From Research to Practice

New Drugs in Development for the Treatment of Diabetes

  1. Terri L. Levien, PharmD and
  2. Danial E. Baker, PharmD, FASHP, FASCP
    Diabetes Spectrum 2009 Mar; 22(2): 92-106. https://doi.org/10.2337/diaspect.22.2.92

    Abstract

    In Brief

    A variety of new agents are in development for the treatment of type 1 or type 2 diabetes. In addition to new dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 analogs, thiazolidinediones, glinides, and new insulin formulations, there are also unique peroxisome proliferator-activated receptor agonists, selective sodium glucose cotransporter 2 inhibitors, and several other unique agents now in development.

    The number of agents available to improve glycemic control in patients with diabetes has increased substantially in recent years. Only 15 years ago, available therapies included only sulfonylureas and insulin. Today, products from multiple additional classes, offering multiple new mechanisms and enhanced opportunities for combination therapy, have substantially increased the ability to individually tailor therapy for any given patient. And development of new products for the treatment of diabetes continues.

    Many new drugs are currently in development for the treatment of diabetes, including more products with new mechanisms. This article will provide a brief overview of some of these drugs. Table 1 lists drugs in development for type 1 or type 2 diabetes by class. Table 2 lists additional drugs with unique mechanisms of action.1-3 Drugs with applications submitted for U.S. Food and Drug Administration (FDA) approval and drugs currently in phase 3 clinical trials are summarized below.

    DIPEPTIDYL PEPTIDASE 4 (DPP-4) INHIBITORS

    The DPP-4 inhibitors are incretin enhancers. DPP-4 inhibitors are thought to work by slowing the inactivation of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide. These agents are released by the gastrointestinal tract in response to food and are involved with the stimulation of glucose-dependent insulin secretion. By inhibiting their inactivation, these drugs prolong the effects of these incretin hormones.

    The DPP-4 inhibitors have been assessed as monotherapy and in conjunction with insulin, metformin, sulfonylureas, and thiazolidinediones in patients with type 2 diabetes. Although the DPP-4 inhibitors have been shown to improve glycemic control, as with most other new agents used in the treatment of diabetes, data have not been published addressing the effects of the DPP-4 inhibitors on key outcome measures such as mortality, diabetes complications, or health-related quality of life.4

    Most of the DPP-4 inhibitors are structurally distinct. Alogliptin is a quinazolinone-based compound, linagliptin is a xanthine derivative, saxagliptin is a hydroxyadamantyl compound, sitagliptin is a triazole-pyrazine compound, and vildagliptin and saxagliptin are pyrrolidine-carbonitrile compounds. The first marketed DPP-4 inhibitor was sitagliptin, which was approved by the FDA in 2006. Applications for approval have also been submitted for alogliptin, saxagliptin, and vildagliptin. Dutogliptin and linagliptin are in phase 3 studies, and numerous additional DPP-4 inhibitors are in phase 2 studies (Table 1). Vildagliptin received an approvable letter from the FDA in 2007 for the treatment of diabetes; however, the FDA approvable letter requested additional data on the safety and efficacy of vildagliptin in renally impaired patients. Vildagliptin is currently available in 18 countries and approved in 51 countries; however, Novartis, its manufacturer, does not plan to resubmit it for FDA approval at this time.5

    View this table:
    Table 1.

    Drugs in Development1-3

    View this table:
    Table 2.

    Other Drugs in Development for Diabetes1-3

    Sitagliptin and the other DPP-4 inhibitors in development are orally administered. Most have long half-lives enabling once-daily administration.6,7

    Alogliptin

    Alogliptin is a highly selective inhibitor of DPP-4, demonstrating > 10,000 times more selectivity for DPP-4 than for other related proteases. After oral administration of alogliptin in a range of doses from 25 to 800 mg, mean DPP-4 inhibition ranged from 93 to 99%, with mean inhibition at 24 hours after dosing ranging from 74 to 97%.7,8

    Very little information has been published on the clinical efficacy and safety of alogliptin, although several large studies have been presented as abstracts at scientific meetings. Alogliptin is capable of decreasing the average A1C level in patients with type 2 diabetes when used alone or in combination with insulin, metformin, a sulfonylurea, or a thiazolidinedione.9-13 The information on common adverse reactions reported in the clinical trials with alogliptin is very limited but has included reports of hypoglycemia with an incidence similar to that of placebo.9-13 Adverse reactions reported have also included nasopharyngitis, headache, and upper respiratory tract infection.9 Alogliptin appears to have a neutral effect on weight and lipids.9-13

    With the addition of alogliptin to glyburide therapy in a randomized, double-blind, placebo-controlled study enrolling 500 patients with type 2 diabetes that was adequately controlled on glyburide alone, A1C was reduced to a greater extent with alogliptin 12.5 mg (-0.38%) and alogliptin 25 mg (-0.52%) than with placebo (+0.01%; P < 0.001). A reduction of ≥ 1% in A1C was achieved in 28.6% of patients treated with alogliptin 12.5 mg and 30% of those treated with alogliptin 25 mg, compared to 8.7% of those treated with placebo (P < 0.001).10 With the addition of alogliptin to insulin therapy in a randomized, double-blind, placebo-controlled study enrolling 390 patients with type 2 diabetes not adequately controlled on insulin alone or insulin plus metformin, A1C was reduced to a greater extent with alogliptin 12.5 mg (-0.63%) and alogliptin 25 mg (-0.71%) than with placebo (-0.13%; P < 0.001).11 Similar improvements in A1C were also observed with the addition of alogliptin to pioglitazone in patients with type 2 diabetes inadequately controlled on a thiazolidinedione alone or on a thiazolidinedione with metformin or a sulfonylurea, and with the addition of alogliptin to metformin therapy.12,13

    Dutogliptin

    Dutogliptin is also an oral DPP-4 inhibitor under evaluation for once-daily dosing in patients with type 2 diabetes. To date, it has demonstrated activity in a short-term study when administered once daily in conjunction with metformin or metformin plus a thiazolidinedione; participants are now being recruited for a phase 3 study.14,15

    Linagliptin

    Linagliptin is another oral DPP-4 inhibitor under evaluation for once daily dosing in patients with type 2 diabetes. To date, it has demonstrated activity in a short-term study when administered once daily in patients with type 2 diabetes; recruitment is ongoing for a number of phase 3 studies assessing linagliptin as monotherapy and in combination with pioglitazone, metformin, or metformin plus a sulfonylurea.16-23

    Saxagliptin

    Very little information has been published on the clinical efficacy and safety of saxagliptin. Saxagliptin is capable of decreasing the average A1C level in patients with type 2 diabetes when used alone or in combination with metformin, a sulfonylurea, or a thiazolidinedione.24-27 Treatment with saxagliptin alone has been weight neutral.27 Common adverse reactions reported in the clinical trials with saxagliptin include nasopharyngitis, headache, diarrhea, upper respiratory infections, influenza, and urinary tract infection.25,27

    When administered as initial therapy in patients with type 2 diabetes in a randomized, double-blind 24-week study enrolling 1,306 patients, A1C was reduced 1.69% with saxagliptin alone, 1.99% with metformin alone, and 2.49-2.53% with saxagliptin plus metformin (P < 0.0001 for combination vs. either monotherapy). A1C < 7% was achieved in 60% of patients treated with the combination compared to 32% of those treated with saxagliptin alone and 41% of those treated with metformin alone.24 A1C reductions of 0.7-0.9% were observed in another study assessing saxagliptin monotherapy in drug-naïve patients with type 2 diabetes.27 When added to a sulfonylurea in a double-blind study enrolling 768 patients with type 2 diabetes, A1C reductions were in the range of 0.54-0.64%.25 When added to a thiazolidinedione in a double-blind study enrolling 565 patients with type 2 diabetes, A1C reductions were in the range of 0.66-0.94%, compared to 0.3% reductions with the addition of a placebo.26

    Additional ongoing studies are assessing saxagliptin as initial monotherapy in patients with type 2 diabetes, as an addition to metformin, insulin, or insulin plus metformin, in comparison with sitagliptin when added to metformin, and in patients with renal impairment.28-33

    Vildagliptin

    Vildagliptin alone or in combination with metformin, a thiazolidinedione, or insulin is capable of decreasing fasting plasma glucose levels and improving A1C levels in patients with type 2 diabetes.

    The efficacy of vildagliptin in drug-naïve patients with type 2 diabetes and “mild” hyperglycemia was evaluated in a multicenter, double-blind, randomized, placebo-controlled, parallel-group study that enrolled 306 patients. The baseline A1C for this population ranged from 6.2 to 7.5% and averaged 6.7% in the vildagliptin group and 6.8% in the placebo group. Patients were randomized to treatment with vildagliptin 50 mg or placebo once daily for 52 weeks. The change in the A1C level was -0.2% in the vildagliptin group and 0.1% in the placebo group; the between-group difference was 0.3% (P < 0.001). Fasting plasma glucose levels and postprandial plasma glucose levels all improved with vildagliptin compared to placebo. The patients' mean body weight decreased by 0.5 kg with vildagliptin therapy and increased by 0.2 kg with placebo. Both drug therapies were well tolerated. With continued administration for an additional year in 131 patients, the placebo-adjusted change from baseline in A1C was -0.5% (P = 0.008).34,35 Additional monotherapy studies in drug-naïve patients with type 2 diabetes and baseline A1C levels of 8.3-8.7% demonstrated mean placebo-adjusted A1C reductions of 0.7-1.2% after therapy for 24 weeks at doses of 50 mg twice daily or 100 mg once daily.36,37

    Several additional studies have assessed vildagliptin as monotherapy in comparison with other oral antidiabetic agents, including acarbose, metformin, pioglitazone, and rosiglitazone. The efficacy of vildagliptin was compared to acarbose in drug-naïve patients with type 2 diabetes in a multicenter, randomized, double-blind, parallel-arm study. Patients were given either vildagliptin 50 mg twice daily (n = 441) or acarbose (n = 220) in three equally divided doses (up to 300 mg daily) for 24 weeks. The average baseline A1C level in both groups was 8.6%. At the end of 24 weeks, the adjusted mean change from baseline was -1.4% in the vildagliptin group and -1.3% in the acarbose group. The decrease in plasma glucose was -1.2 mmol/l with vildagliptin and -1.5 mmol/l with acarbose. The body weight of the vildagliptin group remained unchanged (-0.4 ± 0.1 kg) and decreased by 1.7 ± 0.2 kg in the acarbose group.38

    Vildaglptin has been compared to metformin as monotherapy in a 1-year study enrolling 780 drug-naïve patients with type 2 diabetes. Patients received vildagliptin 50 mg twice daily or metformin titrated to 1,000 mg twice daily. From a mean baseline A1C of 8.7%, A1C at 1 year declined by 1% with vildagliptin therapy and 1.4% with metformin therapy (both P < 0.001 vs. baseline). Body weight was unchanged with vildagliptin (0.3 kg; P = 0.17), but was reduced 1.9 kg (P < 0.001) in the metformin group.39

    Vildagliptin was compared to pioglitazone and the combination of the two agents in another 24-week double-blind study enrolling 607 drug-naïve patients with type 2 diabetes. From baseline (A1C ~ 8.7%), A1C was reduced 1.4% in the group receiving pioglitazone 30 mg once daily as monotherapy, 1.7% in the group received vildagliptin 50 mg plus pioglitazone 15 mg once daily, 1.9% in the group received vildagliptin 100 mg plus pioglitazone 30 mg once daily, and 1.1% in the group received vildagliptin 100 mg once daily as monotherapy.40

