Saxagliptin, a dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes Baptist Gallwitz

Size: px
Start display at page:

Download "Saxagliptin, a dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes Baptist Gallwitz"

Transcription

1 906 DRUG PROFILE IDrugs (12): Thomson Reuters (Scientific) Ltd ISSN Saxagliptin, a dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes Baptist Gallwitz Address Eberhard-Karls-University, Department of Medicine IV, Otfried-Müller-Straße 10, Tübingen, Germany baptist.gallwitz@med.uni-tuebingen.de Saxagliptin, a dipeptidyl peptidase-iv (DPP-IV) inhibitor, is currently under development by Bristol-Myers Squibb Co, AstraZeneca plc and Otsuka Pharmaceutical Co Ltd for the treatment of type 2 diabetes. The compound has high selectivity for DPP-IV compared with other dipeptidyl peptidases and a duration profile designed for once-daily dosing. DPP-IV inhibitors act by increasing levels of glucagon-like peptide-1, which stimulates insulin secretion. In animal studies, saxagliptin improved glucose clearance and raised insulin levels in rodents. Clinical trials have demonstrated a dose-dependent inhibition of DPP-IV by saxagliptin without serious side effects. Results have demonstrated that treatment with saxagliptin lowers blood glucose levels, with good tolerability and safety. The specific advantages of saxagliptin over other DPP-IV inhibitors may lie in its long-lived, effective and highly specific inhibition of DPP-IV, making once-daily treatment feasible, effective and safe. Introduction The worldwide prevalence of type 2 diabetes is rising dramatically as a result of increasingly sedentary life-styles with less physical activity and more frequent consumption of meals with a high caloric density. These issues of increased caloric intake and reduced physical activity have already led to a significant increase in levels of obesity in recent decades, which is a major risk factor and driving force for developing type 2 diabetes. As a consequence of this, an increased incidence of the disorders associated with type 2 diabetes, such as micro- and macrovascular complications (eg, kidney failure, blindness, myocardial infarction, foot amputation and stroke), is also anticipated. The total number of individuals with diabetes (type 1 or type 2) may reach 370 million worldwide by the year 2030 [931353]. Because of this development, and the fact that most patients do not attain their glycemic goals using current treatment strategies, novel, effective and safe treatment options are needed for type 2 diabetes. It is particularly important to develop antidiabetic agents that do not promote further weight gain in already obese patients; weight gain is associated with most of the established therapeutic options (sulfonylureas, glitazones and insulin). Type 2 diabetes is characterized by insulin resistance and dysfunction of the insulin-secreting β-cells of the pancreatic islets. While insulin resistance is constant in the course of type 2 diabetes, β-cell function continuously declines as a result of apoptosis of these cells caused by, among other effects, chronic hyperglycemia, elevated free-fatty-acid concentrations and elevated cytokine levels. This decline in β-cell function is the overall driving force for disease progression. The α-cells in the islets additionally develop a disturbance of glucagon secretion. In healthy individuals, Therapeutic Saxagliptin. Originator Bristol-Myers Squibb Co. Licensees AstraZeneca plc, Otsuka Pharmaceutical Co Ltd. Status Pre-registration. Indication Diabetes mellitus type 2. Actions DPP-IV inhibitor antidiabetic product, Insulin sensitizer. Technology Oral formulation. Synonyms BMS , Onglyza, saxagliptin hydrate glucagon secretion is suppressed under hyperglycemic conditions, whereas in patients with type 2 diabetes glucagon secretion is elevated under such conditions, leading to excessive glucose production by the liver [931356]. H N N H O NH 2 The therapeutic options currently available are limited and do not address the problem of α- and β-cell dysfunction. As a result, the majority of patients persistently have elevated glycemic parameters (glycated hemoglobin, and fasting and postprandial plasma glucose). Only 37% of patients with type 2 diabetes in the US reach the glycemic goal of a glycated hemoglobin A1c (HbA1c; a measure of HO H H

2 Saxagliptin Gallwitz 907 the average blood glucose concentration over a number of weeks) value of < 7%. The percentage of patients achieving this goal has declined during the past decade [947678]. The fraction of patients reaching glycemic goals may differ from country to country depending on various factors, such as the availability of healthcare, antidiabetic medication, healthcare expenditure and patient education. Nevertheless, studies, such as the UK Prospective Diabetes Study (UKPDS) [956152] and A Diabetes Outcome Progression Trial (ADOPT) [956151], have demonstrated that glycemic control deteriorates in type 2 diabetes over time with constant drug treatment as a result of progression of the disease caused by increasing β-cell dysfunction. Classical insulin secretagogues (sulfonylureas and glinides) exclusively stimulate insulin secretion, with the risk of hypoglycemia and weight gain. Metformin and glitazones act on insulin resistance by increasing the body's sensitivity to insulin, and α-glucosidase inhibitors delay the breakdown of complex carbohydrates. Exogenous insulin replaces the endogenous secretory insulin deficit, although it potentially causes weight gain and hypoglycemia. The progressive loss of islet function observed in type 2 diabetes is not ameliorated by any of the current therapeutic options [756003], [931358]. The incretin hormones glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) stimulate insulin secretion after a meal. These peptides are responsible for orally administered glucose evoking a greater insulin response than an intravenously administered glucose infusion calculated to lead to identical serum glucose excursions. This phenomenon is termed the 'incretin effect' [760667] and accounts for approximately 70% of the postprandial insulin secretion in healthy individuals. This effect is reduced or absent in patients with type 2 diabetes [931364]. The therapeutic potential of GLP-1 as a pharmacological tool for treating type 2 diabetes was discovered in the 1990s. In contrast to other insulinotropic agents, such as the sulfonylureas, the insulinotropic effect of GLP-1 depends on the actual glucose concentration only under hyperglycemic conditions, providing the possibility of glucose normalization without the risk of hypoglycemia. In patients with type 2 diabetes, exogenous GLP-1 stimulates insulin secretion and normalizes both fasting and postprandial blood glucose, and further restores the defective first phase of insulin secretion in type 2 diabetes [760659]. In addition to the glucose-lowering effect resulting from increased insulin secretion, GLP-1 has additional 'non-insulinotropic' physiological actions that may be advantageous in type 2 diabetes therapy: GLP-1 suppresses glucagon secretion from the α-cells and slows gastric emptying. Additionally, GLP-1 acts as a mediator of satiety in the hypothalamus, where it also functions as a neurotransmitter [931358]. In patients with type 2 diabetes, exogenous GLP-1 infusions cause weight loss [580792]. Furthermore, GLP-1 stimulates β-cell formation from precursor cells and also inhibits their apoptosis, leading to an increase in β-cell mass and an improvement in β-cell function [931369]. As a result of the action of dipeptidyl peptidase IV (DPP-IV), however, the biological half-life of exogenous GLP-1 is 1 to 2 min, therefore treatment with native GLP-1 is not feasible. In order to utilize the effects of GLP-1, long-acting GLP-1 analogs or 'incretin mimetics' have been developed as injectable therapies (eg, exenatide and liraglutide [Novo Nordisk A/S]). An alternative approach to utilizing GLP-1 action is the inhibition of the degrading enzyme DPP-IV by orally active DPP-IV inhibitors [760659]. DPP-IV is a ubiquitous enzyme that can be detected in the endothelium of different organs, and which demonstrates measurable circulating enzymatic activity in plasma. In addition to GLP-1 and GIP, peptides such as pituitary adenylate cyclase-activating polypeptide and gastrinreleasing peptide are substrates of DPP-IV; however, the affinity of DPP-IV is higher for GLP-1 than for these other peptides, including GIP [931370]. DPP-IV is also expressed on the cell membrane of activated T-cells as CD26, although the enzymatic properties of the CD26 molecule do not appear to be important; influence of DPP-IV inhibitors on immunological CD26-mediated functions is therefore not expected. In clinical trials with DPP-IV inhibitors, no serious side effects or adverse events relating to immunological regulatory mechanisms or malignant transformation have been observed [760659]. An increase in levels of uncleaved, biologically active GLP-1 caused by DPP-IV inhibitors offers an alternative therapeutic option in type 2 diabetes. Additionally, and in contrast to incretin mimetics, DPP-IV inhibitors are orally active [760659]. DPP-IV is a member of a large enzyme family of endopeptidases; therefore, DPP-IV inhibitors need to have high selectivity to inhibit DPP-IV exclusively and not other DPPs. The DPP-IV inhibitors sitagliptin [891499] and vildagliptin [931378] are two compounds of this class that have been approved for use in various countries. Sitagliptin has been approved for almost 2 years, and has proved to be efficacious and safe in clinical trials [891499] and also in everyday use outside of clinical trials [947681]. For sitagliptin and vildagliptin, fixed-dose combinations with metformin are available to reduce the number of tablets administered to patients prescribed this combination of antihyperglycemic therapy. Further DPP-IV inhibitors are currently in development, including saxagliptin (Bristol-Myers Squibb Co/AstraZeneca plc/ Otsuka Pharmaceutical Co Ltd) [927366], alogliptin (Takeda Pharmaceutical Co Ltd) [872709], linagliptin (Boehringer Ingelheim Corp) [873599], [881116], PF (Pfizer Inc) [950369], and dutogliptin tartrate (Phenomix Corp) [920208]. Saxagliptin is a novel DPP-IV inhibitor for potentially oncedaily oral dosing in the treatment of type 2 diabetes,

