Sitagliptin and other ‘gliptins’ - why prescribe them?

Introduction In 2008, the Federal Drug Administration (FDA) required all new glucose-lowering therapies to show cardiovascular safety, and this applies to the dipeptidyl peptidase (DPP)-4 inhibitors (‘gliptins’). At present, there is contradictory evidence on whether the gliptins increase hospitalizations for heart failure. Areas covered This is an evaluation of the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) in high risk cardiovascular subjects with type 2 diabetes [1]. TECOS demonstrated non-inferiority for sitagliptin over placebo for the primary outcome, which was cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. There was no difference in the rate of hospitalization for heart failure between sitagliptin and placebo. Expert Opinion Despite the results of TECOS, debate over the effects of sitagliptin on the rates of hospitalizations for heart failure continues with some recent studies suggesting increased rates. Recently, empagliflozin (an inhibitor of sodium-glucose cotransporter 2) has been shown to reduce cardiovascular outcomes in subjects with type 2 diabetes, including the rates of hospitalization for heart failure. In our opinion, these positive findings with empagliflozin suggest that it should be prescribed in preference to the gliptins, including sitagliptin, unless any positive cardiovascular outcomes are reported for the gliptins.

Fixed-dose combination therapy for type 2 diabetes: sitagliptin plus pioglitazone

Importance of the field: Type 2 diabetes is typically associated with insulin resistance and dysfunction of insulin-secreting pancreatic beta-cells. Addressing these defects often requires therapy with a combination of differently acting antidiabetic agents. A potential novel combination in development brings together the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin with the thiazolidinedione pioglitazone into a fixed-dose single-tablet combination. The former component acts mainly to increase prandial insulin secretion; the latter improves insulin sensitivity.

Exenatide and sitagliptin decrease interleukin 1β, matrix metalloproteinase 9, and nitric oxide synthase 2 gene expression but does not reduce alveolar bone loss in rats with periodontitis

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Fixed-dose combination therapy for type 2 diabetes:sitagliptin plus pioglitazone

Type 2 diabetes is typically associated with insulin resistance and dysfunction of insulin-secreting pancreatic beta-cells. Addressing these defects often requires therapy with a combination of differently acting antidiabetic agents. A potential novel combination in development brings together the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin with the thiazolidinedione pioglitazone into a fixed-dose single-tablet combination. The former component acts mainly to increase prandial insulin secretion; the latter improves insulin sensitivity.

The efficacy and safety of imeglimin as add-on therapy in patients with type 2 diabetes inadequately controlled with sitagliptin monotherapy

OBJECTIVE: This 12-week study assessed the efficacy and tolerability of imeglimin as add-on therapy to the dipeptidyl peptidase-4 inhibitor sitagliptin in patients with type 2 diabetes inadequately controlled with sitagliptin monotherapy. RESEARCH DESIGN AND METHODS: In a multicenter, randomized, double-blind, placebo-controlled, parallel-group study, imeglimin (1,500 mg b.i.d.) or placebo was added to sitagliptin (100 mg q.d.) over 12weeks in 170 patientswith type 2 diabetes (mean age 56.8 years; BMI 32.2 kg/m2) that was inadequately controlled with sitagliptin alone (A1C ≥7.5%) during a 12-week run-in period. The primary ef ficacy end point was the change in A1C from baseline versus placebo; secondary end points included corresponding changes in fasting plasma glucose (FPG) levels, strati fication by baseline A1C, and percentage of A1C responders. RESULTS: Imeglimin reduced A1C levels (least-squares mean difference) from baseline (8.5%) by 0.60% compared with an increase of 0.12% with placebo (between-group difference 0.72%, P < 0.001). The corresponding changes in FPG were -0.93 mmol/L with imeglimin vs. -0.11 mmol/L with placebo (P = 0.014). With imeglimin, the A1C level decreased by ≥0.5% in 54.3% of subjects vs. 21.6% with placebo (P < 0.001), and 19.8%of subjects receiving imeglimin achieved a decrease in A1C level of ≤7% compared with subjects receiving placebo (1.1%) (P = 0.004). Imeglimin was generally well tolerated, with a safety pro file comparable to placebo and no related treatment-emergent adverse events. CONCLUSIONS: Imeglimin demonstrated incremental efficacy benefits as add-on therapy to sitagliptin, with comparable tolerability to placebo, highlighting the potential for imeglimin to complement other oral antihyperglycemic therapies. © 2014 by the American Diabetes Association.