    Vildagliptin was compared to rosiglitazone as monotherapy in another 24-week, double-blind study enrolling 786 drug-naïve patients with type 2 diabetes. Patients received vildagliptin 50 mg twice daily or rosiglitazone 8 mg once daily. A1C was reduced 1.1% in the vildagliptin group and 1.3% in the rosiglitazone group (both P < 0.001 vs. baseline). Body weight was unchanged (0.3 kg) in the vildagliptin group and increased 1.6 kg in the rosiglitazone group (P < 0.001 vs. vildagliptin).41

    Vildagliptin has also been assessed when added to metformin in patients with type 2 diabetes with inadequate glycemic control. Addition of vildagliptin 50 mg daily and 100 mg daily for 24 weeks in a randomized, double-blind, placebo-controlled study enrolling 544 patients resulted in a placebo-adjusted reduction in A1C of 0.7% at the 50-mg dose (P < 0.001) and 1.1% in the 100-mg dose (P < 0.001).42 Addition of vildagliptin 50 mg once daily for 52 weeks in a randomized, placebo-controlled, double-blind study enrolling 107 patients resulted in a placebo-adjusted reduction in A1C of 0.7% at 12 weeks (P < 0.0001) and 1.1% at 52 weeks (P < 0.0001).43 Another 24-week double-blind study compared vildagliptin and pioglitazone when added to metformin in 576 patients with type 2 diabetes. A1C was reduced from a mean baseline value of 8.4% by 0.9% in the vildagliptin group and 1% in the pioglitazone group.44

    Patients whose diabetes was inadequately controlled with a sulfonylurea were treated with either vildagliptin or placebo in another multicenter, randomized, double-blind, placebo-controlled study. All 515 type 2 diabetic patients enrolled in this trial received glimepiride 4 mg once daily plus their assigned study medication for 24 weeks. The vildagliptin was given either as 50 mg once daily or 50 mg twice daily. Both vildagliptin doses were better than placebo in improving the patients' A1C levels. The between-group difference (vildagliptin vs. placebo) for the A1C was -0.6% with vildagliptin 50 mg once daily and -0.7% with vildagliptin 50 mg twice daily (P < 0.001 vs. placebo).45

    Similar improvements in A1C of ~ 0.5-1% were observed with the addition of vildagliptin to therapy with pioglitazone and the addition of vildagliptin to insulin.46,47

    Adverse reactions reported in the clinical trials have generally been similar to those reported with placebo and have included cough, nasopharyngitis, headache, hypoglycemia, dizziness, dyspepsia, nausea, constipation, and diarrhea. Vildagliptin had no impact on patient weight in the majority of studies.

    A study of the safety of vildagliptin in patients with type 2 diabetes and severe renal insufficiency, as required by the FDA, is currently underway.48

    GlLUCAGON-LIKE PEPTIDE 1 (GLP-1) ANALOGS

    The GLP-1 analogs induce their activity through a glucose-dependent stimulation of insulin secretion, inhibition of glucagon secretion, slowing of gastric emptying, and reduction in appetite. The first marketed GLP-1 analog was exenatide, which was approved by the FDA in 2005. Exenatide is currently used as adjunctive therapy in type 2 diabetes in patients currently using metformin, a sulfonylurea, a combination of metformin and sulfonylurea, or a combination of metformin and a thiazolidinedione; an application for use of exenatide as monotherapy in type 2 diabetes is under FDA review.

    An application for approval has been submitted for liraglutide. Several other GLP-1 analogs are in phase 3 studies, including AVE0010/ZP-10, LY2189265, taspoglutide, and the once-weekly exenatide formulation called exenatide LAR.

    Exenatide is administered subcutaneously twice daily. Most of the other products in development are administered subcutaneously once daily (liraglutide, AVE0010/ZP-10) or once weekly (exenatide LAR, LY2189265, albiglutide, NN9535, taspoglutide).49,50

    AVE0010/ZP-10

    Limited clinical data are available for AVE0010. Study results from a dose-ranging study including 542 patients with type 2 diabetes treated with metformin have been presented in abstract form at a scientific meeting. A1C was reduced 0.28% to 0.69% compared to placebo in a range of doses from 5 mμ once daily to 30 mμ twice daily administered subcutaneously. Efficacy was similar with once-daily and twice-daily regimens. Greater weight loss with AVE0010 than with placebo was observed at doses of 20 and 30 mμ once daily and 30 mμ twice daily. Nausea and vomiting were the most common adverse effects.50 Recruitment is ongoing for a number of phase 3 studies evaluating AVE0010 as monotherapy and in addition to basal insulin, metformin, a sulfonylurea, or pioglitazone in patients with type 2 diabetes, as well as a study comparing AVE0010 and exenatide in association with metformin in patients with type 2 diabetes.51-57

    Exenatide LAR

    The slow-release or long-acting release (LAR) formulation of exenatide is in phase 3 development. It is intended for once-weekly subcutaneous administration for the treatment of type 2 diabetes.

    In a randomized, placebo-controlled study enrolling 45 patients with type 2 diabetes suboptimally controlled on metformin or diet and exercise, exenatide LAR administered subcutaneously once weekly for 15 weeks reduced A1C 1.4% (0.8 mg dose) and 1.7% (2 mg dose; both P < 0.0001). An A1C of ≤ 7% was achieved in 86% of subjects receiving the 2-mg dose. Patients in this dose group also experienced a 3.8-kg weight loss in this 15-week study (P < 0.05).58

    In a non-inferiority study comparing exenatide LAR 2 mg once weekly with exenatide 10 mμ twice daily in 295 patients with type 2 diabetes, patients treated with exenatide LAR had a greater reduction in A1C at 30 weeks than those treated with exenatide twice daily (-1.9% vs. -1.5%; 95% CI -0.54 to -0.12%; P = 0.0023). A1C of ≤ 7% was achieved in 77% of patients treated with exenatide LAR compared to 61% of those treated with exenatide twice daily (P = 0.0039). Weight loss was similar in the two groups. Nausea and injection site pruritus were the most common adverse effects.59 After 30 weeks, 258 patients entered an open-label treatment with exenatide LAR. Improvements in A1C were sustained in patients continuing therapy with exenatide once weekly for 52 weeks (-2% from baseline) and were similar in those switched to once-weekly therapy (-2% from baseline). Patients in both groups lost ~ 4 kg of weight by week 52, and blood pressure and lipid profiles were improved in both groups.60

    Liraglutide

    Liraglutide is under evaluation for use in the treatment of patients with type 2 diabetes as an adjunct to diet and exercise, either as monotherapy or in combination with commonly used diabetes medications, including sulfonylureas and metformin. In clinical trials, liraglutide has been associated with a reduction in A1C and fasting plasma glucose with either weight loss or no change in body weight. Significant reductions in A1C have been observed at doses of 0.1-2 mg administered subcutaneously once daily.

    A randomized, double-dummy study has compared the addition of liraglutide to glimepiride therapy with glimepiride monotherapy or the addition of rosiglitazone to glimepiride in 1,041 patients with type 2 diabetes and baseline A1C of 8.4%. Patients received liraglutide 0.6, 1.2, or 1.8 mg/day in combination with glimepiride, placebo plus glimepiride 2-4 mg per day, or rosiglitazone 4 mg daily plus glimepiride for 26 weeks. A1C was reduced 1.08% with liraglutide 1.2 mg and by 1.13% with liraglutide 1.8 mg, compared with a reduction of 0.44% with the addition of rosiglitazone and an increase of 0.23% with glimepiride monotherapy (P < 0.0001). A1C < 6.5% was achieved in 22% treated with liraglutide 1.2 mg plus glimepiride and 21% of those treated with liraglutide 1.8 mg plus glimepiride, compared to 4% of those treated with glimepiride monotherapy, and 10% of those treated with rosiglitazone plus glimepiride (P ≤ 0.0003).61 A 52-week study also compared liraglutide and glimepiride as monotherapy in 746 patients with type 2 diabetes. At 52 weeks, A1C was reduced 0.51% with glimepiride 8 mg daily, 0.84% with liraglutide 1.2 mg once daily (P = 0.0014), and 1.14% with liraglutide 1.8 mg once daily (P < 0.0001).62

    Liraglutide has also been evaluated in combination with metformin therapy in a randomized, double-blind study enrolling 1,091 patients with type 2 diabetes and baseline A1C of 8.4%. Patients received liraglutide 0.6, 1.2, or 1.8 mg once daily added to metformin 1 g twice daily, placebo plus metformin, or glimepiride 4 mg once daily added to metformin for 26 weeks. A1C was reduced 0.7% with liraglutide 0.6 mg and 1% with liraglutide 1.2 mg and 1.8 mg plus metformin, compared to an increase of 0.1% with metformin monotherapy and a reduction of 1% with glimepiride plus metformin (P < 0.05 vs. liraglutide plus metformin vs. placebo plus metformin). A1C < 6.5% was achieved in 11.3% of patients treated with liraglutide 0.6 mg plus metformin, 19.8% of those treated with liraglutide 1.2 mg plus metformin, 24.6% of those treated with liraglutide 1.8 mg plus metformin, compared to 4.2% of those treated with placebo plus metformin and 22.2% of those treated with glimepiride plus metformin. Weight loss was greater in all three liraglutide plus metformin groups than in the glimepiride plus metformin group.63

    In another 26-week study enrolling 533 patients, liraglutide was added to metformin and rosiglitazone. A1C was reduced 1.48% in the groups treated with liraglutide 1.2 mg once daily and liraglutide 1.8 mg once daily in conjunction with metformin and rosiglitazone, compared to reductions of 0.54% in patients receiving placebo with metformin and rosiglitazone (P < 0.05 for both liraglutide doses vs. placebo). A1C < 7% was achieved in 58% of patients treated with liraglutide 1.2 mg and 54% of those treated with liraglutide 1.8 mg, compared to 28% of those treated with placebo (P < 0.05 for both liraglutide doses vs. placebo). Weight loss was also greater in the liraglutide groups (-1.02 and -2.02 kg vs. +0.6 kg).64

    Liraglutide has also been compared to insulin glargine as add-on to therapy with metformin and glimepiride in a study enrolling 581 patients with type 2 diabetes and a baseline A1C of 8.2%. Patients received liraglutide 1.8 mg once daily, placebo, or insulin glargine in addition to metformin 1 g twice daily and glimepiride 2-4 mg once daily for 26 weeks. A1C was reduced 1.33% with the addition of liraglutide, 0.24% with the addition of placebo, and 1.09% with the addition of insulin glargine (P < 0.05 for liraglutide vs. placebo and insulin glargine). A1C < 6.5% was achieved in 37.1% of those treated with liraglutide compared to 10.9% of those in the placebo group and 23.6% of those in the insulin glargine group. A weight loss of 1.81 kg was observed in the liraglutide group compared to a loss of 0.42 kg in the placebo group and a weight gain of 1.62 kg in the insulin glargine group.65

    Adverse effects associated with liraglutide therapy have included headache, dizziness, nausea, and vomiting.