3 908 IDrugs 2008 Vol 11 No 12 and was undergoing phase III clinical trials in Canada [819085] and phase I clinical trials in Japan [921510] at the time of publication. An NDA was submitted to the FDA in June 2008 and simultaneously, an MAA was submitted to the EMEA [927366]. These submissions were based on clinical data from an extensive clinical trial program either in formerly drug-naive patients with type 2 diabetes as a monotherapy or in patients who received saxagliptin as an add-on medication to an existing established oral antidiabetic treatment regime, such as metformin. The entire phase III clinical trial program was designed to assess the efficacy and safety of saxagliptin in > 4000 patients, with 75% of the trial population receiving saxagliptin. In dose-finding and safety studies, some patients received doses up to 80-fold higher than the therapeutic clinical dose [927366]. Synthesis and SAR Previous studies investigated the SARs of various DPP-IV inhibitors with β-quaternary amino-acid-linked l-cis-4,5-methanoprolinenitrile and led to promising candidate compounds with a vinyl substitution at the β-position of α-cycloalkyl-substituted glycines. These compounds had a longer duration of action than previous 4,5-methanoprolinenitrile analogs in ex vivo models measuring DPP-IV inhibition. Further development of these compounds by forming oxygenated metabolites did not lead to a loss of potency, and duration of action was increased [554377], [676852]. Further exploration of compounds with an adamantyl group provided a compound with good potency, but poor bioavailability and some cytochrome P450 (CYP)3A4 inhibition. Hydroxylating the adamantyl group at the 1,1-bridgehead position produced saxagliptin, which demonstrated high in vitro and in vivo potency, good oral bioavailability (F = 75%), good duration of action (t 1/2 = 2.1 h) and no CYP3A4 inhibition [676852]. Saxagliptin can be prepared using a seven-step synthesis via the key intermediate (S)-N-tert-butoxycarbonyl [Boc]-2-(3'-hydroxyadamantyl)glycine. The synthesis begins with 1-adamantyl zinc bromide, which is coupled with ethyl oxalyl chloride to provide the corresponding α-keto ester. The α-keto ester is then hydroxylated to the hydroxyadamantyl keto ester, followed by hydrolysis to provide the keto acid. This keto acid is then subjected to reductive amination and Boc-protected to give the (S)-N-Boc-2-(3'-hydroxyadamantyl)glycine intermediate. This key glycine intermediate is coupled with l-cis-4,5- methanoprolinamide, and the amide group of the resulting compound is converted to the nitrile. This nitrile-containing compound is then deprotected to provide saxagliptin [903379]. An alternative synthesis via the same key intermediate has also been reported, which begins with 1-adamantane methanol and requires 10 steps to attain the key glycine intermediate [903379]. A third reported synthesis begins with the formation of the l-cis- 4,5-methanoprolinamide in six steps starting with l-pyroglutamic acid, which is then coupled to the Bocprotected glycine intermediate and converted to saxagliptin as described previously [949452]. It is proposed that saxagliptin interacts with DPP-IV initially by forming an encounter complex, which is followed by the formation of a covalent intermediate and then the final inhibitory complex. The formation of the covalent complex is dependent upon a pk-related ionization of an enzyme residue and is reversible, with a dissociation constant (k off ) of (5.5 ± 0.4) 10-5 s -1, thus yielding an equilibrium constant K i * (as k off /k on ) for the formation of the covalent intermediate of 0.35 nm. This value is similar to the value obtained from steadystate inhibition studies (0.6 nm). The adamantyl ring is suggested to occupy the S2 site of the enzyme, forming an interaction with Ser 630 [676851]. Saxagliptin interacts with DPP-IV via histidine-assisted covalent bond formation between the hydroxyl oxygen of the amino acid Ser 630 in the active center of DPP-IV and the inhibitor nitrile carbon group of saxagliptin [903377]. Preclinical development In vitro, saxagliptin was 400- and 75-fold more potent against DPP-IV than DPP-8 or DPP-9, respectively. Saxagliptin also demonstrated potency that was more than 4000-fold greater for DPP-IV when tested against a number of other proteases. Saxagliptin provided a dissociation constant for inhibitor binding (K i ) of 1.3 ± 0.3 nm for inhibiting DPP-IV, making it 10- and 14- fold more potent than vildagliptin (13 ± 3 nm) and sitagliptin (18 ± 2 nm), respectively [931232]. Saxagliptin demonstrated an IC 50 value for DPP-IV inhibition of 30 nm, and ED 50 values of 0.5 and 6 h were attained with saxagliptin at 0.1 and 0.5 µmol/kg, respectively, indicating good activity over time (no further information was provided). No inhibition of T-cell activity was detected and a significant rise of endogenous GLP-1 was observed after oral glucose challenge in healthy rats with saxagliptin (3 µmol/kg), compared with placebo [554377], [556348]. In a study of in vivo DPP-IV inhibitory activity, healthy Sprague-Dawley rats were orally administered saxagliptin (4 mmol/kg). After both 30 min and 4 h, the ex vivo DPP-IV plasma inhibition was 87%. The K i value was 0.6 ± 0.06 nm, and no significant inhibition of DPP-2 was observed. ED 50 values at 0.5, 2, 4 and 6 h postadministration were 0.12 ± 0.04, 0.2 ± 0.07, 0.3 ± 0.10 and 0.5 ± 0.15 µmol/kg, respectively. Zucker fa/fa rats (an obesityinduced insulin resistance model) were administered saxagliptin (0.3 to 3 µmol/kg po). Saxagliptin improved glucose clearance by 28 to 61% relative to controls at 2 h after glucose challenge. Saxagliptin (1, 3 or 10 µmol/kg po) was also effective at raising insulin levels and increasing glucose clearance in ob/ob mice (a model of obesity and type 2 diabetes) [676852]. Toxicity No toxicity data were available at the time of publication.

4 Saxagliptin Gallwitz 909 Metabolism and pharmacokinetics Saxagliptin demonstrated a dissociation half-life of 50 min at 37 C; such slow dissociation was not observed with DPP-8 or DPP-9 [931232]. Pharmacokinetic and pharmacodynamic characteristics of saxagliptin were investigated in healthy volunteers (n = 50; 40, 100, 150, 200, 300 and 400 mg/day po) and in patients with type 2 diabetes (n = 40; 2.5, 5, 15, 30 and 50 mg/day po) in a 2-week clinical trial. The pharmacokinetic profiles were the same in the healthy volunteers and patients with type 2 diabetes [808237]. To examine the effects of age and gender on the pharmacokinetics of saxagliptin, an open-label, parallel group clinical trial of healthy volunteers (n = 56) was conducted. Volunteers were assigned to four different demographic groups: young males or females (aged 18 to 40 years) and elderly males or females (older than 65 years). The volunteers received a single dose of saxagliptin (10 mg po) and pharmacokinetic analysis was performed. The C max and AUC values were 1.2- and 1.6-fold higher, respectively, for saxagliptin in the elderly groups than in the younger groups. This was likely the result of a lower volume of distribution and lower metabolic clearance rates through the kidneys in the older groups. Approximately 50% of the difference in the pharmacokinetic parameters between the young and the elderly groups was related to age-associated loss of renal function. A gender specific difference in the pharmacokinetic data was not observed, although female participants had an approximately 25% higher exposure to the active metabolite. Between the age groups, a < 2-fold difference in the pharmacokinetic parameters of the active metabolite of saxagliptin was observed. This finding led to the conclusion that a saxagliptin dose adjustment was not necessary on the basis of age or gender [931233]. A further study was conducted to establish the effect on pharmacokinetic parameters of a single dose of saxagliptin (10 mg po) in patients (n = 18) with different degrees of hepatic impairment compared with those of healthy volunteers (n = 18). AUC values for saxagliptin were higher in healthy volunteers than for patients with hepatic impairment, and AUC values for the CYP3A-generated metabolite (BMS ) of saxagliptin were lower in healthy volunteers than patients. These results indicated a reduced capacity to metabolize the drug with increasing hepatic dysfunction [915053]. Clinical trials were also conducted in healthy volunteers to assess the effects of pioglitazone, glyburide and metformin on the pharmacokinetics of saxagliptin. Coadministration of saxagliptin and pioglitazone increased the C max of pioglitazone by 14%, although this was not considered to be clinically relevant. The AUC of pioglitazone was not affected. Pioglitazone did not affect the pharmacokinetics of saxagliptin [957594]. For combination treatment with glyburide, the C max and AUC values of glyburide increased by 16 and 6%, respectively. For saxagliptin, C max increased by 8% and AUC decreased by 2%, although these changes were also not expected to have a significant clinical effect [957596]. In the clinical trial combining saxagliptin with metformin, the C max and AUC values of saxagliptin were decreased by 21 and 2%, respectively, while the C max and AUC values of metformin were increased by 9 and 20%, respectively. These changes were not considered to be clinically meaningful [957597]. Clinical development Phase I In a phase I clinical trial, saxagliptin inhibited DPP-IV over a range of doses in healthy volunteers (n = 50; 40, 100, 150, 200, 300 and 400 mg/day po) and patients with type 2 diabetes (n = 40; 2.5, 5, 15, 30 and 50 mg/day po). A dose-dependent inhibition of DPP-IV was observed at all saxagliptin doses, and a maximally inhibiting effect was observed at saxagliptin doses of 150 mg/day. DPP-IV inhibition at 24 h after the first dose for the 2.5- and 400-mg doses of saxagliptin was 50 and 79%, respectively, compared with baseline. On day 13 for the patients with type 2 diabetes and day 14 for the healthy volunteers, endogenous postprandial GLP-1 concentrations were increased by 1.5- to 3.0-fold across all doses of saxagliptin [808237]. Saxagliptin has also been evaluated in phase I clinical trials in Japan, although no detailed data were available at the time of publication [921510]. A third phase I clinical trial (NCT ) is planned in healthy volunteers (n = 16) in China, in which patients are to receive single or multiple doses of saxagliptin (5 mg po) over 1 or 5 days. The primary endpoint of this trial is the measurement of the pharmacokinetic profile of saxagliptin, with secondary endpoints being measurement of the pharmacokinetic profile of the major metabolite of saxagliptin and safety parameters [950382]. Phase II In a phase II, multicenter, randomized, parallel-group, double-blind, placebo-controlled clinical trial, drug-naive patients (n = 350) with inadequately controlled type 2 diabetes (HbA1c = 6.8 to 9.7%) were administered saxagliptin (2.5, 5, 10, 20 or 40 mg/day po for 12 weeks or 100 mg/day po for 6 weeks) or placebo [903376], [903381]. For patients in all of the saxagliptin-treatment groups, HbA1c was reduced at the end of the treatment period and β-cell function was increased. In the placebo group, 20% of patients achieved HbA1c levels of < 7%, compared with 50, 47, 41, 50 and 53% of patients in the five lowerdose saxagliptin groups, respectively. A reduction of 24, 35, 41, 28 and 34 mg/dl was observed in glucose levels 1 h after a liquid meal in the five lower-dose saxagliptin groups, respectively, compared with a reduction of 1 mg/dl for placebo. Levels of fasting glucose were decreased by 11, 22, 16, 14 and 16 mg/dl in these