Drugs for diabetes and obesity

14.1 Drugs for diabetes 14.1.1 Diabetes mellitus 14.1.2 Physiology of the pancreas 14.1.3 Insulin replacement therapy 14.1.4 Metformin 14.1.5 Acarbose 14.1.6 Sulfonylureas 14.1.7 Glitazones 14.1.8 Glucagon-like peptide-1, exenatide and sitagliptin 14.2 Drugs for obesity 14.2.1 Introduction 14.2.2 Amphetamine 14.2.3 Phentermine 14.2.5 Orlistat

Exenatide extended-release; clinical trials, patient preference, and economic considerations

Type 2 diabetes remains an escalating world-wide problem, despite a range of treatments. The revelation that insulin secretion is under the control of a gut hormone, glucagon-like peptide 1 (GLP-1) led to a new paradigm in the management of type 2 diabetes, medicines that directly stimulate, or that prolong the actions of the endogenous GLP-1, at its receptors. Exenatide is an agonist at the GLP-1 receptors, and was initially developed as a subcutaneous twice daily medication, ExBID. The clinical trials with ExBID established a role for exenatide in the treatment of type 2 diabetes. Subsequently, once weekly exenatide (ExQW) was shown to have advantages over ExBID, and there is now more emphasis on the development of ExQW. ExQW alone reduces glycosylated haemoglobin (HbA1c) and body weight, and is well tolerated. ExQW has been compared to sitagliptin, pioglitazone and metformin, and shown to have a greater ability to reduce HbA1c than these other medicines. The only preparation of insulin, which ExQW has been compared to, is insulin glargine, and the ExQW has some favourable properties in this comparison, notably causing weight loss, compared to the gain with insulin glargine. ExQW has been compared to another GLP-1 receptor agonist, liraglutide, and ExQW is non-inferior to liraglutide in reducing HbA1c. The small amount of evidence available, shows that subjects with type 2 diabetes, prefer ExQW to ExBID, and that adherence was high to these in the clinical trial setting. Healthcare and economic modelling suggests that ExQW will reduce diabetic complications and be cost-effective, compared to other medications, with long term use. Little is known about whether subjects with type 2 diabetes prefer ExQW to other medicines, and whether adherence is good to ExQW in practice, and these important topics require further study.

Dapagliflozin – do we need it registered for type 2 diabetes?

INTRODUCTION: Inhibitors of the sodium-glucose co-transporter 2 (SGLT2) promote the excretion of glucose to reduce glycated hemoglobin (HbA1c) levels. Canagliflozin was the first SGLT2 inhibitor to be approved by the US FDA for use in the treatment of type 2 diabetes, and recently dapagliflozin has also been approved. AREAS COVERED: We evaluated a recent Phase III clinical trial with dapagliflozin. EXPERT OPINION: Dapagliflozin was studied as add-on therapy to sitagliptin with or without metformin, and was shown to lower HbA1c levels and body weight. The incidence of hypoglycaemia was low with dapagliflozin, but it did increase the incidence of urogenital infections. As no clear benefits have been identified for dapagliflozin over canagliflozin, which was the first gliflozin registered by the FDA, we do not fully understand why it was necessary to register dapagliflozin. Given that there are no completed cardiovascular/clinical outcome studies with dapagliflozin, and therefore no evidence of beneficial effect, it also seems premature to be using it extensively or considering it as an alternative to the clinically proven metformin.