    LY2189265

    Results of studies with LY2189265 have not been published. Recruitment is currently ongoing for a phase 2/3 study comparing LY2189265 with sitagliptin in patients with type 2 diabetes on metformin.66

    Taspoglutide

    Taspoglutide administered subcutaneously once weekly has been associated with reductions in fasting blood glucose, improvement in A1C, and weight loss when added to metformin therapy in patients with type 2 diabetes in short-term studies.67,68 Recruitment is ongoing for studies assessing taspoglutide as initial monotherapy and in conjunction with metformin, metformin plus pioglitazone, metformin plus a sulfonylurea, or metformin plus a thiazolidinedione. In several of these studies, taspoglutide is being compared head-to-head with exenatide, insulin glargine, and sitagliptin.69-73

    PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) AGONISTS

    The PPAR-γ agonists act as insulin sensitizers, reducing fasting glucose and A1C. The thiazolidinediones were the first class of PPAR-γ agonists to be approved for use in diabetes. Balaglitazone and rivoglitazone are thiazolidinediones in phase 3 studies in patients with type 2 diabetes. Balaglitazone is a partial agonist; rivoglitazone is a full agonist. The partial PPAR-γ agonists, also known as selective PPAR modulators, have been developed in an attempt to minimize the side effects of the full agonists while maintaining the therapeutic effect.74-76 Insufficient data are available at this time to determine if the selective PPAR modulators will have fewer adverse effects. In light of the recent experience with rosiglitazone, long-term studies will likely be required for approval of any new drugs in this class.

    Other PPAR agonists in early-phase development include the dual agonists or glitazars, which stimulate both PPAR-α and -γ receptors, resulting in effects on insulin resistance and dyslipidemia, and pan agonists, which act at the α, γ, and δ PPAR receptors and may have activity in diabetes, dyslipidemia, and obesity.74

    Balaglitazone

    Balaglitazone is a selective partial PPAR-γ agonist. It has been suggested that partial PPAR-γ agonists may have a favorable adverse effect profile relative to the full PPAR-γ agonists pioglitazone and rosiglitazone. However, results of clinical studies directly comparing these agents are not yet available.75 A phase 3 study assessing the efficacy and safety of balaglitazone compared to pioglitazone in patients with type 2 diabetes receiving stable insulin therapy is currently enrolling patients.77

    Rivoglitazone

    Rivoglitazone is a potent PPAR-γ agonist currently under evaluation in a phase 3 study comparing it to placebo and pioglitazone in patients with type 2 diabetes not adequately controlled with diet and exercise or with nonthiazolidinedione antihyperglycemic monotherapy.78 In an earlier open-label comparative 6-week study, rivoglitazone 2-mg and 5-mg doses once daily were associated with greater reductions in fasting plasma glucose than pioglitazone 30 mg; however, these rivoglitazone doses were also associated with a greater incidence of peripheral edema and weight gain.79 In a double-blind 26-week study comparing rivoglitazone and pioglitazone in patients with type 2 diabetes, rivoglitazone doses of 2 mg and 3 mg were associated with greater reductions in A1C than pioglitazone 45 mg; however, rivoglitazone was again associated with higher incidence of peripheral edema and weight gain.80 The ongoing study is comparing rivoglitazone 1-mg and 1.5-mg doses with pioglitazone 45 mg.78

    SELECTIVE SODIUM GLUCOSE COTRANSPORTER 2 INHIBITORS

    The selective sodium glucose cotransporter 2 inhibitors are a new class of agents. The sodium glucose cotransporter type 2 (SGLT2) located in the plasma membrane of cells lining the proximal tubule mediates the majority of renal glucose reabsorption from the tubular fluid. Blood glucose is continuously filtered by the renal glomeruli and then reabsorbed in the renal proximal tubules by SGLT2, and to a lesser extent SGLT1, preventing the loss of glucose in the urine. Competitive inhibitors of SGLT2 provoke renal excretion of glucose, potentially lowering elevated blood glucose levels in patients with diabetes.80 These agents are expected to improve plasma glucose levels and decrease body weight in patients with type 2 diabetes without causing hypoglycemia.81 Dapagliflozin is the only agent in this class in phase 3 studies.

    Dapagliflozin

    Dapagliflozin is in the early portion of phase 3 development for use as a monotherapy agent or in combination with other oral hypoglycemic agents. The drug has been well tolerated in early clinical studies with the most common adverse reactions being urinary tract infection, dizziness, headache, fatigue, back pain, and nasopharyngitis.82

    In a randomized, double-blind, placebo-controlled, dose-ranging 12-week study enrolling 389 treatment-naïve patients with type 2 diabetes, dapagliflozin doses from 2.5 to 50 mg once daily were associated with greater reductions in A1C than placebo (-0.55% to -0.9% vs. -0.18%; P < 0.01). Fasting plasma glucose was reduced at doses from 5 to 50 mg once daily compared with placebo (-19.3 to -30.5 vs. -5.8 mg/dl; P < 0.01). Urinary glucose excretion ranged from 51.8 to 85 g/day at week 12 in the dapagliflozin arms compared with 5.8-10.9 g/day at baseline and 5.7 g/day at 12 weeks in the placebo group. Mean weight loss at week 12 ranged from 2.5 to 3.2% in the dapagliflozin groups compared with 1.2% in the placebo group.82,83

    Dapagliflozin is currently under evaluation in a number of phase 3 studies assessing the agent as monotherapy in patients with type 2 diabetes not adequately controlled with diet and exercise, as well as studies assessing dapagliflozin in conjunction with metformin, a sulfonylurea, a thiazolidinedione, or insulin.84-91

    GLINIDES

    The glinides, including nateglinide, repaglinide, and mitiglinide, are agents that enhance mealtime insulin secretion and reduce postprandial hyperglycemia. Nateglinide and repaglinide have been available in the United States since 2000 and 1997, respectively.

    Mitiglinide

    Mitiglinide has been available in Japan since 2004 and is currently in phase 3 studies in the United States. It has been reported to have a more β-cell-selective effect on the adensine triphosphate-dependent potassium channels than nateglinide and repaglinide and to have no active metabolites or cytochrome P450 drug interactions.92,93

    Several recently published studies conducted in Japan have assessed premeal mitiglinide combined with once-daily insulin glargine and twice-daily premixed insulin.94-96 In a study comparing mitiglinide with acarbose in elderly patients, glycemic control was better maintained in the mitiglinide group at 6 months (A1C 7.43% in the mitiglinide group and 7.75% in the acarbose group; P < 0.001).92 In a study assessing mitiglinide in combination with metformin compared with metformin alone or mitiglinide alone, glycemic control was better in the group receiving the combination at 7 months (A1C 7.13% vs. 7.7% on metformin alone, P < 0.001).92,93 An additional ongoing study is assessing mitiglinide in combination with metformin compared to metformin alone.97

    INSULINS

    A variety of insulin formulations are currently in development including inhaled formulations, intranasal formulations, oral formulations, and injectable analogs.

    Inhaled Technosphere Insulin

    Inhaled Technosphere insulin is an inhaled insulin in development for administration using a palm-sized handheld breath-activated inhaler. The Technosphere particles are composed of human regular insulin loaded into a diketopiperazine molecule. The particles dissolve rapidly at physiological pH, providing for rapid insulin absorption from the lungs.98 Technosphere insulin is absorbed within 15 minutes, has an onset of action of ~ 25-30 minutes, and has a duration of action of ~ 2-3 hours.98

    In a study comparing inhaled Technosphere insulin and insulin lispro as prandial insulin in conjunction with basal insulin glargine in a 12-week study enrolling 111 patients with type 1 diabetes, inhaled insulin was associated with fewer postprandial glucose excursions, less late postprandial hypoglycemia, and greater weight loss. A1C was improved in both groups but did not differ between groups.99 In a 12-week study assessing inhaled Technosphere insulin in 126 patients with type 2 diabetes not adequately controlled with oral agents, inhaled insulin reduced the mean A1C by 0.72% compared to a reduction of 0.3% in the placebo group (P = 0.003). Postprandial glucose excursions were reduced 56%. Body weight was unchanged.98 In other smaller studies, inhaled Technosphere insulin was associated with improvements in postprandial glycemic control in patients with type 2 diabetes and glycemic control without weight gain in both type 1 and type 2 diabetes.100,101

    Other studies are assessing inhaled Technosphere insulin compared to insulin aspart in type 1 diabetes, with basal insulin glargine compared to a regimen of insulin lispro and insulin glargine in type 1 diabetes, with basal insulin compared to subcutaneous premixed insulin therapy in type 2 diabetes, and in combination with metformin or compared to oral antidiabetic agents in patients with type 2 diabetes.102-105

    Inhaled Technosphere insulin did not affect pulmonary function in a 6-month study enrolling 306 patients with type 2 diabetes.106 An additional 2-year study is currently assessing pulmonary outcomes in patients with type 1 or type 2 diabetes treated with Technosphere insulin.107

    Oral Insulin Spray

    An oral insulin spray in development by Generex Biotechnology is in phase 3 studies in the United States but has already been approved in Ecuador and India. The insulin is absorbed buccally following administration with a proprietary RapidMist device that resembles the metered-dose inhalers used in the treatment of asthma. The formulation is tasteless and odorless.108

    Compared to preprandial subcutaneous injection of regular insulin, preprandial oral insulin spray was associated with similar pre- and postmeal glucose concentrations.109 Compared to a regimen of premeal subcutaneous regular insulin and twice-daily NPH insulin, a regimen of mealtime (half-dose before meal and half-dose after meal) oral insulin spray plus twice-daily NPH insulin was associated with greater reduction in A1C.110 Compared to a regimen of once-daily subcutaneous insulin glargine and premeal insulin lispro, a regimen of twice-daily NPH insulin plus mealtime oral insulin spray was also associated with lower premeal glucose, A1C, and fructose during a 372-day treatment period.111 Additional small preliminary studies have assessed mealtime oral insulin spray in adolescents with type 1 diabetes, in adults with type 2 diabetes requiring insulin injections, in conjunction with metformin in patients with type 2 diabetes not adequately controlled with oral agents, and as initial therapy in patients with type 2 diabetes not adequately controlled with diet and exercise.108,112

    A 26-week phase 3 study is currently underway comparing oral insulin spray to subcutaneous regular human insulin in patients with type 1 diabetes receiving twice-daily NPH insulin. The oral insulin is administered as half the dose immediately before meals and half the dose immediately after meals. Subcutaneous regular human insulin is administered 30 minutes before meals. All patients receive twice-daily NPH insulin.113

    Rapid-Acting Insulin for Injection (VIAject)

    VIAject is a novel ultra-fast insulin formulation composed of human soluble insulin and ingredients designed to increase the rate of absorption (EDTA and citric acid). These ingredients pull the zinc ions away from human insulin hexamers and mask charges on the surface of the insulin molecule, causing the insulin hexamers to dissociate and preventing re-association to the hexameric state with subcutaneous administration.114 VIAject has exhibited a quicker onset of action than insulin lispro and human soluble insulin (time to early half-maximal activity 33 minutes with VIAject vs. 51 minutes with insulin lispro and 66 minutes with human soluble insulin; P < 0.05).114 When administered immediately before a meal, VIAject was associated with improved postprandial blood glucose control, reduced hyperglycemia in the first 3 hours after a meal, and reduced hypoglycemia through 8 hours compared to regular human insulin.115

    Phase 3 studies comparing insulin VIAject and regular human insulin in patients with type 1 and type 2 diabetes have recently been completed.116,117

    Other AGENTS

    A wide variety of other agents are also in development for the treatment of type 1 or type 2 diabetes.