5 910 IDrugs 2008 Vol 11 No 12 treatment groups, respectively, while levels increased by 3 mg/dl in the placebo group. Patients in the 100-mg dose group presented with similar results, with 66% of patients achieving an HbA1c level of < 7%, a reduction in fasting glucose level of 26 mg/dl, and a glucose level 1 h after a liquid meal of 45 mg/dl [903376], [903381]. Phase III In a phase III, multicenter, randomized, doubleblind, placebo-controlled clinical trial (NCT ), patients with type 2 diabetes (n = 743) not optimally controlled with a stable metformin monotherapy (1500 to 2550 mg/day; HbA1c = 7 to 10%) were administered saxagliptin (2.5, 5 or 10 mg/day po) or placebo in addition to their existing metformin therapy for 24 weeks. Saxagliptin treatment led to decreased adjusted-mean, placebo-subtracted HbA1c levels of 0.73, 0.83 and 0.71% from baseline (p < ) at the three saxagliptin doses, respectively. Similarly, fasting plasma glucose was reduced by 16, 24 and 21 mg/dl from baseline (p < ). In oral glucose tolerance tests, saxagliptin significantly reduced the AUC values of glucose and glucagons, while increasing the AUC values for insulin and C-peptide [810540], [951554]. A phase III, multicenter, randomized, double-blind, placebo-controlled clinical trial (NCT ) has also been completed in patients with type 2 diabetes (n = 460) who had not received previous treatment, but whose diabetes was inadequately controlled by diet and exercise (HbA1c = 7 to 10%). Patients received saxagliptin (2.5, 5 or 10 mg/day po) or placebo for 24 weeks. The reduction in HbA1c under saxagliptin therapy was the primary endpoint, with the secondary endpoints being specific laboratory measures [819085]. Saxagliptin reduced the HbA1c levels by 0.62, 0.64 and 0.73% in the 2.5-, 5- and 10-mg groups, respectively (p < ), with reductions observed from week 4 of treatment. The proportion of patients attaining the goal of an HbA1c of < 7% at week 24 was 35, 38 and 41% for 2.5-, 5- and 10-mg doses of saxagliptin, respectively, compared with 24% for placebo. In line with these findings, from the second week of treatment, fasting plasma glucose was also reduced by 21, 15 and 23 mg/dl, respectively (p < ). The postprandial glucose AUC was also improved by saxagliptin treatment, as demonstrated by an increase in the postprandial insulin and C-peptide AUC values. In an open-label extension arm of this trial, patients with HbA1c between 10 and 12% also received saxagliptin (10 mg/day po). Patients in this extension arm achieved similar results in terms of reductions from baseline in HbA1c, fasting glucose and postprandial AUC [931238]. In a phase III, multicenter, randomized, double-blind, placebo-controlled clinical trial (NCT ), the efficacy and safety of a combination therapy of saxagliptin with thiazolidinediones was investigated in patients with type 2 diabetes (n = 555) not optimally controlled with a stable dose of either pioglitazone or rosiglitazone (HbA1c = 7.0 to 10.5% at baseline). Patients were administered saxagliptin (2.5 or 5 mg/day po) or placebo for 24 weeks concomitantly with their existing thiazolidinedione therapy (pioglitazone 30 or 45 mg, or rosiglitazone 4 or 8 mg). The primary endpoint was the reduction in HbA1c under additional saxagliptin therapy over the course of the trial, with secondary endpoints being change in glucose levels from 0 to 180 min following a meal, change in fasting glucose levels and the proportion of patients achieving a therapeutic glycemic response (ie, HbA1c < 7.0%) [819099]. Treatment with 2.5 or 5 mg of saxagliptin resulted in reductions in HbA1c levels relative to baseline of 0.66 and 0.94%, respectively, compared with a reduction of 0.33% for placebo. Fasting glucose levels were also significantly reduced relative to baseline, with the two saxagliptin doses reducing fasting glucose levels by 14.3 and 17.3 mg/dl, respectively, compared with a reduction of 2.8 mg/dl for placebo. At the end of the trial period, 42.2 and 41.8% of patients in the two saxagliptin dose groups, respectively, achieved an HbA1c level of < 7.0%, compared with 25.6% in the placebo group. The higher saxagliptin dose group also demonstrated an improvement in β-cell function compared with placebo [956471]. In a phase III, multicenter, randomized, double-blind, placebo-controlled clinical trial (NCT ), the effect of saxagliptin monotherapy was compared with metformin monotherapy and saxagliptin/metformin combination therapy. Patients (n = 1396) with inadequately controlled type 2 diabetes (Hb1Ac = 8.0 to 12.0%) received metformin alone (500 mg/day po), saxagliptin alone (10 mg/day po), a combination of saxagliptin (5 or 10 mg/day po) plus metformin (500 mg/day po) or placebo for 24 weeks. The primary endpoint of the trial was reduction in HbA1c values at the end of the trial period, and secondary endpoints were patients attaining the goal of HbA1c levels of less than 7%, changes in fasting glucose levels, changes in postprandial glucose levels and patients requiringadditional treatment after failing to achieve targets [951635]. The greatest reductions in Hb1Ac level from baseline were in the combination treatment groups, with both groups achieving a reduction of 2.5%, compared with 1.7% for saxagliptin alone and 2.0% for metformin alone. In the 5- and 10-mg saxagliptin and metformin combination groups, 60.3 and 59.7% of patients, respectively, achieved Hb1Ac levels of < 7.0% at the end of the study period, compared with 32.2 and 41.1% of patients in the saxagliptin- and metformin-only groups, respectively. Fasting plasma glucose levels were also reduced in all groups, with the greatest reduction occurring in the 5- and 10-mg saxagliptin combination therapy groups (60 and 62 mg/dl, respectively), compared with saxagliptin or metformin alone (31 and 47 mg/dl, respectively) [956683]. In a similar phase III multicenter, randomized, doubleblind, placebo-controlled clinical trial (NCT ), the effects of saxagliptin in combination with glyburide were compared with glyburide alone in patients with

6 Saxagliptin Gallwitz 911 type 2 diabetes (n = 768) not optimally controlled with glyburide. Patients were administered saxagliptin (2.5 or 5 mg/day po) plus glyburide (7.5 mg/day po) or glyburide (2.5 mg titrated to 7.5 mg po) plus glyburide (7.5 mg/day po) for 24 weeks. Primary and secondary endpoints were as described for the metformin combination trial [951660]. Patients receiving glyburide only were optionally up-titrated during the study period to receive a maximum dose of 15 mg/day; this option was applied to 92% of the glyburide-only patients by the end of the study period. Treatment with saxagliptin at a dose of 2.5 or 5 mg reduced HbA1c levels by 0.54 and 0.64%, respectively, relative to baseline, compared with a 0.08% reduction for the up-titrated glyburide group. Fasting plasma glucose levels were also significantly reduced, by 7.1 and 9.7 mg/dl in the two saxagliptin groups, respectively, compared with 0.7 mg/dl for the up-titrated glyburide group [956654]. Two phase III multicenter, randomized, double-blind, placebo-controlled clinical trials of saxagliptin in drug-naive patients with type 2 diabetes inadequately controlled with diet or exercise had been completed by the time of publication. In the first of these trials (NCT ), patients (n = 37) received saxagliptin (5 mg/day po) or placebo for 12 weeks, and the primary and secondary endpoints were measures of insulin secretion [888877]. In the second of these trials (NCT ), patients (n = 365) received oral saxagliptin (2.5 mg/day in the morning, 2.5 mg/day titrated to 5 mg/day in the morning, 5 mg/day in the morning or 5 mg/day in the evening) for 24 weeks. The primary endpoint of the trial was reduction in HbA1C values at the end of the trial period, and secondary endpoints were patients attaining HbA1c levels of < 7%, changes in fasting glucose levels and changes in postprandial glucose levels [951667]. Data from these trials were not available at the time of publication. A further seven phase III clinical trials are planned, active or in recruitment. These trials include comparison trials with sitagliptin (NCT ) [951681] and sulfonylureas (NCT ) [951677] as add-ons to metformin therapy, a comparison trial of saxagliptin plus metformin compared with metformin alone (NCT ) [951683], efficacy and safety trials of saxagliptin as a monotherapy (NCT ) [951688] and also in conjunction with metformin (NCT ) [951691], trials in patients with type 2 diabetes and renal impairment (NCT ) [883473], and a trial of saxagliptin in conjunction with insulin therapy with or without metformin (NCT ) [951696]. Side effects and contraindications In the phase I clinical trial, saxagliptin was tested in doses up to 100 mg once daily without any adverse reactions in type 2 diabetic patients [572056]. In healthy volunteers, doses up to 400 mg were well tolerated [808237]. In the 12-week phase II clinical trial, a small cohort of patients with type 2 diabetes received doses of up to 40 mg/day of saxagliptin. Adverse events were similar across all groups, including placebo, without a significant increase in specific adverse reactions in any treatment group. There were two confirmed cases of hypoglycemia in the 100-mg saxagliptin group, although symptoms were mild and did not require treatment. Saxagliptin treatment in this trial was well tolerated and weight neutral [903376], [903381]. In the phase III clinical trials, saxagliptin was well tolerated without increases in specific adverse reactions compared with placebo. The incidence of hypoglycemia was not increased compared with placebo [808165], [808237], [810540], [931238], [956471], [956654], [956683] and treatment was generally weight neutral [808165], [808237] [810540], [931238], [956683]. In the comparison trial with glyburide, 29.6% of patients in the up-titrated glyburide group dropped out of the trial because of poor glycemic control, compared with 18.1 and 16.6% of patients receiving 2.5 and 5 mg of saxagliptin, respectively [956654]. In patients with renal or hepatic organ dysfunction, more data need to be generated to provide a conclusion of the effect of saxagliptin. In hepatic impairment, dose adjustments to reduce doses appeared to be feasible as a result of higher saxagliptin AUC values. Saxagliptin, however, was well tolerated in this small study of volunteers with mild, moderate or severe hepatic impairment receiving a single dose of saxagliptin [915053]. A clinical trial in patients with renal impairment is ongoing [883473]. No specific drug-drug interactions were observed when saxagliptin was combined with other common medications, such as diltiazem, ketoconazole, simvastatin, digoxin, and magnesium and aluminum hydroxides in conjunction with simethicone, famotidine or omeprazole [888918], [888943], [903382], [903383], [903385]. Patent summary Saxagliptin is claimed as new in WO (claim 8, page 130), assigned to Bristol-Myers Squibb Co (BMS). Granted equivalents EP and US have expiry dates in March and February 2021, respectively, based on priority. Divisional EP was awaiting examination at the time of publication. The synthesis of an intermediate for cyclopropyl-fused pyrrolidine-based DPP-IV inhibitors, which was later used for the synthesis of saxagliptin, was claimed in WO by BMS. Enzymatic ammonolysis of this intermediate, leading to the synthesis of saxagliptin, was claimed in WO (granted as US , with an expiry date in August 2024), which was also filed by BMS. The company has several other filings describing processes for the preparation of saxagliptin, including WO , WO , WO and WO Processes for the preparation of

7 912 IDrugs 2008 Vol 11 No 12 the saxagliptin precursor hydroxyadamantyl-2-oxoacetic acid have been claimed by KemFine Oy and Albemarle Corp in WO and WO , respectively. The coated tablet formulation of saxagliptin is claimed by BMS in WO Saxagliptin is contained in the second coating layer of the tablet, over an inner seal coating layer. This provides a stable formulation of saxagliptin that is labile and prone to intramolecular cyclization to an inactive cyclic amidine. Saxagliptin is named in several patent applications from companies other than BMS relating to combination therapies, typically for diabetes treatment, where it is included in lists of possible DPP-IV inhibitors. WO from F Hoffmann-La Roche Ltd describes an oral tablet or capsule formulation for the release of DPP-IV inhibitors in the lower gastrointestinal tract, in which saxagliptin is one of seven specifically claimed DPP-IV inhibitors for use in the formulation. WO , assigned to Merck & Co Inc, describes a fixed-dose, immediate-release tablet comprising a DPP-IV inhibitor and metformin hydrochloride. Sitagliptin is the preferred DPP-IV inhibitor in the tablet, but saxagliptin is one of two claimed alternatives. Filings for combination therapies in which saxagliptin is mentioned as a possible component include WO from Novartis AG and WO from Waratah Pharmaceuticals Inc. Current opinion DPP-IV inhibitors represent a highly promising, novel class of oral agents for the treatment of type 2 diabetes. Their novelty lies in their dual action on α- and β-cell function, leading to an improved profile of glucagon and insulin secretion patterns after a meal. Insulin and glucagon secretion are regulated in a glucose-dependent manner by DPP-IV inhibitors, such that the risk of hypoglycemia is low and hormonal counter-regulation at low glucose concentrations is not affected. In addition to demonstrating no intrinsic risk for causing hypoglycemia, DPP-IV inhibitors are weight neutral, which represents an advantage over established treatment options: sulfonylureas, glinides and insulin cause weight gain and hypoglycemia, and glitazones also lead to an increase in body weight. Animal studies and in vitro data from isolated human islets suggest the potential of DPP-IV inhibitors to increase β-cell function and mass. These findings indicate a potential role for DPP-IV inhibitors to positively influence the disease progression characterized by increasing β-cell dysfunction and loss of β-cell mass in type 2 diabetes [760659]. Because of these favorable properties, numerous DPP-IV inhibitors are currently being developed by major pharmaceutical companies. Other non-dpp-iv inhibitor agents that act by incretin action are the GLP-1 receptor agonists, such as exenatide [606500]. These compounds are peptides for injectable therapy and lead to a constant pharmacological elevation of GLP-1 receptor agonist molecules at 5- to 10-fold the physiological concentrations. Because of the high GLP-1 agonist concentrations, these agents also promote weight loss. The most common adverse event caused by these agents is nausea at the beginning of therapy, which is unrelated to weight loss. Antibody formation without loss of clinical efficacy has been observed with molecules that have lower amino-acid sequence similarity compared with native human GLP-1 [760659]. Sitagliptin and vildagliptin have been launched as the first two agents in the DPP-IV inhibitor class [931378], [947681]. In addition to these two established DPP-IV inhibitors, further compounds are in clinical development, such as alogliptin and linagliptin. Clinical trials of saxagliptin have produced highly satisfactory data in terms of improving glycemic parameters, together with a good safety profile and good tolerability over a period of up to 24 weeks. As with other DPP-IV inhibitors, saxagliptin is efficacious and safe as a monotherapy and in combination with metformin or a thiazolidienedione. Data from longer term clinical trials with greater numbers of patients are needed to ultimately determine the efficacy and safety of saxagliptin and to characterize the patient cohorts that would profit most from treatment with this compound. Important small clinical trials have demonstrated that there are no adverse drug-drug interactions with certain anticoagulants, antacids, digitoxin and other agents that are often used by patients with type 2 diabetes. A small pilot clinical trial investigating the pharmacokinetics of saxagliptin in volunteers with hepatic dysfunction demonstrated a slower metabolization of saxagliptin, but without severe side effects [915053]. A clinical trial in patients with type 2 diabetes with renal impairment is also underway [883473]. If the ongoing clinical trials lead to positive results, saxagliptin will likely find its way into the treatment algorithm of type 2 diabetes. Because head to head comparisons with other DPP-IV inhibitors are lacking, the relative advantages of each substance can only be deduced from their pharmacological profile and from existing trial data. Saxagliptin has some structural similarity with vildagliptin (also an adamantyl 2-cyanopyrrolidine-based DPP-IV inhibitor), but not with sitagliptin, alogliptin or linagliptin, and may therefore have more biological and pharmacological characteristics in common with vildagliptin than with these other DPP-IV inhibitors [482284], [952254], [952259]. Vildagliptin has been approved by the EMEA as an oral treatment option (50 mg bid) for patients whose glucose levels are not optimally controlled with metformin monotherapy, and has successfully entered the market in many countries. In clinical trials using vildagliptin in a once-daily, 100-mg therapeutic regime, elevated liver enzymes were reported in a small number of patients [848551]. This effect was not associated with hepatitis or hepatic failure and was completely reversible after cessation of treatment. When administered in once- or twice-daily doses of 50 mg,