Comparator clinical trials of surrogate endpoints with albiglutide are in HARMONY

Introduction: Agonists of glucagon-like peptide-1 (GLP-1) receptors are used in the treatment of type 2 diabetes. Albiglutide is a new long acting GLP-1 receptor agonist being developed for once-weekly use. Areas covered: This evaluation is of 2 clinical trials in the HARMONY clinical trials series. HARMONY 3 compares albiglutide to sitagliptin and glimepiride in subjects with type 2 diabetes poorly controlled with metformin, and HARMONY 6 compares albiglutide to insulin lispro in subjects poorly controlled with slow/medium release preparations of insulin. Expert opinion: Both studies showed that albiglutide lowered HbA1c, and had advantages over its comparator drugs. However, questions remain about the safety of albiglutide. Albiglutide is not being used in subjects with a history of thyroid cancer, as it is not known whether this is a rare adverse effect with albiglutide. Also, the safety of albiglutide in subjects with type 2 diabetes and high cardiovascular risk is unknown.

Common variants at 12q14 and 12q24 are associated with hippocampal volume

Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10 -7. In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10 -11) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10 -11). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10 -7) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10 -7); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.

Remodelamento do fígado, pâncreas e tecido adiposo em modelo experimental de síndrome metabólica tratado com telmisartana, sitagliptina e metformina

A intervenção farmacológica pode minimizar ou até mesmo reverter o remodelamento adverso em órgãos num modelo de síndrome metabólica. Este trabalho teve como objetivo avaliar os efeitos das monoterapias e associações medicamentosas sobre a morfologia do tecido adiposo, remodelamento hepático e pancreático em camundongos C57bl/6 alimentados com dieta very high-fat. Camundongos C57bl/6 machos foram alimentados com dieta very high-fat (HF, 60% de lipídios) ou dieta padrão (SC, 10% de lipídios) por 10 semanas, quando foram iniciados os tratamentos: HF-T (HF + Telmisartana, 5.2mg/Kg/dia), HF-S (HF + Sitagliptina, 1.08g/Kg/dia), HF-M (HF + Metformina, 310.0mg/Kg/dia) e as associações medicamentosas HF-TM, HF-TS e HF-SM. Os grupos tratados também tiveram livre acesso à dieta high fat e os tratamentos duraram 6 semanas. Técnicas morfométricas, estereológicas, imunohistoquímicas, ELISA, western blotting e microscopia eletrônica foram utilizadas. A dieta high-fat causou sobrepeso, intolerância oral à glucose, hiperinsulinemia, hipertrofia de ilhotas e adipócitos, grau 2 de esteatose hepatica (<33%) redução da expressão de PPAR-alfa e de GLUT-2, concomitante com aumento da expressão de SREBP-1 no grupo HF (P<0.0001). Por outro lado, todos os tratamentos resultaram em perda de peso significativa, reversão da resistência à insulina, hipertrofia de ilhotas e adipócitos e alívio da esteatose hepática. Somente os grupos HF-T e HF-TS apresentaram massa corporal similar ao grupo SC ao final do experimento, sendo que o ultimo também apresentou reversão da esteatose hepática. O aumento da expressão do PPAR-alfa paralelamente ao decréscimo da expressão do SREBP-1 explica os achados favoráveis para o fígado. A normalização do tamanho do adipócito foi consistente com os níveis maiores de adiponectina e com a redução dos níveis de TNF-alfa (P<0.0001) nos grupos tratados.Todos os tratamentos foram eficazes para controlar a síndrome metabólica. Os melhores resultados foram alcançados com a telmisartana e sitagliptina como monoterapias ou como associação entre essas, combinando a ativação parcial do PPAR-alfa no fígado com a extensão do tempo de ação das incretinas