    Bromocriptine

    Bromocriptine is a dopamine D2 receptor agonist that is approved for the treatment of dysfunctions associated with hyperprolactinemia, acromegaly, and Parkinson's disease and has been in development for the treatment of type 2 diabetes for several years. A new drug application for a quick-release formulation was granted approvable status by the FDA in 2006. However, at least one additional safety study was necessary before the drug could be approved.118

    Results of the studies submitted in support of approval have not been published. In one small study in patients with type 2 diabetes, bromocriptine was associated with reduced fasting plasma glucose and reduced A1C.119 The required 1-year randomized, double-blind, placebo-controlled safety study enrolled 3,070 patients with type 2 diabetes. A1C was reduced 0.6% more in the bromocriptine-treated subjects than in the placebo-treated subjects compared to baseline. Target A1C of ≤ 7% was achieved in 32% of the bromocriptine group compared to 10% of the placebo group (P = 0.0001). Reductions were consistently greater in the bromocriptine group than in the placebo group when combined with multiple oral hypoglycemic agents, including metformin, sulfonylureas, thiazolidinediones, and combinations of these oral hypoglycemic agents.120

    Otelixizumab

    Otelixizumab is a humanized anti-CD3 monoclonal antibody currently being evaluated in clinical studies in patients with new-onset type 1 diabetes. Otelixizumab binds to the CD3/TCR complex and blocks full T-cell activation, proliferation, and cytokine release. It has been hypothesized that otelixizumab's downregulation of T effector cells via binding of the T-cell receptors will result in inhibition of the autoimmune attack on β-cells in the pancreatic islets and establishment of longlasting operational tolerance by the generation and expansion of regulatory T-cells, which prevent further autoimmune destruction.121

    A phase 3 study is currently underway assessing whether an 8-day series of otelixizumab infusions will lead to greater improvement in insulin secretion than placebo in adults 18-35 years of age with new-onset type 1 diabetes.122

    Recombinant Human Glutamic Acid Decarboxylase-65 (rhGAD65)

    RhGAD65 is a vaccine that induces immunotolerization and may thereby slow or prevent autoimmune destruction of pancreatic islet cells.123 Antibodies against GAD are present at the time of diagnosis in 80-90% of patients with type 1 diabetes.124 In patients with adult-onset autoimmune diabetes and the presence of antibodies against GAD, administration of rhGAD65 has been associated with reduced A1C and increased fasting and stimulated C-peptide levels for 2 years.124,125

    Two phase 3 studies were recently initiated to assess whether rhGAD65 formulated in alum preserves the body's own insulin-producing capacity in patients recently diagnosed with type 1 diabetes. One study will enroll subjects 10-20 years of age; the other will enroll subjects 8-45 years of age. Results will not be available for several years.123,126

    Succinobucol

    Succinobucol is an oral antioxidant lipid peroxidation inhibitor and vascular cell adhesion molecule antagonist that is in phase 3 development for the treatment of atherosclerosis and type 2 diabetes. It is a monosuccinate ester of probucol, a previously approved lipid-lowering agent.127

    The first of these studies failed to achieve its primary endpoint in the treatment of patients with acute coronary syndrome. The double-blind, placebo-controlled multicenter trial was designed to evaluate the efficacy of succinobucol in the treatment of acute coronary syndrome in 6,144 patients. Patients were randomized to succinobucol 300 mg/day or placebo. The primary endpoint for the study was the composite of cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke, unstable angina, or coronary revascularization. The secondary endpoints were primary composite endpoint with all-cause death, primary composite endpoint without coronary revascularization, and primary composite endpoint without coronary revascularization or unstable angina. After 24 months of treatment, the primary endpoint of the study was the same in both the succinobucol and placebo groups (17.2% vs. 17.3%, respectively; P = 0.99). However, the secondary endpoint of cardiovascular death, cardiac arrest, myocardial infarction, or stroke was lower in patients randomized to succinobucol (6.7% vs. 8.2%, P = 0.028). New-onset atrial fibrillation occurred more frequently in the succinobucol group (hazard ratio [HR] 1.87, 95% CI 1.67-2.09; P = 0.0002). New-onset diabetes occurred less frequently in the succinobucol group (HR 0.37, 95% CI 0.24-0.56; P < 0.0001).128 This study included 2,271 patients with type 2 diabetes at study entry with a mean A1C of 7.2% who were followed for an average of 2 years. A1C was reduced in the succinobucol treatment group. An A1C of < 7% was achieved in 68.9% in the succinobucol group compared to 57.8% of the placebo group (P < 0.001).129

    The manufacturer has reported preliminary results from a recently completed phase 3 study enrolling 999 patients with type 2 diabetes treated with succinobucol or placebo. The primary endpoint for the study was the change in A1C at the end of 6 months of therapy. A1C was reduced 0.6% in the succinobucol 150 mg group (P < 0.001) and 0.4% in the succinobucol 75 mg group (P = 0.016) compared to baseline, whereas A1C was reduced 0.2% in the placebo group. Succinobucol was not associated with weight gain or hypoglycemia. Liver enzyme elevations were observed in a small number of succinobucol-treated patients.130,131

    Tagatose

    Tagatose is a naturally occurring, sweet-tasting, low-calorie monosaccharide hexoketose found in dairy products. It is the epimer of D-fructose. Tagatose was originally developed as a sugar substitute for calorie and weight control. It was granted “Generally Recognized as Safe” status for use as a sweetener in foods and beverages by the FDA in 2001.132

    The product in development by Spherix for the treatment of diabetes is produced by isomerization of galactose, which is produced by the hydrolysis of lactose derived from whey.132 Oral administration of this product decreases the postprandial glucose peaks seen in patients with type 2 diabetes when it is administered before meals.133 Administration three times a day with meals in patients with type 2 diabetes has been associated with weight loss, reduced A1C, and increased HDL cholesterol levels.134 It is believed to exert its effect on postprandial glucose by attenuating glucose absorption in the intestine, as well as increasing glycogen synthesis and decreasing glycogen utilization.132,133 Adverse effects have primarily included diarrhea, nausea, and flatulence.133,134 The current 1-year clinical trial to demonstrate the efficacy of tagatose as monotherapy in the treatment of type 2 diabetes is scheduled for completion in 2009.132,135

    Teplizumab

    Teplizumab is a humanized anti-CD3 monoclonal antibody. Like otelixizumab, teplizumab is hypothesized to minimize cytokine release and prevent the progressive destruction of β-cells.136

    Teplizumab was administered to 12 patients with new-onset type 1 diabetes in a placebo-controlled phase 1/2 study. Teplizumab was administered as a daily intravenous injection for 14 consecutive days within 6 weeks after diagnosis. After 1 year, insulin production was maintained or improved in 9 of the 12 patients treated with teplizumab compared to 2 of 12 placebo recipients (P = 0.01). A1C levels and insulin doses were reduced and C-peptide responses were maintained in the teplizumab group compared to the placebo group at 1 year and 2 years after treatment. Adverse effects included fever, rash, and anemia.137,138

    A phase 3 study is currently evaluating the effects of 14 days of intravenous teplizumab in patients 8-35 years of age with new-onset type 1 diabetes, followed by retreatment at 6 months. The primary study endpoint is a successful clinical response as assessed by subjects' total daily insulin usage and A1C at 1 year.136,139

    CONCLUSION

    A wide range of agents are in development for use in the treatment of type 1 or type 2 diabetes. All of these agents appear to be effective in improving glycemic control, but it is unknown whether they will have an impact on the course of the disease or alter the micro- and macrovascular consequences of uncontrolled diabetes. One of the DPP-4 inhibitors is most likely to reach market next, as well as possibly liraglutide or mitiglinide. The PPAR-γ agonists and SGLT2 inhibitors are still early in phase 3 development.

    Footnotes

    • Terri L. Levien, PharmD, is a clinical associate professor of pharmacotherapy, and Danial E. Baker, PharmD, FASHP, FASCP, is a professor of pharmacology and director of the Drug Information Center in the College of Pharmacy at Washington State University in Spokane.

