients with impaired renal function. Br. J. Clin. Pharmacol. 2003; 55: 368–74.

94. Bril V, Hirose T, Tomioka S, Buchanan R; Ranirestat Study Group. Ranirestat for the management of diabetic sensorimotor polyneuropathy. Diabetes Care 2009; 32: 1256–60.

95. Cox PJ, Ryan DA, Hollis FJ et al. Absorption, disposition, and metabolism of rosiglitazone, a potent thiazolidinedione insulin sen- sitizer, in humans. Drug Metab. Dispos. 2000; 28: 772–80.

96. Scott AK, Webster J, Petrie JC. Sorbinil pharmacokinetics in male and female elderly volunteers. Br. J. Clin. Pharmacol. 1987; 23: 495–7.

97. Gross AS, Bridge S, Shenfield GM. Pharmacokinetics of tolbuta- mide in ethnic Chinese. Br. J. Clin. Pharmacol. 1999; 47: 151–6.

98. Loi CM, Young M, Randinitis E, Vassos A, Koup JR. Clinical pharmacokinetics of troglitazone. Clin. Pharmacokinet. 1999; 37: 91–104.

99. Bergman AJ, Cote J, Yi B et al. Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibi- tor. Diabetes Care 2007; 30: 1862–4.

100. Capuano A, Sportiello L, Maiorino MI, Rossi F, Giugliano D, Esposito K. et al. Dipeptidyl peptidase-4 inhibitors in type 2 dia- betes therapy–focus on alogliptin. Drug Des. Devel. Ther. 2013; 7: 989–1001.

138 Z-X He et al.

Copyright of Clinical & Experimental Pharmacology & Physiology is the property of Wiley- Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.