8 Saxagliptin Gallwitz 913 vildagliptin is efficacious and safe, with no significant elevation in liver enzymes [861815]. In clinical trials with saxagliptin, elevated liver enzymes have not been observed, even at doses up to 400 mg/day, which exceeds the doses currently being evaluated in clinical trials. Furthermore, in a safety trial in type 2 diabetes patients with impaired hepatic function, doses of 10 mg of saxagliptin did not result in any deterioration in liver function and the agent was well tolerated. The specific advantages of saxagliptin over other DPP-IV inhibitors may lie in its long-lasting, effective and highly specific inhibition of DPP-IV, making once-daily treatment feasible, effective and safe. The slow dissociation of saxagliptin from DPP-IV is responsible for most of these properties. Furthermore, the properties of renal, as well as hepatic, excretion are advantageous. As data from clinical trials in drug-naive patients have demonstrated good efficacy and safety profiles for saxagliptin in patients with type 2 diabetes, saxagliptin may prove useful in early stages of type 2 diabetes as a monotherapy. Some regulatory agencies, such as the EMEA, have been restrictive, however, in approving novel drugs for type 2 diabetes for monotherapy; metformin is a well-established therapy with long-standing experience and low costs, making it preferable as a first-line treatment. For this reason, DPP-IV inhibitors have thus far been approved by the EMEA as second-line treatments only. At this stage of development of saxagliptin, clinical data have mostly only been published in abstract form, but, in parallel with past developments, it can be expected that these data will be published as complete reports in diabetes journals and journals covering related subjects within a short timeframe. The development of saxagliptin, as well as the other DPP-IV inhibitors, emphasizes the advantages of DPP-IV inhibitors over classical insulin secretagogues (sulfonylureas and metiglinides) in terms of their glucose-dependent action without intrinsic hypoglycemia risk and with weight neutrality. Deals Otsuka Pharmaceutical Co Ltd In December 2006, BMS granted Otsuka Pharmaceutical exclusive rights in Japan to develop and commercialize saxagliptin for type 2 diabetes. Otsuka would be responsible for all development costs in Japan, and would make upfront, milestone and sales-based payment to BMS. BMS also retained rights to co-promote saxagliptin with Otsuka in Japan [753448]. AstraZeneca plc In January 2007, AstraZeneca acquired worldwide rights, excluding Japan, to codevelop saxagliptin (and dapagliflozin). BMS would receive US $100 million upfront, up to US $650 million in milestone payments plus royalties and up to US $300 million per product in sales milestones. BMS would manufacture the product and AstraZeneca would provide development funding for 2 years. Both companies would share additional development and commercialization costs equally, and would have the option to develop additional compounds. Sales milestones of US $300 million per product could be achieved [757301], [756936]. Development status Developer Country Status Indication Date Reference AstraZeneca plc EU Pre-registration Diabetes mellitus type 2 23-JUL AstraZeneca plc US Pre-registration Diabetes mellitus type 2 30-JUN Bristol-Myers Squibb Co EU Pre-registration Diabetes mellitus type 2 23-JUL Bristol-Myers Squibb Co US Pre-registration Diabetes mellitus type 2 30-JUN Bristol-Myers Squibb Co Canada Phase III Diabetes mellitus type 2 31-JUL Otsuka Pharmaceutical Co Ltd Japan Phase I Diabetes mellitus type 2 09-JUN Literature classifications Chemistry Study type Result Reference Synthesis 1-Adamantyl zinc bromide is coupled with ethyl oxalyl chloride to provide the corresponding α-keto ester, which is hydroxylated to the hydroxyadamantyl keto ester, and then hydrolyzed to provide the keto acid. This keto acid is then subjected to reductive amination and Boc-protected to give (S)-N-Boc-2-(3'-hydroxyadamantyl)glycine, a key intermediate. The glycine intermediate is coupled with l-cis-4,5-methanoprolinamide, and the amide group of the resulting compound is converted to the nitrile. This nitrile-containing compound is then deprotected to produce saxagliptin

9 914 IDrugs 2008 Vol 11 No 12 Chemistry (continued) Study type Result Reference SAR Biology The SARs of various DPP-IV inhibitors with β-quaternary amino-acid-linked l-cis-4,5-methanoprolinenitrile were investigated, leading to promising candidate compounds with a vinyl substitution at the β-position of α-cycloalkylsubstituted glycines. These compounds had a longer duration of action than prior 4,5-methanoprolinenitrile analogs in ex vivo models measuring DPP-IV inhibition. The formation oxygenated metabolites of these compounds did not affect potency, and duration of action was increased. Inclusion of an adamantyl group provided a compound with good potency, but poor bioavailability and some CYP3A4 inhibition. Hydroxylating the adamantyl group at the 1,1-bridgehead position produced saxagliptin, which demonstrated high in vitro and in vivo potency, good oral bioavailability (F = 75%), good duration of action (t 1/2 = 2.1 h) and no CYP3A4 inhibition Study type Effect studied Model used Result Reference In vitro Potency Ex vivo inhibition of plasma enzymatic activity. In vivo Activity Sprague-Dawley rats administered saxagliptin (4 mmol/kg po). In vivo Activity Zucker fa/fa rats administered saxagliptin (0.3 to 3 µmol/kg po). In vivo Activity Ob/ob mice administered saxagliptin (1, 3 or 10 µmol/kg po). Metabolism Saxagliptin was 400- and 75-fold more potent against DPP-IV than DPP-8 or DPP-9, respectively. The potency of saxagliptin was also more than 4000-fold greater for DPP-IV when tested against a number of other proteases. Saxagliptin had a K i value of 1.3 ± 0.3 nm. After both 30 min and 4 h, the DPP-IV plasma inhibition was 87% compared with controls. The K i value was 0.6 nm, with no significant inhibition of DPP-2. ED 50 values at 0.5, 2, 4 and 6 h were 0.12, 0.2, 0.3 and 0.5 µmol/kg, respectively. Saxagliptin improved glucose clearance by 28 to 61% relative to controls at 2 h after glucose challenge. Saxagliptin was effective at raising insulin levels and increasing glucose clearance Study type Effect studied Model used Result Reference In vivo Pharmacokinetics Saxagliptin administered to healthy volunteers (n = 50; 40, 100, 150, 200, 300 and 400 mg/day po) and patients with type 2 diabetes (n = 40; 2.5, 5, 15, 30 and 50 mg/day po) over a 2-week period. In vivo Pharmacokinetics An open-label, parallel group clinical trial of healthy volunteers (n = 56): young males and females (aged 18 to 40 years) and elderly males or females (older than 65 years) administered a single dose of saxagliptin (10 mg po). The pharmacokinetic parameters were the same in both healthy volunteers and patients with type 2 diabetes. In the elderly male and female groups, the C max and AUC values were 1.2- and 1.6-fold higher, respectively, compared with C max and AUC values for the two younger groups. Age-associated loss of renal function was responsible for ~ 50% of the difference in the pharmacokinetic parameters between the young and elderly groups. No genderspecific difference in the pharmacokinetics was observed, although female participants had an ~ 25% higher exposure for the active metabolite In vivo Pharmacokinetics Patients with hepatic impairment (n = 18) and healthy volunteers (n = 18) administered a single dose of saxagliptin (10 mg po). AUC values were higher in healthy volunteers than for patients with hepatic impairment, and AUC values for the CYP3A-generated metabolite of saxagliptin were lower in healthy volunteers than in patients Clinical Effect studied Study type Result Reference Efficacy and safety A phase I clinical trial of saxagliptin in healthy volunteers (n = 50; 40, 100, 150, 200, 300 and 400 mg/day po) and patients with type 2 diabetes (n = 40; 2.5, 5, 15, 30 and 50 mg/day po). DPP-IV was inhibited dose-dependently, with maximal inhibition at 150 mg/day and corresponding elevations in postprandial GLP-1 (1.5- to 3.0-fold). DPP-IV inhibition at 24 h after the first dose was 50 and 79% for doses of 2.5 and 400 mg, respectively. Saxagliptin was well tolerated at all doses