    References

    1. ↵
      1. Pharmaceutical Research and Manufacturers of America
      : New medicines database [database online]. Available from http://newmeds.phrma.org. Accessed 19 November 2008
      1. Wolters Kluwer Health
      : Adis R&D Insight [database online]. Available from http://www.adisinsight.com. Accessed 19 November 2008
    3. ↵
      DiabesityDigest.com: Drugs in development [article online]. Available from http://www.diabesitydigest.com. Accessed 19 November 2008
    4. ↵
      1. Richter B,
      2. Bandeira-Echtler E,
      3. Bergerhoff K,
      4. Lerch CL
      : Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev 2008;2:CD006739
    5. ↵
      1. Novartis
      : Data show Galvus better tolerated by patients with type 2 diabetes, with no weight gain, a favorable cardiovascular profile and equal efficacy compared to widely-used TZDs [press release online]. Available from http://www.novartis.com/newsroom. Accessed 3 December 2008
    6. ↵
      1. Thomas L,
      2. Eckhardt M,
      3. Langkopf E,
      4. Tadayyon M,
      5. Himmelsbach F,
      6. Mark M
      : (R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione (BI 1356), a novel xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other dipeptidyl peptidase-4 inhibitors. J Pharmacol Exp Ther 325:175-182, 2008
      OpenUrlAbstract/FREE Full Text
    7. ↵
      1. Christopher R,
      2. Covington P,
      3. Davenport M,
      4. Fleck P,
      5. Mekki QA,
      6. Wann ER,
      7. Karim A
      : Pharmacokinetics, pharmacodynamics, and tolerability of single increasing doses of the dipeptidyl peptidase-4 inhibitor alogliptin in healthy male subjects. Clin Ther 30:513-527, 2008
      OpenUrlCrossRefPubMedWeb of Science
    8. ↵
      1. Covington P,
      2. Christopher R,
      3. Davenport M,
      4. Fleck P,
      5. Mekki QA,
      6. Wann ER,
      7. Karim A
      : 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 30:499-512, 2008
      OpenUrlCrossRefPubMedWeb of Science
    9. ↵
      1. Mekki Q,
      2. Fleck P,
      3. Wilson C,
      4. DeFronzo R
      : Efficacy and safety of alogliptin monotherapy in patients with type 2 diabetes inadequately controlled with diet and exercise [abstract]. Diabetologia 51 (Suppl. 1):S344, 2008
      OpenUrl
    10. ↵
      1. Fleck P,
      2. Mekki Q,
      3. Kipnes M,
      4. Wilson C,
      5. Pratley R
      : Efficacy and safety of alogliptin and glyburide combination therapy in patients with type 2 diabetes [abstract]. Diabetologia 51 (Suppl. 1):S37, 2008
      OpenUrl
    11. ↵
      1. Rendell M,
      2. Rosenstock J,
      3. Gross J,
      4. Fleck P,
      5. Wilson C,
      6. Mekki Q
      : Addition of alogliptin to insulin therapy reduces HbA1c without increasing weight gain or hypoglycaemia in patients with type 2 diabetes [abstract]. Diabetologia 51 (Suppl. 1):S37-S38, 2008
      OpenUrl
    12. ↵
      1. Pratley R,
      2. Reusch J,
      3. Fleck P,
      4. Wilson C,
      5. Mekki Q
      : Alogliptin added to pioglitazone therapy improves glycaemic control in patients with type 2 diabetes without increasing weight gain or hypoglycaemia [abstract]. Diabetologia 51 (Suppl. 1):S343, 2008
      OpenUrl
    13. ↵
      1. Ellis G,
      2. Fleck P,
      3. Wilson C,
      4. Mekki Q,
      5. Nauck M
      : Alogliptin added to metformin therapy in patients with type 2 diabetes reduces HbA1c without changing weight or increasing gastrointestinal symptoms or hypoglycaemia [abstract]. Diabetologia 51 (Suppl. 1):S343-S344, 2008
      OpenUrl
    14. ↵
      1. Garcia-Soria G,
      2. Gonzalez-Galvez G,
      3. Argoud GM,
      4. Gerstman M,
      5. Littlejohn TW,
      6. Schwartz SL,
      7. O'Farrell AM,
      8. Li X,
      9. Cherrington JM,
      10. Bennett C,
      11. Guler HP
      : The dipeptidyl peptidase-4 inhibitor PHX1149 improves blood glucose control in patients with type 2 diabetes mellitus. Diab Obes Metab 10:293-300, 2008
      OpenUrl
    15. ↵
      1. Phenomix
      : Safety and efficacy study of dutogliptin/PHX1149T to treat type 2 diabetes mellitus [online]. Available from http://clinicaltrials.gov/show/NCT00690638 (NLM Identifier: NCT00690638). Accessed 3 December 2008
    16. ↵
      1. Forst T,
      2. Uhlig-Laske B,
      3. Ring A,
      4. Ritzhaupt A,
      5. Graefe-Mody U,
      6. Dugi KA
      : The novel, potent, and selective DPP-IV inhibitor BI 1356 significantly lower HbA1c after only 4 weeks of treatment in patients with type 2 diabetes [abstract]. Diabetes 56 (Suppl. 1):A157-158, 2007
      OpenUrl
      1. Boehringer Ingelheim Pharmaceuticals
      : Efficacy and safety of BI 1356 versus placebo in type 2 diabetic patients with insufficient glycemic control [article online]. Available from http://clinicaltrials.gov/show/NCT00621140 (NLM Identifier: NCT00621140). Accessed 3 December 2008
      1. Boehringer Ingelheim Pharmaceuticals
      : Efficacy vs. placebo as initial combination therapy with pioglitazone [article online]. Available from: http://clinicaltrials.gov/show/NCT00641043 (NLM Identifier: NCT00641043). Accessed 3 December 2008
      1. Boehringer Ingelheim Pharmaceuticals
      : A randomized, db, placebo-controlled study of BI 1356 for 18 weeks followed by a 34 week double-blind extension period (placebo patients switched to glimepiride) in type 2 diabetic patients for whom treatment with metformin is inappropriate [article online]. Available from http://clinicaltrials.gov/show/NCT00740051 (NLM Identifier: NCT00740051). Accessed 3 December 2008
      1. Boehringer Ingelheim Pharmaceuticals
      : Safety and efficacy of BI 1356 as monotherapy or in combination in type 2 DM [article online]. Available from http://clinicaltrials.gov/show/NCT00736099 (NLM Identifier: NCT00736099). Accessed 3 December 2008
      1. Boehringer Ingelheim Pharmaceuticals
      : BI 1356 in combination with metformin and a sulphonylurea in type 2 diabetes [article online]. Available from http://clinicaltrials.gov/show/NCT00602472 (NLM Identifier: NCT00602472). Accessed 3 December 2008
      1. Boehringer Ingelheim Pharmaceuticals
      : Efficacy and safety of BI 1356 vs. placebo added to metformin background therapy in patients with type 2 diabetes [article online]. Available from http://clinicaltrials.gov/show/NCT00601250 (NLM Identifier: NCT00601250). Accessed 3 December 2008
    23. ↵
      1. Boehringer Ingelheim Pharmaceuticals
      : Efficacy and safety of BI 1356 in combination with metformin in patients with type 2 diabetes [article online]. Available from http://clinicaltrials.gov/show/NCT00622284 (NLM Identifier: NCT00622284). Accessed 3 December 2008
    24. ↵
      1. Chen R,
      2. Pfutzner A,
      3. Jadzinsky M,
      4. Paz-Pacheco E,
      5. Xu Z,
      6. Allen E
      : Initial combination therapy with saxagliptin and metformin improves glycaemic control compared with either monotherapy alone in drug-nave patients with type 2 diabetes [abstract]. Diabetologia 51 (Suppl. 1):S38, 2008
      OpenUrl
    25. ↵
      1. Ravichandran S,
      2. Chacra AR,
      3. Tan GH,
      4. Apanovitch A,
      5. Chen R
      : Saxagliptin added to a sulfonylurea is safe and more effective than up-titrating a sulfonylurea in patients with type 2 diabetes [abstract]. Diabetologia 51 (Suppl. 1):S342, 2008
      OpenUrl
    26. ↵
      1. Allen E,
      2. Hollander P,
      3. Li J,
      4. Chen R
      : Saxagliptin added to a thiazolidinedione improves glycaemic control in patients with inadequately controlled type 2 diabetes [abstract]. Diabetologia 51 (Suppl. 1):S342-S343, 2008
      OpenUrl
    27. ↵
      1. Rosenstock J,
      2. Sankoh S,
      3. List JF
      : Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetes. Diabetes Obes Metab 10:376-386, 2008
      OpenUrlCrossRefPubMedWeb of Science
    28. ↵
      1. AstraZeneca,
      2. Bristol-Myers Squibb
      : Evaluate efficacy and safety of saxagliptin in adult patients with type 2 diabetes inadequate glycemic control [article online]. Available from http://clinicaltrials.gov/show/NCT00698932 (NLM Identifier: NCT00698932). Accessed 15 December 2008
      1. AstraZeneca,
      2. Bristol-Myers Squibb
      : 18-Week add-on to metformin comparison of saxagliptin and sitagliptin [article online]. Available from: http://clinicaltrials.gov/show/NCT00666458 (NLM Identifier: NCT00666458). Accessed 15 December 2008
      1. AstraZeneca,
      2. Bristol-Myers Squibb
      : Evaluate efficacy and safety of saxagliptin in combination with metformin in adult patients with type 2 diabetes [article online]. Available from http://clinicaltrials.gov/show/NCT00661362 (NLM Identifier: NCT00661362). Accessed 15 December 2008
      1. AstraZeneca,
      2. Bristol-Myers Squibb
      : Safety and efficacy study of subjects that are taking saxagliptin added onto metformin XR compared to subjects taking Metformin XR alone [article online]. Available from http://clinicaltrials.gov/show/NCT00683657 (NLM Identifier: NCT00683657). Accessed 15 December 2008
      1. AstraZeneca,
      2. Bristol-Myers Squibb
      : Safety and efficacy study of saxagliptin added to insulin alone or to insulin taken with metformin [article online]. Available from http://clinicaltrials.gov/show/NCT00757588 (NLM Identifier: NCT00757588). Accessed 15 December 2008
    33. ↵
      1. AstraZeneca,
      2. Bristol-Myers Squibb
      : Treatment effect of saxagliptin compared with placebo in patients with type 2 diabetes and renal impairment [article online]. Available from http://clinicaltrials.gov/show/NCT00614939 (NLM Identifier: NCT00614939). Accessed 15 December 2008
    34. ↵
      1. Scherbaum WA,
      2. Schweizer A,
      3. Mari A,
      4. Nilsson PM,
      5. Lalanne G,
      6. Jauffret S,
      7. Foley JE
      : Efficacy and tolerability of vildagliptin in drug-naïve patients with type 2 diabetes and mild hyperglycaemia. Diabetes Obes Metab 10:675-682, 2008
      OpenUrlCrossRefPubMedWeb of Science
    35. ↵
      1. Scherbaum WA,
      2. Schweizer A,
      3. Mari A,
      4. Nilsson PM,
      5. Lalanne G,
      6. Wang Y,
      7. Dunning BE,
      8. Foley JE
      : Evidence that vildagliptin attenuates deterioration of glycaemic control during 2-year treatment of patients with type 2 diabetes and mild hyperglycaemia. Diabetes Obes Metab 10:1114-1124, 2008
      OpenUrlCrossRefPubMed
    36. ↵
      1. Pi-Sunyer FX,
      2. Schweizer A,
      3. Mills D,
      4. Dejager S
      : Efficacy and tolerability of vildagliptin monotherapy in drug-naïve patients with type 2 diabetes. Diabetes Res Clin Pract 76:132-138, 2007
      OpenUrlCrossRefPubMedWeb of Science
    37. ↵
      1. Pratley RE,
      2. Schweizer A,
      3. Rosenstock J,
      4. Couturier A,
      5. Pi-Sunyer FX,
      6. Dejager S,
      7. Banerji MA
      : Management of type 2 diabetes in treatment-naïve elderly patients. Diabetes Care 30:3017-3022, 2007
      OpenUrlAbstract/FREE Full Text
    38. ↵
      1. Pan C,
      2. Yang W,
      3. Barona JP,
      4. Wang Y,
      5. Niggli M,
      6. Mohideen P,
      7. Wang Y,
      8. Foley JE
      : Comparison of vildagliptin and acarbose monotherapy in patients with type 2 diabetes: a 24-week, double-blind, randomized trial. Diabet Med 25:435-441, 2008
      OpenUrlCrossRefPubMed
    39. ↵
      1. Schweizer A,
      2. Couturier A,
      3. Foley JE,
      4. Dejager S
      : Comparison between vildagliptin and metformin to sustain reductions in HbA1c over 1 year in drug-naïve patients with type 2 diabetes. Diabet Med 24:955-961, 2007
      OpenUrlCrossRefPubMedWeb of Science
    40. ↵
      1. Rosenstock J,
      2. Kim SW,
      3. Baron MA,
      4. Camisasca RP,
      5. Cressier F,
      6. Couturier A,
      7. Dejager S
      : Efficacy and tolerability of initial combination therapy with vildagliptin and pioglitazone compared with component monotherapy in patients with type 2 diabetes. Diabetes Obes Metab 9:175-185, 2007
      OpenUrlCrossRefPubMedWeb of Science
    41. ↵
      1. Rosenstock J,
      2. Mills D,
      3. Baron MA,
      4. Schweizer A,
      5. Dejager S
      : Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes. Diabetes Care 30:217-223, 2007
      OpenUrlAbstract/FREE Full Text
    42. ↵
      1. Bosi E,
      2. Rochotte E,
      3. Camisasca RP,
      4. Garber AJ,
      5. Collober C
      : Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care 30:890-895, 2007
      OpenUrlAbstract/FREE Full Text
    43. ↵
      1. Ahren B,
      2. Mills D,
      3. Gomis R,
      4. Schweizer A,
      5. Standl E
      : Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes. Diabetes Care 27:2874-2880, 2004
      OpenUrlAbstract/FREE Full Text
    44. ↵
      1. Bolli G,
      2. Dotta F,
      3. Rochotte E,
      4. Cohen SE
      : Efficacy and tolerability of vildagliptin vs. pioglitazone when added to metformin: a 24-week, randomized, double-blind study. Diabetes Obes Metab 10:82-90, 2008
      OpenUrlPubMedWeb of Science
    45. ↵
      1. Garber AJ,
      2. Foley JE,
      3. Banerji MA,
      4. Ebeling P,
      5. Gudbjornsdottir S,
      6. Camisasca RP,
      7. Couturier A,
      8. Baron MA
      : Effects of vildagliptin on glucose control in patients with type 2 diabetes inadequately controlled with a sulphonylurea. Diabetes Obes Metab10:1047-1056, 2008
      OpenUrlCrossRefPubMedWeb of Science
    46. ↵
      1. Garber AJ,
      2. Schweizer A,
      3. Baron MA,
      4. Rochotte E,
      5. Dejager S
      : Vildagliptin in combination with pioglitazone improves glycaemic control in patients with type 2 diabetes failing thiazolidinedione monotherapy: a randomized, placebo-controlled study. Diabetes Obes Metab 9:166-174, 2007
      OpenUrlCrossRefPubMedWeb of Science
    47. ↵
      1. Fonseca V,
      2. Schweizer A,
      3. Albrecht D,
      4. Baron MA,
      5. Chang I,
      6. Dejager S
      : Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes. Diabetologia 50:1148-1155, 2007
      OpenUrlCrossRefPubMedWeb of Science
    48. ↵
      1. Novartis
      : Safety and tolerability of vildagliptin versus sitagliptin in patients with type 2 diabetes and severe renal insufficiency [article online]. Available from http://clinicaltrials.gov/show/NCT00616811 (NLM Identifier: NCT00616811). Accessed 15 December 2008
    49. ↵
      1. Matthews JE,
      2. Stewart MW,
      3. De Boever EH,
      4. Dobbins RL,
      5. Hodge RJ,
      6. Walker SE,
      7. Holland MC,
      8. Bush MA,
      9. Albiglutide Study Group
      : Pharmacodynamics, pharmacokinetics, safety and tolerability of albiglutide, a long-acting GLP-1 mimetic, in patients with type 2 diabetes. J Clin Endocrin Metab 93:4810-4817, 2008
      OpenUrlCrossRefPubMed
    50. ↵
      1. Rosenstock J,
      2. Ratner RE,
      3. Botka G
      : Dose range effects of the new once daily GLP-1 receptor agonist AVE0010 added to metformin in type 2 diabetes [abstract]. Diabetologia 51 (Suppl. 1):S66, 2008
      OpenUrl
    51. ↵
      1. Sanofi-Aventis
      : GLP-1 agonist AVE0010 in patients with type 2 diabetes for glycemic control and safety evaluation in monotherapy (GETGOAL-MONO) [article online]. Available from http://clinicaltrials.gov/show/NCT00688701 (NLM Identifier: NCT00688701). Accessed 4 December 2008
      1. Sanofi-Aventis
      : GLP-1 agonist AVE0010 (morning or evening) in patients with type 2 diabetes for glycemic control and safety evaluation on top of metformin (GETGOAL-M) [article online]. Available from http://clinicaltrials.gov/show/NCT00712673 (NLM Identifier: NCT00712673). Accessed 4 December 2008
      1. Sanofi-Aventis
      : GLP-1 agonist AVE0010 in patients with type 2 diabetes for glycemic control and safety evaluation, on top of metformin (GETGOAL-F1) [article online]. Available from http://clinicaltrials.gov/show/NCT00763451 (NLM Identifier: NCT00763451). Accessed 4 December 2008
      1. Sanofi-Aventis
      : GLP-1 agonist AVE0010 in patients with type 2 diabetes for glycemic control and safety evaluation, on top of sulfonylurea (GETGOAL-S) [article online]. Available from http://clinicaltrials.gov/show/NCT00713830 (NLM Identifier: NCT00713830). Accessed 4 December 2008
      1. Sanofi-Aventis
      : GLP-1 agonist AVE0010 in patients with type 2 diabetes for glycemic control and safety evaluation, on top of basal insulin (GETGOAL-L) [article online]. Available from http://clinicaltrials.gov/show/NCT00715624 (NLM Identifier: NCT00715624). Accessed 4 December 2008
      1. Sanofi-Aventis
      : GLP-1 agonist AVE0010 in patients with type 2 diabetes for glycemic control and safety evaluation, on top of pioglitazone (GETGOAL-P) [article online]. Available from http://clinicaltrials.gov/show/NCT00763815 (NLM Identifier: NCT00763815). Accessed 4 December 2008
    57. ↵
      1. Sanofi-Aventis
      : GLP-1 agonist AVE0010 versus exenatide in patients with type 2 diabetes for glycemic control and safety evaluation, on top of metformin (GETGOAL-X) [article online]. Available from http://clinicaltrials.gov/show/NCT00707031 (NLM Identifier: NCT00707031). Accessed 4 December 2008
    58. ↵
      1. Kim D,
      2. Trautman M,
      3. MacConell L,
      4. Fineman M,
      5. Zhuang D,
      6. Taylor K,
      7. Kothare PA
      : Effects of once-weekly dosing of a long-acting release formulation of exenatide on glucose control and body weight in subjects with type 2 diabetes. Diabetes Care 30:1487-1493, 2007
      OpenUrlAbstract/FREE Full Text
    59. ↵
      1. Drucker DJ,
      2. Buse JB,
      3. Taylor K,
      4. Kendall DM,
      5. Trautmann M,
      6. Zhuang D,
      7. Porter L
      : Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet 372:1240-1250, 2008
      OpenUrlCrossRefPubMedWeb of Science
    60. ↵
      1. Buse J,
      2. Drucker D,
      3. Taylor K,
      4. Kim T,
      5. Wilhelm K,
      6. Kendall D,
      7. Trautmann M,
      8. Zhuang D,
      9. Porter L
      : Exenatide once weekly elicits sustained glycaemic control and weight loss over 52 weeks [abstract]. Diabetologia 51 (Suppl. 1):S67, 2008
      OpenUrl
    61. ↵
      1. Marre M,
      2. Shaw J,
      3. Brandle M,
      4. Wan Bebakar WM,
      5. Kamaruddin NA,
      6. Strand J,
      7. Zdravkovic M,
      8. Le-Thi TD,
      9. Colagiuri S
      : Liraglutide added to a sulphonylurea (SU) offers significantly better glycaemic control and favourable weight change compared with rosiglitazone and SU combination therapy in T2D [abstract]. Diabetologia 51 (Suppl. 1):S359, 2008
      OpenUrl
    62. ↵
      1. Garber A,
      2. Henry R,
      3. Ratner R,
      4. Garcia-Hernandez PA,
      5. Rodriguez-Pattzi H,
      6. Olivera-Alvarez I,
      7. Hale PM,
      8. Zdravkovic M,
      9. Bode B,
      10. LEAD-3 (Mono) Study Group
      : Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet 373:473-481, 2008
      OpenUrlCrossRefPubMed
    63. ↵
      1. Nauck M,
      2. Frid A,
      3. Hermansen K,
      4. Shah NS,
      5. Tankova T,
      6. Mitha IH,
      7. Zdravkovic M,
      8. During M,
      9. Matthews DR,
      10. LEAD-2 Study Group
      : Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin in type 2 diabetes mellitus (LEAD-2 Met). Diabetes Care 32:84-90, 2009
      OpenUrlAbstract/FREE Full Text
    64. ↵
      1. Zinman B,
      2. Gerich J,
      3. Buse J,
      4. Lewin A,
      5. Schwartz SL,
      6. Raskin P,
      7. Hale PM,
      8. Zdravkovic M,
      9. Blonde L
      : Effect of the GLP-1 analogue liraglutide on glycaemic control and weight reduction in patients on metformin and rosiglitazone: a randomized double-blind placebo-controlled trial [abstract]. Diabetologia 51 (Suppl. 1):S359-S360, 2008
      OpenUrl
    65. ↵
      1. Russell-Jones D,
      2. Vaag A,
      3. Schmitz O,
      4. Sethi B,
      5. Lalic NM,
      6. Antic S,
      7. Zdravkovic M,
      8. Ravn GM,
      9. Simo R
      : Significantly better glycemic control/weight reduction with human GLP-1 analogue liraglutide, than with insulin glargine: all as add-on to metformin + sulphonylurea in type 2 diabetes [abstract]. Diabetologia 51 (Suppl. 1):S68, 2008
      OpenUrl
    66. ↵
      1. Eli Lilly and Co.,
      2. United Biosource Corporation,
      3. Tessella Inc.,
      4. Berry Consultants LLC
      : A study of LY2189265 compared to sitagliptin in patients with type 2 diabetes mellitus on metformin [article online]. Available from http://clinicaltrials.gov/show/NCT00734474 (NLM Identifier: NCT00734474). Accessed 4 December 2008
    67. ↵
      1. Ratner R,
      2. Nauck M,
      3. Asnagi V,
      4. Berria R,
      5. Cressier F,
      6. Boldrin M,
      7. Balena R
      : Safety and tolerability of high doses of the long acting, human GLP1 analogue R1583 in diabetic subjects treated with metformin: a double-blind, placebo-controlled phase 2 study [abstract]. Diabetes 57 (Suppl. 1):A3, 2008
      OpenUrl
    68. ↵
      1. Balena R,
      2. Ratner R,
      3. Berria R,
      4. Asnaghi V,
      5. Grant R,
      6. Snaith J,
      7. Boldrin M,
      8. Nauck M
      : Eight weeks of treatment with the long acting, human GLP-1 analogue R1583 improves glycemic control and lowers body weight in subjects with type 2 diabetes mellitus (T2DM) treated with metformin: a double-blind placebo-controlled phase 2 study [abstract]. Diabetes 57 (Suppl. 1):A33, 2008
      OpenUrl
    69. ↵
      1. Hoffmann-La Roche
      : A study of taspoglutide versus placebo for the treatment of patients with type 2 diabetes mellitus inadequately controlled with diet and exercise [article online]. Available from http://clinicaltrials.gov/show/NCT00744926 (NLM Identifier: NCT00744926). Accessed 4 December 2008
      1. Hoffmann-La Roche
      : A study of taspoglutide versus placebo for the treatment of patients with type 2 diabetes mellitus inadequately controlled with metformin plus pioglitazone [article online]. Available from http://clinicaltrials.gov/show/NCT00744367 (NLM Identifier: NCT00744367). Accessed 4 December 2008
      1. Hoffmann-La Roche