10 Saxagliptin Gallwitz 915 Clinical (continued) Effect studied Study type Result Reference Efficacy Efficacy Efficacy Efficacy A phase II, multicenter, randomized, parallelgroup, double-blind, placebo-controlled clinical trial of drug-naive patients (n = 350) with inadequately controlled type 2 diabetes (HbA1c = 6.8 to 9.7%) administered saxagliptin (2.5, 5, 10, 20 or 40 mg/day po for 12 weeks or 100 mg/day po for 6 weeks). A phase III, multicenter, randomized, doubleblind, placebo-controlled clinical trial of patients with type 2 diabetes (n = 743) not optimally controlled with a stable metformin monotherapy (1500 to 2550 mg/day; HbA1c = 7 to 10%) administered saxagliptin (2.5, 5 or 10 mg/day po) in addition to their existing metformin therapy for 24 weeks. A phase III, multicenter, randomized, doubleblind, placebo-controlled clinical trial of drugnaive patients with type 2 diabetes (n = 460) whose diabetes was inadequately controlled by diet and exercise (HbA1c = 7 to 10%) administered saxagliptin (2.5, 5 or 10 mg/day po) for 24 weeks. A phase III, multicenter, randomized, doubleblind, placebo-controlled clinical trial of patients with type 2 diabetes (n = 555) not optimally controlled with a stable dose of either pioglitazone or rosiglitazone (HbA1c = 7.0 to 10.5% at baseline) administered saxagliptin (2.5 or 5 mg/day po) or placebo for 24 weeks concomitantly with their existing thiazolidinedione therapy (pioglitazone 30 or 45 mg, or rosiglitazone 4 or 8 mg). In the placebo group, 20% of patients achieved HbA1c levels of < 7.0%, compared with 50, 47, 41, 50, 53 and 66% of patients in the saxagliptin groups, respectively. A reduction of 24, 35, 41, 28, 34 and 45 mg/dl was observed in glucose levels 1 h after a liquid meal in the saxagliptin groups, respectively, compared with a reduction of 1 mg/dl for placebo. Levels of fasting glucose were decreased by 11, 22, 16, 14, 16 and 26 mg/dl in the treatment groups, respectively, while levels increased by 3 mg/dl in the placebo group. Saxagliptin treatment led to decreases in HbA1c of 0.73, 0.83 and 0.71% from baseline at the three saxagliptin doses, respectively. Similarly, fasting plasma glucose was reduced by 16, 24 and 21 mg/dl from baseline (p < ). In oral glucose tolerance tests, saxagliptin significantly reduced the AUCs of glucose and glucagons, while increasing the AUCs for insulin and C-peptide. Saxagliptin reduced HbA1c levels by 0.62, 0.64 and 0.73%, for the three saxagliptin groups, respectively. An HbA1c of < 7% at week 24 was attained by 35, 38 and 41% of patients in the three saxagliptin groups, respectively, compared with 24% for placebo. From week 2 of treatment, fasting plasma glucose was also reduced significantly, by 21, 15 and 23 mg/dl, respectively. The postprandial glucose AUC was also improved by saxagliptin treatment, as demonstrated by an increase in the postprandial insulin and C-peptide AUC values. Saxagliptin (2.5 or 5 mg) reduced HbA1c levels relative to baseline by 0.66 and 0.94%, respectively, compared with a reduction of 0.33% for placebo. Fasting glucose levels were also significantly reduced relative to baseline, with the two saxagliptin doses reducing fasting glucose levels by 14.3 and 17.3 mg/dl, respectively, compared with 2.8 mg/dl for placebo. After 24 weeks, 42.2 and 41.8% of patients in the two saxagliptin dose groups, respectively, achieved an HbA1c level of < 7.0%, compared with 25.6% in the placebo group Associated patent Title Cyclopropyl-fused pyrrolidine derivatives used for the inhibition of dipeptidyl peptidase IV and for the treatment of diabetes. Assignee Bristol-Myers Squibb Co Publication WO SEP-01 Priority US MAR-01 Inventors Robl JA, Sulsky RB, Augeri DJ, Magnin DR, Hamann LG, Betebenner DA. References of outstanding interest of special interest Synthesis of novel potent DPP-IV inhibitors with enhanced chemical stability: Interplay between the alkyl fragment of the N-terminal amino acid moiety and the cyclopropyl group of α-aminoacyl-(l)-(cis)-4,5-methanoprolinenitrile-based inhibitors. Magnin D, Robl J, Sulsky RB, Augieri DJ, Huang Y, Taunk P, Betebenner DA, Simpkins LM, Robertson JG, Khanna A, Abboa-Offei B et al ACS MEDI Design, synthesis, and pharmacology of BMS : A long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type II diabetes. Hamann LG, Augeri DJ, Betebenner DA, Robl J, Magnin D, Khann A, Robertson JG, Simpkins LM, Taunk P, Sitkoff D, Weigelt C et al ACS MEDI American Chemical Society 228th National Meeting (Part VII) OVERNIGHT REPORT, Philadelphia, PA, USA. Ognjenovic M IDDB MEETING REPORT 2004 August Bristol-Myers Squibb R and D review, November 17, Bristol-Myers Squibb Co COMPANY PRESENTATION 2004 November Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes. Zander M, Madsbad S, Madsen JL, Holst JJ Lancet Newly approved first-in-class treatment for type 2 diabetes is now available. Eli Lilly & Co/Amylin Pharmaceuticals Inc PRESS RELEASE 2005 June Mechanism of Gly-Pro-pNA cleavage catalyzed by dipeptidyl peptidase-iv and its inhibition by saxagliptin (BMS ). Kim YB, Kopcho LM, Kirby MS, Hamann LG, Weigelt CA, Metzler WJ, Marcinkeviciene J Arch Biochem Biophys Discovery and preclinical profile of saxagliptin (BMS ): A highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Augeri DJ, Robl JA, Betebenner DA, Magnin DR, Khanna A, Robertson JG, Wang A, Simpkins LM, Taunk P, Huang Q, Hamann LG et al J Med Chem Bristol-Myers Squibb and Otsuka Pharmaceutical Co., Ltd. announce exclusive licensing agreement for diabetes compound saxagliptin in Japan. Bristol-Myers Squibb Co PRESS RELEASE 2006 December Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O'Neill M C, Zinman B, Viberti G N ENGL J MED

Practical Strategies for the Clinical Use of Incretin Mimetics CME/CE. CME/CE Released: 09/15/2009; Valid for credit through 09/15/2010

Practical Strategies for the Clinical Use of Incretin Mimetics CME/CE. CME/CE Released: 09/15/2009; Valid for credit through 09/15/2010 Practical Strategies for the Clinical Use of Incretin Mimetics CME/CE Robert R. Henry, MD Authors and Disclosures CME/CE Released: 09/15/2009; Valid for credit through 09/15/2010 Introduction Type 2 diabetes

More information

Diabetes Management DPP-4 Inhibitors

Diabetes Management DPP-4 Inhibitors Drug Profile Saxagliptin, a Novel Dipeptidyl Peptidase-4 Inhibitor for the Treatment of Type 2 Diabetes Baptist Gallwitz, MD, PhD Professor of Medicine, Department of Medicine IV, Eberhard Karls University

More information

T2DM is a global epidemic with

T2DM is a global epidemic with : a new option for the management of type 2 diabetes Marc Evans MRCP, MD, Consultant Diabetologist, Llandough Hospital, Cardiff Incretin-based therapies for the treatment of diabetes mellitus (T2DM) present

More information

National Horizon Scanning Centre. Saxagliptin (BMS ) for type 2 diabetes. April 2008

National Horizon Scanning Centre. Saxagliptin (BMS ) for type 2 diabetes. April 2008 Saxagliptin (BMS 477118) for type 2 diabetes This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement

More information

The Many Faces of T2DM in Long-term Care Facilities

The Many Faces of T2DM in Long-term Care Facilities The Many Faces of T2DM in Long-term Care Facilities Question #1 Which of the following is a risk factor for increased hypoglycemia in older patients that may suggest the need to relax hyperglycemia treatment

More information

Scope. History. History. Incretins. Incretin-based Therapy and DPP-4 Inhibitors

Scope. History. History. Incretins. Incretin-based Therapy and DPP-4 Inhibitors Plasma Glucose (mg/dl) Plasma Insulin (pmol/l) Incretin-based Therapy and Inhibitors Scope Mechanism of action ผศ.ดร.นพ.ว ระเดช พ ศประเสร ฐ สาขาว ชาโภชนว ทยาคล น ก ภาคว ชาอาย รศาสตร คณะแพทยศาสตร มหาว ทยาล

More information

Incretin-based Therapies for Type 2 Diabetes Comparisons Between Glucagon-like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors

Incretin-based Therapies for Type 2 Diabetes Comparisons Between Glucagon-like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors Incretin-based Therapies for Type 2 Diabetes Comparisons Between Glucagon-like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors Timothy Bailey, MD, FACE, CPI Director, AMCR Institute,

More information

Drug Class Monograph

Drug Class Monograph Drug Class Monograph Class: Dipeptidyl-Peptidase 4 (DPP-4) Inhibitors Drugs: alogliptin, alogliptin/metformin, Januvia (sitagliptin), Janumet (sitagliptin/metformin), Janumet XR (sitagliptin/metformin),

More information

NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE. Proposed Health Technology Appraisal

NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE. Proposed Health Technology Appraisal NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE Proposed Health Technology Appraisal Dapagliflozin in combination therapy for the Final scope Remit/appraisal objective To appraise the clinical and

More information

Sitagliptin: first DPP-4 inhibitor to treat type 2 diabetes Steve Chaplin MSc, MRPharmS and Andrew Krentz MD, FRCP

Sitagliptin: first DPP-4 inhibitor to treat type 2 diabetes Steve Chaplin MSc, MRPharmS and Andrew Krentz MD, FRCP Sitagliptin: first DPP-4 inhibitor to treat type 2 diabetes Steve Chaplin MSc, MRPharmS and Andrew Krentz MD, FRCP KEY POINTS sitagliptin (Januvia) is a DPP-4 inhibitor that blocks the breakdown of the

More information

NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE. Single Technology Appraisal. Canagliflozin in combination therapy for treating type 2 diabetes

NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE. Single Technology Appraisal. Canagliflozin in combination therapy for treating type 2 diabetes NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE Single Technology Appraisal Canagliflozin in combination therapy for Final scope Remit/appraisal objective To appraise the clinical and cost effectiveness

More information

Management of Type 2 Diabetes

Management of Type 2 Diabetes Management of Type 2 Diabetes Pathophysiology Insulin resistance and relative insulin deficiency/ defective secretion Not immune mediated No evidence of β cell destruction Increased risk with age, obesity

More information

Scottish Medicines Consortium

Scottish Medicines Consortium Scottish Medicines Consortium saxagliptin, 5mg film-coated tablet (Onglyza ) No. (603/10) Bristol-Myers Squibb Pharmaceuticals Ltd 05 February 2010 The Scottish Medicines Consortium (SMC) has completed

More information

Drug Class Monograph

Drug Class Monograph Class: Dipeptidyl-Peptidase 4 (DPP-4) Inhibitors Drug Class Monograph Drugs: alogliptin, Januvia (sitagliptin), Janumet (sitagliptin/metformin), Janumet XR (sitagliptin/metformin), Jentadueto (linagliptin/metformin),

More information

Disclosure. Learning Objectives. Case. Diabetes Update: Incretin Agents in Diabetes-When to Use Them? I have no disclosures to declare

Disclosure. Learning Objectives. Case. Diabetes Update: Incretin Agents in Diabetes-When to Use Them? I have no disclosures to declare Disclosure Diabetes Update: Incretin Agents in Diabetes-When to Use Them? I have no disclosures to declare Spring Therapeutics Update 2011 CSHP BC Branch Anar Dossa BScPharm Pharm D CDE April 20, 2011

More information

GLP-1 agonists. Ian Gallen Consultant Community Diabetologist Royal Berkshire Hospital Reading UK

GLP-1 agonists. Ian Gallen Consultant Community Diabetologist Royal Berkshire Hospital Reading UK GLP-1 agonists Ian Gallen Consultant Community Diabetologist Royal Berkshire Hospital Reading UK What do GLP-1 agonists do? Physiology of postprandial glucose regulation Meal ❶ ❷ Insulin Rising plasma

More information

Effect of macronutrients and mixed meals on incretin hormone secretion and islet cell function

Effect of macronutrients and mixed meals on incretin hormone secretion and islet cell function Effect of macronutrients and mixed meals on incretin hormone secretion and islet cell function Background. Following meal ingestion, several hormones are released from the gastrointestinal tract. Some