      : A study of taspoglutide versus exenatide for the treatment of patients with type 2 diabetes mellitus inadequately controlled with metformin, thiazolidinedione or a combination of both [article online]. Available from http://clinicaltrials.gov/show/NCT00717457 (NLM Identifier: NCT00717457). Accessed 4 December 2008
      1. Hoffmann-La Roche
      : A study of the safety, tolerability and effect on glycemic control of taspoglutide versus insulin glargine in insulin naïve type 2 diabetic patients inadequately controlled with metformin plus sulphonylurea [article online]. Available from http://clinicaltrials.gov/show/NCT00755287 (NLM Identifier: NCT00755287). Accessed 4 December 2008
    73. ↵
      1. Hoffmann-La Roche
      : A study of taspoglutide versus sitagliptin for the treatment of patients with type 2 diabetes mellitus inadequately controlled with metformin [article online]. Available from http://clinicaltrials.gov/show/NCT00754988 (NLM Identifier: NCT00754988). Accessed 4 December 2008
    74. ↵
      1. Chang F,
      2. Jaber LA,
      3. Berlie HD,
      4. O'Connell MB
      : Evolution of peroxisome proliferator-activated receptor agonists. Ann Pharmacother 41:973-983, 2007
      OpenUrlCrossRefPubMedWeb of Science
    75. ↵
      1. Larsen PJ,
      2. Lykkegaard K,
      3. Larsen LK,
      4. Fleckner J,
      5. Sauerberg P,
      6. Wassermann K,
      7. Wulff EM
      : Dissociation of antihyperglycaemic and adverse effects of partial perioxisome proliferator-activated receptor (PPAR-γ) agonist balaglitazone. Eur J Pharmacol 506:173-179, 2008
      OpenUrl
    76. ↵
      1. Zhang F,
      2. Lavan BE,
      3. Gregoire FM
      : Selective modulators of PPAR-γ activity: molecular aspects related to obesity and side-effects. PPAR Research 2007 electronically published (doi:10.1144/2007/32696)
    77. ↵
      1. Rheoscience A/S
      : Efficacy and safety of treatment with balaglitazone in type 2 diabetes patients on stable insulin therapy (BALLET) [article online]. Available from http://clinicaltrials.gov/show/NCT00515632 (NLM Identifier: NCT00515632). Accessed 12 December 2008
    78. ↵
      1. Daiichi Sankyo Inc.
      : Randomized, double-blind active comparator-controlled study of rivoglitazone in type 2 diabetes mellitus [article online]. Available from http://clinicaltrials.gov/show/NCT00484198 (NLM Identifier: NCT00484198). Accessed 12 December 2008
    79. ↵
      1. Truitt K,
      2. Chou HS,
      3. Wang A,
      4. Walker JR,
      5. Rosenstock J
      : A randomized, multiple-dose, placebo-controlled comparative study of rivoglitazone (Rivo, CS-011) and open-label pioglitazone (Pio) in patients with type 2 diabetes (T2DM) [abstract]. Diabetes 57 (Suppl. 1):A130-131, 2008
      OpenUrl
    80. ↵
      1. Chou HS,
      2. Wang A,
      3. Walker JR,
      4. Truitt K,
      5. Rosenstock J
      : A randomized, placebo-controlled, 26-week dose response study of rivoglitazone (RIVO, CS-011) versus pioglitazone (PIO) in patients with type 2 diabetes (T2DM) [abstract]. Diabetes 57 (Suppl. 1):A87, 2008
      OpenUrl
    81. ↵
      1. Jabbour SA,
      2. Goldstein BJ
      : Sodium glucose co-transporter 2 inhibitors: blocking renal tubular reabsorption of glucose to improve glycaemic control in patients with diabetes. Int J Clin Pract 62:1279-1284, 2008
      OpenUrlCrossRefPubMedWeb of Science
    82. ↵
      1. List JF,
      2. Woo V,
      3. Morales E,
      4. Tang Q,
      5. Fiedorek FT
      : Efficacy and safety of dapagliflozin in a dose-ranging monotherapy study of treatment-naïve patients with type 2 diabetes [abstract]. Diabetologia 51 (Suppl. 1):S22-S23, 2008
      OpenUrl
    83. ↵
      1. Woo V,
      2. List JF,
      3. Morales E,
      4. Tang W,
      5. Fiedorek FT
      : Dapagliflozin-induced glucosuria is accompanied by weight loss in type 2 diabetes patients [abstract]. Diabetologia 51 (Suppl. 1):S317-S318, 2008
      OpenUrl
    84. ↵
      1. Bristol-Myers Squibb,
      2. AstraZeneca
      : Safety and efficacy of dapagliflozin as monotherapy in subjects with type 2 diabetes [article online]. Available from http://clinicaltrials.gov/show/NCT00736879 (NLM Identifier: NCT00736879). Accessed 12 December 2008
      1. Bristol-Myers Squibb,
      2. AstraZeneca
      : A Phase III study of BMS-512148 (dapagliflozin) in patients with type 2 diabetes who are not well controlled with diet and exercise [article online]. Available from http://clinicaltrials.gov/show/NCT00528372 (NLM Identifier: NCT00528372). Accessed 12 December 2008
      1. Bristol-Myers Squibb,
      2. AstraZeneca
      : Efficacy and safety of dapagliflozin in combination with metformin in type 2 diabetes patients [article online]. Available from http://clinicaltrials.gov/show/NCT00660907 (NLM Identifier: NCT00660907). Accessed 12 December 2008
      1. Bristol-Myers Squibb,
      2. AstraZeneca
      : An efficacy & safety study of BMS-512148 in combination with metformin extended release tablets [article online]. Available from http://clinicaltrials.gov/show/NCT00643851 (NLM Identifier: NCT00643851). Accessed 12 December 2008
      1. Bristol-Myers Squibb,
      2. AstraZeneca
      : A phase III study of BMS-512148 (dapagliflozin) in patients with type 2 diabetes who are not well controlled on metformin alone [article online]. Available from http://clinicaltrials.gov/show/NCT00528879 (NLM Identifier: NCT00528879). Accessed 12 December 2008
      1. AstraZeneca,
      2. Bristol-Myers Squibb
      : Efficacy and safety of dapagliflozin in combination with glimepiride (a sulphonylurea) in type 2 diabetes patients [article online]. Available from http://clinicaltrials.gov/show/NCT00680745 (NLM Identifier: NCT00680745). Accessed 12 December 2008
      1. Bristol-Myers Squibb,
      2. AstraZeneca
      : Add-on to thiazolidinedione (TZD) failures [article online]. Available from http://clinicaltrials.gov/show/NCT00683878 (NLM Identifier: NCT00683878). Accessed 12 December 2008
    91. ↵
      1. AstraZeneca,
      2. Bristol-Myers Squibb
      : Efficacy and safety of dapagliflozin, added to therapy of patients with type 2 diabetes with inadequate glycemic control on insulin [article online]. Available from http://clinicaltrials.gov/show/NCT00673231 (NLM Identifier: NCT00673231). Accessed 12 December 2008
    92. ↵
      1. Sinclair AJ,
      2. Whisnant JK
      : A randomized, double-blind trial comparing a new, rapid onset and short duration insulin secretagogue, mitiglinide, to acarbose for the treatment of elderly patients with type 2 diabetes mellitus (T2DM) [abstract]. Diabetes 56 (Suppl. 1):A563, 2007
      OpenUrl
    93. ↵
      1. O'Brien R,
      2. Scott RS,
      3. Whisnant JK
      : Synergistic efficacy by addition of mitiglinide, a new rapid onset and short duration insulin secretagogue, to standard metformin for type 2 diabetes mellitus (T2DM) in a large randomized, double-blind trial [abstract]. Diabetes 56 (Suppl. 1):A553, 2007
      OpenUrl
    94. ↵
      1. Yoshihara T,
      2. Kumashiro N,
      3. Kanazawa Y,
      4. Mita T,
      5. Sakurai Y,
      6. Kawai J,
      7. Abe M,
      8. Motojima K,
      9. Hara K,
      10. Yamazaki Y,
      11. Kanazawa A,
      12. Miwa S,
      13. Sato F,
      14. Kanno R,
      15. Shimizu T,
      16. Sakai K,
      17. Uchino H,
      18. Watada H,
      19. Tanaka Y,
      20. Kawamori R,
      21. Hirose T
      : Therapeutic efficacy of mitiglinide combined with once daily insulin glargine after switching from multiple daily insulin regimen of aspart insulin and glargine in patients with type 2 diabetes mellitus. Endocr J 53:67-72, 2006
      OpenUrlCrossRefPubMed
      1. Kumashiro N,
      2. Yoshihara T,
      3. Kanazawa Y,
      4. Shimizu T,
      5. Watada H,
      6. Tanaka Y,
      7. Fujitani Y,
      8. Kawamori R,
      9. Hirose T
      : Long-term effect of combination therapy with mitiglinide and once daily insulin glargine in patients who were successfully switched from intensive insulin therapy in short-term study. Endocr J 54:163-166, 2007
      OpenUrlCrossRefPubMed
    96. ↵
      1. Yamada S,
      2. Watanabe M,
      3. Funae O,
      4. Atsumi Y,
      5. Suzuki R,
      6. Yajima K,
      7. Nakamura Y,
      8. Kawai T,
      9. Oikawa Y,
      10. Shimada A
      : Effect of combination therapy of a rapid-acting insulin secretagogue (glinide) with premixed insulin in type 2 diabetes mellitus. Intern Med 46:1893-1897, 2007
      OpenUrlCrossRefPubMed
    97. ↵
      1. Elixir Pharmaceuticals
      : Mitiglinide in combination with metformin vs. metformin alone in patients with type 2 diabetes mellitus [article online]. Available from http://clinicaltrials.gov/show/NCT00519142 (NLM Identifier: NCT00519142). Accessed 12 December 2008
    98. ↵
      1. Rosenstock J,
      2. Bergenstal R,
      3. Defronzo RA,
      4. Hirsch IB,
      5. Klonoff D,
      6. Boss AH,
      7. Kramer D,
      8. Petrucci R,
      9. Yu W,
      10. Levy B,
      11. 0008 Study Group
      : Efficacy and safety of technosphere inhaled insulin compared with technosphere powder placebo in insulin-naïve type 2 diabetes suboptimally controlled with oral agents. Diabetes Care 31:2177-2182, 2008
      OpenUrlAbstract/FREE Full Text
    99. ↵
      1. Boss AH,
      2. Baughman RA,
      3. Evans SH,
      4. Firsov I,
      5. Kramer DA,
      6. Richardson P
      : A 3 month comparison in type 1 diabetes of inhaled Technosphere®/insulin (TI) to sc administered rapid-acting insulin analogue (RAA) as prandial insulin in a basal/prandial regimen [abstract]. Diabetes 55 (Suppl. 1):A97, 2006
      OpenUrl
    100. ↵
      1. Rave K,
      2. Pfutzner A,
      3. Heise T,
      4. Boss AH
      : Coverage of postprandial blood glucose excursions with inhaled Technosphere insulin in comparison to subcutaneously injected regular human insulin in subjects with type 2 diabetes. Diabetes Care 30:2307-2308, 2007
      OpenUrlFREE Full Text
    101. ↵
      1. Tu N,
      2. Kramer D,
      3. Baughman R
      : Inhaled Technosphere®/insulin improves glycemic control without weight gain [abstract]. Diabetes 56 (Suppl. 1):A125, 2007
      OpenUrl
    102. ↵
      1. Mannkind Corporation
      : Efficacy and safety of prandial inhalation of Technosphere/insulin in combination with metformin or Technosphere/insulin alone versus 2 oral anti-diabetic agents in subjects with type 2 diabetes [article online]. Available from http://clinicaltrials.gov/show/NCT00332488 (NLM Identifier: NCT00332488). Accessed 12 December 2008
      1. Mannkind Corporation
      : Safety and efficacy of Technosphere® insulin inhalation powder and Lantus® compared to Humalog® and Lantus® over 16-weeks [article online]. Available from http://clinicaltrials.gov/show/NCT00700622 (NLM Identifier: NCT00700622). Accessed 12 December 2008
      1. Mannkind Corporation
      : Efficacy and safety in subjects with type 2 diabetes receiving subcutaneous basal insulin and prandial inhalation of Technosphere/insulin versus subcutaneous premixed insulin therapy over a 52-week treatment period and a 4-week follow-up [article online]. Available from http://clinicaltrials.gov/show/NCT00309244 (NLM Identifier: NCT00309244). Accessed 12 December 2008
    105. ↵
      1. Mannkind Corporation
      : Efficacy & safety of inhaled insulin in type 1 diabetes [article online]. Available from http://clinicaltrials.gov/show/NCT00308308 (NLM Identifier: NCT00308308). Accessed 12 December 2008
    106. ↵
      1. Baughman RA,
      2. Evans SH,
      3. Boss AH,
      4. Firsov I,
      5. Harris R,
      6. Ren H,
      7. Richardson PC
      : Technosphere insulin does not affect pulmonary function in a 6 month study of patients with type 2 diabetes [abstract]. Diabetologia 49 (Suppl. 1):117, 2006
      OpenUrlPubMed
    107. ↵
      1. Mannkind Corporation
      : Safety of inhaled insulin with type 1 and type 2 diabetes [article online]. Available from http://clinicaltrials.gov/show/NCT00308737 (NLM Identifier: NCT00308737). Accessed 12 December 2008
    108. ↵
      1. Modi P,
      2. Mihic M,
      3. Lewin A
      : The evolving role of oral insulin in the treatment of diabetes using a novel RapidMist™ system. Diabetes Metab Res Rev 18 (Suppl. 1):S38-S42, 2002
      OpenUrlCrossRefPubMed
    109. ↵
      1. Guevara-Aguirre J,
      2. Guevara-Aguirre M,
      3. Saavedra J,
      4. Bernstein G,
      5. Rosenbloom AL
      : Comparison of oral insulin spray and subcutaneous regular insulin at mealtime in type 1 diabetes. Diabetes Technol Ther 9:372-376, 2007
      OpenUrlCrossRefPubMedWeb of Science
    110. ↵
      1. Guevara-Aguirre J,
      2. Guevara-Aguirre M,
      3. Saavedra J
      : Comparison of pre-prandial s.c. regular insulin vs prandial oral insulin in adult type-1 DM subjects receiving basal s.c. twice daily isophan insulin (NPH) [abstract]. Diabetes 56 (Suppl. 1):0474-P, 2007
      OpenUrl
    111. ↵
      1. Guevara-Aguirre J,
      2. Guevara-Aguiree M,
      3. Saavedra J,
      4. Rosenbloom A,
      5. Bernstein G
      : Insulin analogue (basal + pre-prandial injection) vs. human insulin (basal injection + prandial oral insulin (Generex Oral-lynTM) in type-1 diabetes mellitus: a 372-day comparison [abstract]. Diabetes 57 (Suppl. 1):A559-A560, 2008
      OpenUrl
    112. ↵
      1. Guevara-Aguirre J,
      2. Guevara-Aguirre M,
      3. Saavedra J,
      4. Bernstein G
      : 6-month safety and efficacy of lunch-time oral insulin in juvenile type-1 DM subjects receiving basal glargine insulin and pre-breakfast and pre-dinner S.C. regular insulin [abstract]. Diabetes 56 (Suppl. 1):2760-PO, 2007
      OpenUrl
    113. ↵
      1. Generex Biotechnology Corp.
      : Active comparator study of Generex Oral-LynTM spray and injected human insulin [article online]. Available from http://clinicaltrials.gov/show/NCT00668850 (NLM Identifier: NCT00668850). Accessed 12 December 2008
    114. ↵
      1. Steiner S,
      2. Hompesch M,
      3. Pohl R,
      4. Simms P,
      5. Flacke F,
      6. Mohr T,
      7. Pfutzner A,
      8. Heinemann L
      : A novel insulin formulation with a more rapid onset of action. Diabetologia 51:1602-1606, 2008
      OpenUrlCrossRefPubMedWeb of Science
    115. ↵
      1. Steiner S,
      2. Hompesch M,
      3. Pohl R,
      4. Flacke F,
      5. Pfuetzner A,
      6. Simms PV,
      7. Heinemann L
      : Pharmacokinetics and pharmacodynamics of insulin VIAjectTM and regular human insulin when injected subcutaneously directly before a meal in patients with type 1 diabetes [abstract]. Diabetes 56 (Suppl. 1):A9, 2007
      OpenUrl
    116. ↵
      1. Biodel
      : An open label, multi-center, randomized, parallel group study comparing the efficacy and safety of insulin VIAjectTM and regular human insulin in patients with type 1 diabetes mellitus [article online]. Available from http://clinicaltrials.gov/show/NCT00542724 (NLM Identifier: NCT00542724). Accessed 12 December 2008
    117. ↵
      1. Biodel
      : An open label, multi-center, randomized, parallel group study comparing the efficacy and safety of insulin VIAjectTM and regular human insulin in patients with type 2 diabetes mellitus [article online]. Available from http://clinicaltrials.gov/show/NCT00542633 (NLM Identifier: NCT00542633). Accessed 12 December 2008
    118. ↵
      1. Scranton RE,
      2. Gaziano JM,
      3. Rutty D,
      4. Ezrokhi M,
      5. Cincotta A
      : A randomized, double-blind, placebo-controlled trial to assess safety and tolerability during treatment of type 2 diabetes with usual diabetes therapy and either CyclosetTM or placebo. BMC Endocr Dis 2007; 7:3 electronically published (doi:10.1186/1472-6823-7-3)
      OpenUrl
    119. ↵
      1. Pijl H,
      2. Pipek R,
      3. Ohashi S,
      4. Iozzo P,
      5. Matsuda M,
      6. Lancaster JL,
      7. Cincotta AH,
      8. DeFronzo RA
      : Bromocriptine: a novel approach to the treatment of type 2 diabetes. Diabetes Care 23:1154-1161, 2000
      OpenUrlAbstract/FREE Full Text
    120. ↵
      1. Cincotta AH,
      2. Gaziano JM,
      3. Ezrokhi M,
      4. Scranton R
      : Cycloset (quick-release bromocriptine mesylate), a novel centrally acting treatment for type 2 diabetes [abstract]. Diabetologia 51 (Suppl. 1):S22, 2008
      OpenUrl
    121. ↵
      1. Forman D,
      2. Vaickus L,
      3. Rosenzweig M
      : Otelixizumab induces expansion of human CD4+FoxP3+ cells in vitro and in vivo [abstract]. Diabetes 57 (Suppl. 1):A154, 2008
      OpenUrl
    122. ↵
      1. Tolerx Inc.
      : Phase 3 trial of otelixizumab for adults with newly diagnosed type 1 (autoimmune) diabetes mellitus: DEFEND-1 [article online]. Available from http://clinicaltrials.gov/show/NCT00678886 (NLM Identifier: NCT00678886). Accessed 12 December 2008
    123. ↵
      1. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
      : Effects of recombinant human glutamic acid decarboxylase (rhGAD65) formulated in alum (GAD-alum) on the progression of type 1 diabetes in new onset subjects [article online]. Available from http://clinicaltrials.gov/show/NCT00529399 (NLM Identifier: NCT00529399). Accessed 12 December 2008
    124. ↵
      1. Agardh CD,
      2. Cilio CM,
      3. Lethagen AL,
      4. Lynch K,
      5. Leslie RDG,
      6. Palmer M,
      7. Harris RA,
      8. Robertson JA,
      9. Lernmark A
      : Clinical evidence for the safety of GAD65 immunomodulation in adult-onset autoimmune diabetes. J Diabetes Complications 19:238-246, 2005
      OpenUrlCrossRefPubMedWeb of Science
    125. ↵
      1. Agardh CD,
      2. Lethagen A,
      3. Cilio CM,
      4. Lynch K,
      5. Palmer M,
      6. Leslie DRG,
      7. Harris RA,
      8. Robertson JA,
      9. Lernmark A
      : Beta cell function and metabolic control during two years of follow-up after GAD65 dose-escalation immunomodulation in adult-onset autoimmune diabetes [abstract]. Diabetes 56 (Suppl. 1):1173-P, 2006
      OpenUrl
    126. ↵
      1. Diamyd Therapeutics AB
      : A phase III study to investigate the impact of Diamyd in patients newly diagnosed with type 1 diabetes (USA) [article online]. Available from http://clinicaltrials.gov/show/NCT00751842 (NLM Identifier: NCT00751842). Accessed 12 December 2008
    127. ↵
      1. Franks AM,
      2. Gardner SF
      : AGI-1067: a novel vascular protectant for prevention of restenosis. Ann Pharmacother 40:66-73, 2006
      OpenUrlCrossRefPubMed
    128. ↵
      1. Tardif JC,
      2. McMurray JJV,
      3. Klug E,
      4. Small R,
      5. Schumi J,
      6. Choi J,
      7. Cooper J,
      8. Scott R,
      9. Lewis EF,
      10. L'Allier PL,
      11. Pfeffer MA,
      12. Aggressive Reduction of Inflammation Stops Events (ARISE) Trial Investigators
      : Effects of succinobucol (AGI-1067) after an acute coronary syndrome: a randomised, double-blind, placebo-controlled trial. Lancet 371:1761-1768, 2008
      OpenUrlCrossRefPubMedWeb of Science
    129. ↵
      1. Klug E,
      2. Pfeffer MA,
      3. McMurray JJ,
      4. Fleming AG,
      5. Long WA,
      6. Small R,
      7. Tardif JC
      : AGI-1067 improves glycemic control when added to current regimens in patients with type 2 diabetes [abstract]. Diabetes 57 (Suppl. 1):A132, 2008
      OpenUrl
    130. ↵
      1. AtheroGenics
      : ANDES-AGI-1067 as a novel antidiabetic agent evaluation study [article online]. Available from http://clinicaltrials.gov/show/NCT00525577 (NLM Identifier: NCT00525577). Accessed 12 December 2008
    131. ↵
      1. AtheroGenics, Inc.
      : AtheroGenics reports positive results from ANDES phase 3 clinical trial of AGI-1067 in type 2 diabetes [press release online]. Atlanta, Ga., AtheroGenics, Inc., July 31, 2008. Available from www.atherogenics.com. Accessed 15 December 2008
    132. ↵
      1. Lu Y,
      2. Levin GV,
      3. Donner TW
      : Tagatose, a new antidiabetic and obesity control drug. Diabetes Obes Metab 10:109-134, 2008
      OpenUrlCrossRefPubMed
    133. ↵
      1. Donner TW,
      2. Wilber JF,
      3. Ostrowski D
      : D-tagatose, a novel hexose: acute effects on carbohydrate tolerance in subjects with and without type 2 diabetes. Diabetes Obes Metab 1:285-291, 1999
      OpenUrlCrossRefPubMed
    134. ↵
      1. Donner TW
      : The metabolic effects of dietary supplementation with D-tagatose in patients with type 2 diabetes [abstract]. Diabetes 55 (Suppl. 1):A110, 2006
      OpenUrl
    135. ↵
      1. BioSpherix,
      2. Spherix
      : A clinical study to evaluate the effect of Naturlose (tagatose) [article online]. Available from http://clinicaltrials.gov/show/NCT00451477 (NLM Identifier: NCT00451477). Accessed 12 December 2008
    136. ↵
      1. Pillemer SR,
      2. Carlin D,
      3. Protégé Trial Group
      : Protégé Trial: Teplizumab, a monoclonal antibody, for treatment of type 1 diabetes mellitus [abstract]. Diabetes 57 (Suppl. 1):A585-A586, 2008
      OpenUrl
    137. ↵
      1. Herold KC,
      2. Hagopian W,
      3. Auger JA,
      4. Poumian-Ruiz E,
      5. Taylor L,
      6. Donaldson D,
      7. Gitelman SE,
      8. Harlan DM,
      9. Xu D,
      10. Zivin RA,
      11. Bluestone JA
      : Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 346:1692-1698, 2002
      OpenUrlCrossRefPubMedWeb of Science
    138. ↵
      1. Herold KC,
      2. Gitelman SE,
      3. Masharani U,
      4. Hagopian W,
      5. Bisikirska B,
      6. Donaldson D,
      7. Rother K,
      8. Diamond B,
      9. Harlan DM,
      10. Bluestone JA
      : A single course of anti-CD3 monoclonal antibody hOKT3γ1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes 54:1763-1769, 2005
      OpenUrlAbstract/FREE Full Text
    139. ↵
      1. MacroGenics, Juvenile Diabetes Research Foundation (JDRF)
      : The Protégé Study: clinical trial of MGA031 in children and adults with recent-onset type 1 diabetes mellitus [article online]. Available from http://clinicaltrials.gov/show/NCT00385697 (NLM Identifier: NCT00385697). Accessed 12 December 2008
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    March 2009, 22(2)
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    New Drugs in Development for the Treatment of Diabetes
    Terri L. Levien, Danial E. Baker
    Diabetes Spectrum Mar 2009, 22 (2) 92-106; DOI: 10.2337/diaspect.22.2.92
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