More information

VICTOSA and Renal impairment DR.R.S.SAJAD

VICTOSA and Renal impairment DR.R.S.SAJAD VICTOSA and Renal impairment DR.R.S.SAJAD February 2019 Main effect of GLP-1 is : Stimulating glucose dependent insulin release from the pancreatic islets. Slow gastric emptying Inhibit inappropriate

More information

Early treatment for patients with Type 2 Diabetes

Early treatment for patients with Type 2 Diabetes Israel Society of Internal Medicine Kibutz Hagoshrim, June 22, 2012 Early treatment for patients with Type 2 Diabetes Eduard Montanya Hospital Universitari Bellvitge-IDIBELL CIBERDEM University of Barcelona

More information

Chief of Endocrinology East Orange General Hospital

Chief of Endocrinology East Orange General Hospital Targeting the Incretins System: Can it Improve Our Ability to Treat Type 2 Diabetes? Darshi Sunderam, MD Darshi Sunderam, MD Chief of Endocrinology East Orange General Hospital Age-adjusted Percentage

More information

Data from an epidemiologic analysis of

Data from an epidemiologic analysis of CLINICAL TRIAL RESULTS OF GLP-1 RELATED AGENTS: THE EARLY EVIDENCE Lawrence Blonde, MD, FACP, FACE ABSTRACT Although it is well known that lowering A 1c (also known as glycated hemoglobin) is associated

More information

Barbara Cadario, BSc(Hon), BScPhm., MSc Barbara Cadario SAXAGLIPTIN

Barbara Cadario, BSc(Hon), BScPhm., MSc Barbara Cadario SAXAGLIPTIN Volume 31 (1) 2011 Editor: Barbara Cadario, BSc(Hon), BScPhm., MSc Contents - Saxagliptin Barbara Cadario Chairman, Medical Review Laird Birmingham, MD, MHSc, FRCP(C) TRADE NAME: Onglyza CLASSIFICATION

More information

Dipeptidyl-Peptidase 4 (DPP-4) Inhibitors Drug Class Prior Authorization Protocol

Dipeptidyl-Peptidase 4 (DPP-4) Inhibitors Drug Class Prior Authorization Protocol Dipeptidyl-Peptidase 4 (DPP-4) Inhibitors Drug Class Prior Authorization Protocol Line of Business: Medicaid P&T Approval Date: February 21, 2018 Effective Date: April 1, 2018 This policy has been developed

More information

Newer Drugs in the Management of Type 2 Diabetes Mellitus

Newer Drugs in the Management of Type 2 Diabetes Mellitus Newer Drugs in the Management of Type 2 Diabetes Mellitus Dr. C. Dinesh M. Naidu Professor of Pharmacology, Kamineni Institute of Medical Sciences, Narketpally. 1 Presentation Outline Introduction Pathogenesis

More information

INCRETIN-BASED DRUGS: MARKETS FOR DIABETES THERAPIES AND DEVELOPING TREATMENTS

INCRETIN-BASED DRUGS: MARKETS FOR DIABETES THERAPIES AND DEVELOPING TREATMENTS INCRETIN-BASED DRUGS: MARKETS FOR DIABETES THERAPIES AND DEVELOPING TREATMENTS PHM162A February 2015 Kim Lawson Project Analyst ISBN: 1-62296-047-5 BCC Research 49 Walnut Park, Building 2 Wellesley, MA

More information

Drug Class Review Newer Diabetes Medications and Combinations

Drug Class Review Newer Diabetes Medications and Combinations Drug Class Review Newer Diabetes Medications and Combinations Final Update 2 Report July 2016 The purpose reports is to make available information regarding the comparative clinical effectiveness and harms

More information

Diabetes and Current Therapeutics

Diabetes and Current Therapeutics Diabetes and Current Therapeutics MacMillan Group Meeting April 4, 2012 Scott Simonovich Definition and World Prevalence Diabetes mellitus Metablic disease in which abnormally high blood glucose levels

More information

FARXIGA (dapagliflozin) Jardiance (empagliflozin) tablets. Synjardy (empagliflozin and metformin hydrochloride) tablets. GLUCOPHAGE* (metformin)

FARXIGA (dapagliflozin) Jardiance (empagliflozin) tablets. Synjardy (empagliflozin and metformin hydrochloride) tablets. GLUCOPHAGE* (metformin) Type 2 Medications Drug Class How It Works Brand and Generic Names Manufacturers Usual Starting Dose The kidneys filter sugar and either absorb it back into your body for energy or remove it through your

More information

COMMISSIONING POLICY RECOMMENDATION TREATMENT ADVISORY GROUP Policy agreed by (Vale of York CCG/date)

COMMISSIONING POLICY RECOMMENDATION TREATMENT ADVISORY GROUP Policy agreed by (Vale of York CCG/date) Drug, Treatment, Device name ( Vipidia; Takeda) COMMISSIONING POLICY RECOMMENDATION TREATMENT ADVISORY GROUP Policy agreed by (Vale of York CCG/date) Licensed indication To improve glycaemic control in

More information

Scottish Medicines Consortium

Scottish Medicines Consortium Scottish Medicines Consortium liraglutide 6mg/mL prefilled pen for injection (3mL) (Victoza ) Novo Nordisk Ltd. No. (585/09) 06 November 2009 The Scottish Medicines Consortium (SMC) has completed its assessment

More information

GLP-1 (glucagon-like peptide-1) Agonists (Byetta, Bydureon, Tanzeum, Trulicity, Victoza ) Step Therapy and Quantity Limit Criteria Program Summary

GLP-1 (glucagon-like peptide-1) Agonists (Byetta, Bydureon, Tanzeum, Trulicity, Victoza ) Step Therapy and Quantity Limit Criteria Program Summary OBJECTIVE The intent of the GLP-1 (glucagon-like peptide-1) s (Byetta/exenatide, Bydureon/ exenatide extended-release, Tanzeum/albiglutide, Trulicity/dulaglutide, and Victoza/liraglutide) Step Therapy

More information

Type 2 DM in Adolescents: Use of GLP-1 RA. Objectives. Scope of Problem: Obesity. Background. Pathophysiology of T2DM

Type 2 DM in Adolescents: Use of GLP-1 RA. Objectives. Scope of Problem: Obesity. Background. Pathophysiology of T2DM Type 2 DM in Adolescents: Use of GLP-1 RA Objectives Identify patients in the pediatric population with T2DM that would potentially benefit from the use of GLP-1 RA Discuss changes in glycemic outcomes

More information

Horizon Scanning Technology Summary. Liraglutide for type 2 diabetes. National Horizon Scanning Centre. April 2007

Horizon Scanning Technology Summary. Liraglutide for type 2 diabetes. National Horizon Scanning Centre. April 2007 Horizon Scanning Technology Summary National Horizon Scanning Centre Liraglutide for type 2 diabetes April 2007 This technology summary is based on information available at the time of research and a limited

More information

6/1/2018. Lou Haenel, IV, DO, FACE, FACOI Endocrinology Roper St Francis Charleston, SC THE OMINOUS OCTET: HOW PATHOPHYSIOLOGY AND THERAPY MERGE

6/1/2018. Lou Haenel, IV, DO, FACE, FACOI Endocrinology Roper St Francis Charleston, SC THE OMINOUS OCTET: HOW PATHOPHYSIOLOGY AND THERAPY MERGE Lou Haenel, IV, DO, FACE, FACOI Endocrinology Roper St Francis Charleston, SC THE OMINOUS OCTET: HOW PATHOPHYSIOLOGY AND THERAPY MERGE 1 2 3 Sulfonylureas Glipizide Glyburide Glimeperide 4 Metformin Gold

More information

3/8/2011. Julie M. Sease, Pharm D, BCPS, CDE Associate Professor of Pharmacy Practice Presbyterian College School of Pharmacy

3/8/2011. Julie M. Sease, Pharm D, BCPS, CDE Associate Professor of Pharmacy Practice Presbyterian College School of Pharmacy Summarize revisions to the 2011 American Diabetes Association clinical practice guidelines. Evaluate bromocriptine as a therapeutic option in the management of type 2 diabetes. Compare and contrast the

More information

GLP-1. GLP-1 is produced by the L-cells of the gut after food intake in two biologically active forms It is rapidly degraded by DPP-4.

GLP-1. GLP-1 is produced by the L-cells of the gut after food intake in two biologically active forms It is rapidly degraded by DPP-4. GLP-1 GLP-1 is produced by the L-cells of the gut after food intake in two biologically active forms It is rapidly degraded by DPP-4 Food intake éinsulin Gut églucose uptake Pancreas Beta cells Alpha cells

More information

New and Emerging Therapies for Type 2 DM

New and Emerging Therapies for Type 2 DM Dale Clayton MHSc, MD, FRCPC Dalhousie University/Capital Health April 28, 2011 New and Emerging Therapies for Type 2 DM The science of today, is the technology of tomorrow. Edward Teller American Physicist

More information

Role of incretins in the treatment of type 2 diabetes

Role of incretins in the treatment of type 2 diabetes Role of incretins in the treatment of type 2 diabetes Jens Juul Holst Department of Medical Physiology Panum Institute University of Copenhagen Denmark Diabetes & Obesity Spanish Society of Internal Medicine

More information

What s New on the Horizon: Diabetes Medication Update

What s New on the Horizon: Diabetes Medication Update What s New on the Horizon: Diabetes Medication Update Outline of Talk Newly released and upcoming medications: the incretins, DPP-IV inhibitors, and what s coming Revised ADA/EASD and AACE guidelines:

More information

Discussion & Conclusion

Discussion & Conclusion Discussion & Conclusion 7. Discussion DPP-4 inhibitors augment the effects of incretin hormones by prolonging their half-life and represent a new therapeutic approach for the treatment of type 2 diabetes

More information

DPP-4/SGLT2 inhibitor combined therapy for type 2 diabetes

DPP-4/SGLT2 inhibitor combined therapy for type 2 diabetes THERAPY REVIEW DPP-4/SGLT2 inhibitor combined therapy for type 2 diabetes STEVE CHAPLIN SPL DPP-4 inhibitors and SGLT2 inhibitors lower blood glucose by complementary mechanisms of action, and two fixeddose

More information

Multiple Factors Should Be Considered When Setting a Glycemic Goal

Multiple Factors Should Be Considered When Setting a Glycemic Goal Multiple Facts Should Be Considered When Setting a Glycemic Goal Patient attitude and expected treatment effts Risks potentially associated with hypoglycemia, other adverse events Disease duration Me stringent

More information

What s New on the Horizon: Diabetes Medication Update. Michael Shannon, MD Providence Endocrinology, Olympia WA

What s New on the Horizon: Diabetes Medication Update. Michael Shannon, MD Providence Endocrinology, Olympia WA What s New on the Horizon: Diabetes Medication Update Michael Shannon, MD Providence Endocrinology, Olympia WA 1 Outline of Talk Newly released and upcoming medications: the incretins, DPP-IV inhibitors,

More information

sitagliptin, 25mg, 50mg and 100mg film-coated tablets (Januvia ) SMC No. (1083/15) Merck Sharp and Dohme UK Ltd

sitagliptin, 25mg, 50mg and 100mg film-coated tablets (Januvia ) SMC No. (1083/15) Merck Sharp and Dohme UK Ltd sitagliptin, 25mg, 50mg and 100mg film-coated tablets (Januvia ) SMC No. (1083/15) Merck Sharp and Dohme UK Ltd 07 August 2015 The Scottish Medicines Consortium (SMC) has completed its assessment of the

More information

GLP 1 agonists Winning the Losing Battle. Dr Bernard SAMIA. KCS Congress: Impact through collaboration

GLP 1 agonists Winning the Losing Battle. Dr Bernard SAMIA. KCS Congress: Impact through collaboration GLP 1 agonists Winning the Losing Battle Dr Bernard SAMIA KCS Congress: Impact through collaboration CONTACT: Tel. +254 735 833 803 Email: kcardiacs@gmail.com Web: www.kenyacardiacs.org Disclosures I have

More information

Achieving and maintaining good glycemic control is an

Achieving and maintaining good glycemic control is an Glycemic Efficacy, Weight Effects, and Safety of Once-Weekly Glucagon-Like Peptide-1 Receptor Agonists Yehuda Handelsman, MD, FACP, FNLA, FASPC, MACE; Kathleen Wyne, MD, PhD, FACE, FNLA; Anthony Cannon,

More information

Management of Type 2 Diabetes. Why Do We Bother to Achieve Good Control in DM2. Insulin Secretion. The Importance of BP and Glucose Control

Management of Type 2 Diabetes. Why Do We Bother to Achieve Good Control in DM2. Insulin Secretion. The Importance of BP and Glucose Control Insulin Secretion Management of Type 2 Diabetes DG van Zyl Why Do We Bother to Achieve Good Control in DM2 % reduction 0-5 -10-15 -20-25 -30-35 -40 The Importance of BP and Glucose Control Effects of tight

More information

Linagliptin for the treatment of Type 2 diabetes

Linagliptin for the treatment of Type 2 diabetes Linagliptin for the treatment of Type 2 diabetes Practice Points Sri Harsha Tella1, Halis Kaan Akturk1 & Marc Rendell*2,3 Linagliptin is one of the most recent additions to incretin-based therapies for

More information

Treating Type 2 Diabetes with Bariatric Surgery. Goal of Treating T2DM. Remission of T2DM with Bariatric

Treating Type 2 Diabetes with Bariatric Surgery. Goal of Treating T2DM. Remission of T2DM with Bariatric Treating Type 2 Diabetes with Bariatric Surgery Number (in Millions) of Persons with Diagnosed Diabetes, United States, 198 25 The number of Americans with diabetes increased from 5.6 to 15.8 million Guilherme

More information

Merck & Co, Inc. Announced Approval of JANUVIA TM (INN: sitagliptin), a new oral treatment of diabetes, by the US FDA

Merck & Co, Inc. Announced Approval of JANUVIA TM (INN: sitagliptin), a new oral treatment of diabetes, by the US FDA October 23, 2006 Ono Pharmaceutical Co., Ltd., Public Relations Phone: +81-6-6263-5670 Banyu Pharmaceutical Co., Ltd., Public Relations Phone: +81-3-6272-1001 Merck & Co, Inc. Announced Approval of JANUVIA

More information

Dulaglutide (LY ) for the treatment of type 2 diabetes

Dulaglutide (LY ) for the treatment of type 2 diabetes Expert Review of Clinical Pharmacology ISSN: 1751-2433 (Print) 1751-2441 (Online) Journal homepage: http://www.tandfonline.com/loi/ierj20 (LY-2189265) for the treatment of type 2 diabetes André J. Scheen

More information

Results of Phase II Studies of Sitagliptin (MK-0431 / ONO-5345) Investigational Treatment for Type 2 Diabetes Presented by Merck & Co., Inc.

Results of Phase II Studies of Sitagliptin (MK-0431 / ONO-5345) Investigational Treatment for Type 2 Diabetes Presented by Merck & Co., Inc. Ono Pharmaceutical Co., Ltd., Public Relations Tel: +81-6-6263-5670 June 13, 2005 Banyu Pharmaceutical Co., Ltd., Public Relations Tel: +81-3-5203-8105 Results of Phase II Studies of Sitagliptin (MK-0431

More information

Dept of Diabetes Main Desk

Dept of Diabetes Main Desk Dept of Diabetes Main Desk 01202 448060 Glucose management in Type 2 Diabetes in Adults The natural history of type 2 diabetes is for HbA1c to deteriorate with time. A stepwise approach to treatment is

More information

Liraglutide (Victoza) in combination with basal insulin for type 2 diabetes

Liraglutide (Victoza) in combination with basal insulin for type 2 diabetes Liraglutide (Victoza) in combination with basal insulin for type 2 diabetes May 2011 This technology summary is based on information available at the time of research and a limited literature search. It

More information

MLR-1023: A First-in-Class, Clinical Stage Candidate for Type II diabetes

MLR-1023: A First-in-Class, Clinical Stage Candidate for Type II diabetes MLR-1023: A First-in-Class, Clinical Stage Candidate for Type II diabetes» Next generation insulin sensitizer that does not have PPAR activity» Orally bioavailable small molecule» Weight neutral»!-cell

More information

Reviewing Diabetes Guidelines. Newsletter compiled by Danny Jaek, Pharm.D. Candidate

Reviewing Diabetes Guidelines. Newsletter compiled by Danny Jaek, Pharm.D. Candidate Reviewing Diabetes Guidelines Newsletter compiled by Danny Jaek, Pharm.D. Candidate AL AS KA N AT IV E DI AB ET ES TE A M Volume 6, Issue 1 Spring 2011 Dia bet es Dis pat ch There are nearly 24 million

More information

Newer and Expensive treatment of diabetes. Endocrinology Visiting Associate Professor Institute of Medicine TUTH

Newer and Expensive treatment of diabetes. Endocrinology Visiting Associate Professor Institute of Medicine TUTH Newer and Expensive treatment of diabetes Jyoti Bhattarai MD Endocrinology Visiting Associate Professor Institute of Medicine TUTH Four out of every five people with diabetes now live in developing countries.

More information

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors In the Management of Diabetes

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors In the Management of Diabetes DRUG CLASS REVIEW Dipeptidyl Peptidase-4 (DPP-4) Inhibitors In the Management of Diabetes Rolee Pathak, PharmD, RPh, BCPS; and Mary Barna Bridgeman, PharmD, RPh INTRODUCTION Type-2 diabetes mellitus is

More information

Treatment Options for Diabetes: An Update

Treatment Options for Diabetes: An Update Treatment Options for Diabetes: An Update A/Prof. Marg McGill Manager, Diabetes Centre Dr. Ted Wu Staff Specialist Endocrinologist Diabetes Centre Centre of Health Professional Education Education Provider

More information

TABLE OF CONTENTS 1 Table of Contents 2 Introduction 3 Key Marketed Products

TABLE OF CONTENTS 1 Table of Contents 2 Introduction 3 Key Marketed Products TABLE OF CONTENTS 1 Table of Contents 1.1 List of Tables 1.2 List of Figures 2 Introduction 2.1 Epidemiology 2.2 Symptoms 2.3 Etiology 2.4 Pathophysiology 2.5 Co-morbidities and Complications 2.6 Classification

More information

(Incretin) ( glucagon-like peptide-1 GLP-1 ) GLP-1. GLP-1 ( dipeptidyl peptidase IV DPP IV ) GLP-1 DPP IV GLP-1 exenatide liraglutide FDA 2 2 2

(Incretin) ( glucagon-like peptide-1 GLP-1 ) GLP-1. GLP-1 ( dipeptidyl peptidase IV DPP IV ) GLP-1 DPP IV GLP-1 exenatide liraglutide FDA 2 2 2 007 18 189-194 (Incretin) Incretin ( ) -1 ( glucagon-like peptide-1 ) ( dipeptidyl peptidase IV ) liraglutide FDA ( Type diabetes mellitus ) -1 ( Glucagon-like peptide-1, ) ( Incretin ) ( Dipeptidyl peptidase

More information

IDF Regions and global projections of the number of people with diabetes (20-79 years), 2013 and Diabetes Atlas -sixth Edition: IDF 2013

IDF Regions and global projections of the number of people with diabetes (20-79 years), 2013 and Diabetes Atlas -sixth Edition: IDF 2013 IDF Regions and global projections of the number of people with diabetes (20-79 years), 2013 and 2035 Diabetes Atlas -sixth Edition: IDF 2013 Diabetes Atlas -sixth Edition: IDF 2013 Chronic complications

More information

DPP-4 Inhibitors: Strategies for PPG Control

DPP-4 Inhibitors: Strategies for PPG Control Issue 2 Clinical Use o f In c r e t i n-based Therapies to Tr e at Type 2 Diabetes Term of Approval Release date: August 2009 Expiration date: August 31, 2010 DPP-4 Inhibitors: Strategies for PPG Control

More information

TRANSPARENCY COMMITTEE OPINION. 29 April 2009

TRANSPARENCY COMMITTEE OPINION. 29 April 2009 The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 29 April 2009 VELMETIA 50 mg/850 mg, film-coated tablets B/56 (CIP code: 386 778-0) VELMETIA 50 mg/1 000 mg, film-coated

More information

SGLT2 Inhibitors

SGLT2 Inhibitors Federal Employee Program 1310 G Street, N.W. Washington, D.C. 20005 202.942.1000 Fax 202.942.1125 Subject: SGLT2 Inhibitors Page: 1 of 7 Last Review Date: June 22, 2018 SGLT2 Inhibitors Description Invokana

More information

MOA: Long acting glucagon-like peptide 1 receptor agonist

MOA: Long acting glucagon-like peptide 1 receptor agonist Alexandria Rydz MOA: Long acting glucagon-like peptide 1 receptor agonist Increases glucose dependent insulin secretion Decreases inappropriate glucagon secretion Increases β- cell growth and replication

More information

DPP-4 inhibitor. The new class drug for Diabetes

DPP-4 inhibitor. The new class drug for Diabetes DPP-4 inhibitor The new class drug for Diabetes 1 Cause of Death in Korea 1 st ; Neoplasm 2 nd ; Cardiovascular Disease 3 rd ; Cerebrovascular Disease Diabetes 2 Incidence of Fatal or Nonfatal MI During

More information

Current evidence on the effect of DPP-4 inhibitor drugs on mortality in type 2 diabetic (T2D) patients: A meta-analysis

Current evidence on the effect of DPP-4 inhibitor drugs on mortality in type 2 diabetic (T2D) patients: A meta-analysis Current evidence on the effect of DPP-4 inhibitor drugs on mortality in type 2 diabetic (T2D) patients: A meta-analysis Raja Chakraverty Assistant Professor in Pharmacology Bengal College of Pharmaceutical

More information

Obesity, Insulin Resistance, Metabolic Syndrome, and the Natural History of Type 2 Diabetes

Obesity, Insulin Resistance, Metabolic Syndrome, and the Natural History of Type 2 Diabetes Obesity, Insulin Resistance, Metabolic Syndrome, and the Natural History of Type 2 Diabetes Genetics, environment, and lifestyle (obesity, inactivity, poor diet) Impaired fasting glucose Decreased β-cell

More information

Media Contacts: Amy Rose Investor Contact: Graeme Bell (908) (908)

Media Contacts: Amy Rose Investor Contact: Graeme Bell (908) (908) News Release FOR IMMEDIATE RELEASE Media Contacts: Amy Rose Investor Contact: Graeme Bell (908) 423-6537 (908) 423-5185 Tracy Ogden (267) 305-0960 FDA Approves Once-Daily JANUVIA, the First and Only DPP-4

More information

Non-insulin treatment in Type 1 DM Sang Yong Kim

Non-insulin treatment in Type 1 DM Sang Yong Kim Non-insulin treatment in Type 1 DM Sang Yong Kim Chosun University Hospital Conflict of interest disclosure None Committee of Scientific Affairs Committee of Scientific Affairs Insulin therapy is the mainstay

More information

Type 2 Diabetes: Where Do We Start with Treatment? DIABETES EDUCATION. Diabetes Mellitus: Complications and Co-Morbid Conditions

Type 2 Diabetes: Where Do We Start with Treatment? DIABETES EDUCATION. Diabetes Mellitus: Complications and Co-Morbid Conditions Diabetes Mellitus: Complications and Co-Morbid Conditions ADA Guidelines for Glycemic Control: 2016 Retinopathy Between 2005-2008, 28.5% of patients with diabetes 40 years and older diagnosed with diabetic

More information

Society for Ambulatory Anesthesia Consensus Statement on Perioperative Blood Glucose Management in Diabetic Patients Undergoing Ambulatory Surgery

Society for Ambulatory Anesthesia Consensus Statement on Perioperative Blood Glucose Management in Diabetic Patients Undergoing Ambulatory Surgery Society for Ambulatory Anesthesia Consensus Statement on Perioperative Blood Glucose Management in Diabetic Patients Undergoing Ambulatory Surgery Girish P. Joshi, MB BS, MD, FFARCSI Anesthesia & Analgesia

More information

Side Effects of: GLP-1 agonists DPP-4 inhibitors SGLT-2 inhibitors. Bryce Fukunaga PharmD April 25, 2018

Side Effects of: GLP-1 agonists DPP-4 inhibitors SGLT-2 inhibitors. Bryce Fukunaga PharmD April 25, 2018 Side Effects of: GLP-1 agonists DPP-4 inhibitors SGLT-2 inhibitors Bryce Fukunaga PharmD April 25, 2018 Objectives For each drug class: Identify the overall place in therapy Explain the mechanism of action

More information

See Important Reminder at the end of this policy for important regulatory and legal information.

See Important Reminder at the end of this policy for important regulatory and legal information. Clinical Policy: Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists Reference Number: HIM.PA.53 Effective Date: 03.01.18 Last Review Date: 02.18 Line of Business: Health Insurance Marketplace See Important

More information

Results of Phase III Studies of Sitagliptin, new oral treatment of diabetes, were presented by Merck & Co., Inc. at ADA (The 2 nd Announcement)

Results of Phase III Studies of Sitagliptin, new oral treatment of diabetes, were presented by Merck & Co., Inc. at ADA (The 2 nd Announcement) June 14, 2006 Ono Pharmaceutical Co., Ltd., Public Relations Tel: +81-6-6263-5670 Banyu Pharmaceutical Co., Ltd., Public Relations Tel: +81-3-6272-1001 Results of Phase III Studies of Sitagliptin, new

More information

What s New in Diabetes Treatment. Disclosures

What s New in Diabetes Treatment. Disclosures What s New in Diabetes Treatment Shiri Levy M.D. Henry Ford Hospital Senior Staff Physician Service Chief, West Bloomfield Hospital Endocrinology, Metabolism, Bone and Mineral Disorders Disclosures None

More information

Canadian Diabetes Association 2013

Canadian Diabetes Association 2013 Spring 2014 Canadian Diabetes Association 2013 clinical practice guidelines - Do claims data align to the guidelines? Canadian Diabetes Association 2013 clinical practice guidelines - Do claims data align

More information

Diabetes Oral Agents Pharmacology. University of Hawai i Hilo Pre-Nursing Program NURS 203 General Pharmacology Danita Narciso Pharm D

Diabetes Oral Agents Pharmacology. University of Hawai i Hilo Pre-Nursing Program NURS 203 General Pharmacology Danita Narciso Pharm D Diabetes Oral Agents Pharmacology University of Hawai i Hilo Pre-Nursing Program NURS 203 General Pharmacology Danita Narciso Pharm D 1 Learning Objectives Understand the role of the utilization of free

More information

01/09/2017. Outline. SGLT 2 inhibitor? Diabetes Patients: Complex and Heterogeneous. Association between diabetes and cardiovascular events

01/09/2017. Outline. SGLT 2 inhibitor? Diabetes Patients: Complex and Heterogeneous. Association between diabetes and cardiovascular events MICROVASCULAR COMPLICATIONS Incidence of outcome g 1 Cardioprotective Effects of SGLT2s Relevant for Which T2 Diabetes Patient? SGLT 2 inhibitor? 58 year old, waist circumference 5 cm, PMH: IHD On statin,

More information

Modulating the Incretin System: A New Therapeutic Strategy for Type 2 Diabetes

Modulating the Incretin System: A New Therapeutic Strategy for Type 2 Diabetes Modulating the Incretin System: A New Therapeutic Strategy for Type 2 Diabetes Geneva Clark Briggs, PharmD, BCPS Adjunct Professor at University of Appalachia College of Pharmacy Clinical Associate, Medical

More information

Update on Diabetes Mellitus

Update on Diabetes Mellitus Update on Diabetes Mellitus Treatment: Targeting the Incretin System Overview Underlying defects with Type 2 diabetes Importance of managing postprandial glucose control Amylin Incretin Hormones New therapies

More information

Revised: 02/2011 FULL PRESCRIBING INFORMATION: CONTENTS*

Revised: 02/2011 FULL PRESCRIBING INFORMATION: CONTENTS* HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ONGLYZA safely and effectively. See full prescribing information for ONGLYZA. ONGLYZA (saxagliptin)

More information

Wayne Gravois, MD August 6, 2017

Wayne Gravois, MD August 6, 2017 Wayne Gravois, MD August 6, 2017 Americans with Diabetes (Millions) 40 30 Source: National Diabetes Statistics Report, 2011, 2017 Millions 20 10 0 1980 2009 2015 2007 - $174 Billion 2015 - $245 Billion

More information

GLUCAGON LIKE PEPTIDE (GLP) 1 AGONISTS FOR THE TREATMENT OF TYPE 2 DIABETES, WEIGHT CONTROL AND CARDIOVASCULAR PROTECTION.

GLUCAGON LIKE PEPTIDE (GLP) 1 AGONISTS FOR THE TREATMENT OF TYPE 2 DIABETES, WEIGHT CONTROL AND CARDIOVASCULAR PROTECTION. GLUCAGON LIKE PEPTIDE (GLP) 1 AGONISTS FOR THE TREATMENT OF TYPE 2 DIABETES, WEIGHT CONTROL AND CARDIOVASCULAR PROTECTION. Patricia Garnica MS, ANP-BC, CDE, CDTC Inpatient Diabetes Nurse Practitioner North

More information

The Efficacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With Inadequately Controlled Type 2 Diabetes With Metformin Alone

The Efficacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With Inadequately Controlled Type 2 Diabetes With Metformin Alone Emerging Treatments and Technologies O R I G I N A L A R T I C L E The Efficacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With Inadequately Controlled Type 2 Diabetes With Metformin

More information

ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS

ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 1. NAME OF THE MEDICINAL PRODUCT Januvia 25 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains sitagliptin phosphate monohydrate,

More information

22 Emerging Therapies for

22 Emerging Therapies for 22 Emerging Therapies for Treatment of Type 2 Diabetes Siddharth N Shah Abstract: The prevalence of Diabetes is progressively increasing world-wide and the growth of the disease in our country is phenomenal.

More information

ROLE OF DIPEPTIDYL PEPTIDASE-4 INHIBITOR IN GLYCEMIC CONTROL AND CARDIOVASCULAR MORTALITY AND MORBIDITY

ROLE OF DIPEPTIDYL PEPTIDASE-4 INHIBITOR IN GLYCEMIC CONTROL AND CARDIOVASCULAR MORTALITY AND MORBIDITY ROLE OF DIPEPTIDYL PEPTIDASE-4 INHIBITOR IN GLYCEMIC CONTROL AND CARDIOVASCULAR MORTALITY AND MORBIDITY An Article Review By Dr.Shaikh Khalid Anwar, India (PG Diploma in Diabetes, MMSc in Diabetology Student

More information

Current Status of Incretin Based Therapies in Type 2 Diabetes

Current Status of Incretin Based Therapies in Type 2 Diabetes Current Status of Incretin Based Therapies in Type 2 Diabetes DR.M.Mukhyaprana Prabhu Professor of Internal Medicine Kasturba Medical College, Manipal, Manipal University, India 2 nd International Endocrine

More information

LATE BREAKING STUDIES IN DM AND CAD. Will this change the guidelines?

LATE BREAKING STUDIES IN DM AND CAD. Will this change the guidelines? LATE BREAKING STUDIES IN DM AND CAD Will this change the guidelines? Objectives 1. Discuss current guidelines for prevention of CHD in diabetes. 2. Discuss the FDA Guidance for Industry regarding evaluating

More information

Oral Hypoglycemics and Risk of Adverse Cardiac Events: A Summary of the Controversy

Oral Hypoglycemics and Risk of Adverse Cardiac Events: A Summary of the Controversy Oral Hypoglycemics and Risk of Adverse Cardiac Events: A Summary of the Controversy Jeffrey Boord, MD, MPH Advances in Cardiovascular Medicine Kingston, Jamaica December 7, 2012 VanderbiltHeart.com Outline

More information

Eli Lilly and Company

Eli Lilly and Company Eli Lilly and Company Strategic Diabetes Alliance with Boehringer Ingelheim January 11 th, 2011 Safe Harbor Provision This presentation contains forward-looking statements that are based on management's

More information

Glucagon-like peptide-1 (GLP-1) Agonists Drug Class Prior Authorization Protocol

Glucagon-like peptide-1 (GLP-1) Agonists Drug Class Prior Authorization Protocol Glucagon-like peptide-1 (GLP-1) Agonists Drug Class Prior Authorization Protocol Line of Business: Medicaid P&T Approval Date: February 21, 2018 Effective Date: April 1, 2018 This policy has been developed

More information

MLR-1023: A First-in-Class, Clinical Stage Candidate for Type II diabetes

MLR-1023: A First-in-Class, Clinical Stage Candidate for Type II diabetes MLR-1023: A First-in-Class, Clinical Stage Candidate for Type II diabetes» Next generation insulin sensitizer that does not have PPAR activity» Orally bioavailable small molecule» Weight neutral» β-cell

More information

Oral and Injectable Non-insulin Antihyperglycemic Agents

Oral and Injectable Non-insulin Antihyperglycemic Agents Appendix 5: Diabetes Education and Medical Management in Adults with Diabetes Oral and Injectable Non-insulin s This directive will be implemented by RPhs, RNs or RDs who have been deemed authorized implementers.

More information

Drugs used in Diabetes. Dr Andrew Smith

Drugs used in Diabetes. Dr Andrew Smith Drugs used in Diabetes Dr Andrew Smith Plan Introduction Insulin Sensitising Drugs: Metformin Glitazones Insulin Secretagogues: Sulphonylureas Meglitinides Others: Acarbose Incretins Amylin Analogues Damaglifozin

More information

A Practical Approach to the Use of Diabetes Medications

A Practical Approach to the Use of Diabetes Medications A Practical Approach to the Use of Diabetes Medications Juan Pablo Frias, M.D., FACE President, National Research Institute, Los Angles, CA Clinical Faculty, University of California, San Diego, CA OUTLINE

More information

Navigating the New Options for the Management of Type 2 Diabetes

Navigating the New Options for the Management of Type 2 Diabetes Navigating the New Options for the Management of Type 2 Diabetes Clinical Associate Professor Mark Kennedy Department of General Practice, University of Melbourne Chair, Primary Care Diabetes Society of

More information