Recent Advances in Antidiabetic Drug Therapies Targeting the Enteroinsular Axis

The enteroinsular axis (EIA) constitutes a physiological signalling system whereby intestinal endocrine cells secrete incretin hormones following feeding that potentiate insulin secretion and contribute to the regulation of blood glucose homeostasis. The two key hormones responsible are named glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Recent years have witnessed sustained development of antidiabetic therapies that exploit the EIA. Current clinical compounds divide neatly into two classes. One concerns analogues or mimetics of GLP-1, such as exenatide (Byetta) or liraglutide (NN2211). The other group comprises the gliptins (e. g. sitagliptin and vildagliptin) which boost endogenous incretin activity by inhibiting the enzyme dipeptidyl peptidase 4 (DPP 4) that degrades both GLP-1 and GIP. Ongoing research indicates that further incretin and gliptin compounds will become available for clinical use in the near future, offering comparable or improved efficacy. For incretin analogues there is the prospect of prolonged duration of action and alternative routes of administration. This review focuses on recent advances in pre-clinical research and their translation into clinical studies to provide future therapies for type 2 diabetes targeting the EIA.

Antidiabetic drugs and kidney disease - Recommendations of the Swiss Society for Endocrinology and Diabetology.

Patients with diabetes are at risk of early renal function decline. Therefore, kidney function needs monitoring at least once per year. Once the glomerular filtration rate (GFR) is less than 60 ml/min, the pharmacokinetics of antidiabetic drugs may be altered. Sulfonylurea and glinide therapies are associated with a risk of hypoglycaemia which is increased in the presence of renal impairment. Most sulfonylureas must be discontinued once GFR is <60 ml/min. Some glinides may be continued beyond this threshold, in particular repaglinide, which may be used in dialysis patients. In the absence of comorbidities, metformin can be continued at lower doses until a GFR of 45 ml/min, but must be withdrawn in case of dehydration or during the administration of a nephrotoxic drug including dye for radiological investigations. Glitazones may worsen water and sodium retention in patients with renal impairment. The pharmacokinetics of all DPP-IV inhibitors except linagliptin are altered with impaired renal function. Only sitagliptin, saxagliptin and linagliptin may be used in advanced kidney disease, but experience is as yet very limited. GLP-1 agonists are contraindicated in moderate to advanced kidney disease.

Dipeptidyl peptidase IV inhibition attenuates blood pressure rising in young spontaneously hypertensive rats

Objectives The present study aimed to assess the effect of the specific dipeptidyl peptidase IV (DPPIV) inhibitor sitagliptin on blood pressure and renal function in young prehypertensive (5-week-old) and adult spontaneously hypertensive rats (SHRs; 14-week-old). Methods Sitagliptin (40 mg/kg twice daily) was given by oral gavage to young (Y-SHR + IDPPIV) and adult (A-SHR R IDPPIV) SHRs for 8 days. Kidney function was assessed daily and compared with age-matched vehicle-treated SHR (Y-SHR and A-SHR) and with normotensive Wistar-Kyoto rats (Y-WKY and A-WKY). Arterial blood pressure was measured in these animals at the end of the experimental protocol. Additionally, Na(+)/H(+) exchanger isoform 3 (NHE3) function and expression in microvilli membrane vesicles were assessed in young animals. Results Mean arterial blood pressure of Y-SHR + IDPPIV was significantly lower than that of Y-SHR (104 +/- 3 vs. 123 +/- 5 mmHg, P < 0.01) and was similar to Y-WKY (94 +/- 4 mmHg, P > 0.05). Compared to Y-SHR, Y-SHR + IDPPIV exhibited enhanced cumulative urinary flow and sodium excretion and decreased NHE3 activity and expression in proximal tubule microvilli. In the A-SHR, sitagliptin treatment had no significant effect on either renal function or arterial blood pressure. Conclusion Our data suggest that DPPIV inhibition attenuates blood pressure rising in young prehypertensive SHRs, partially by inhibiting NHE3 activity in renal proximal tubule. J Hypertens 29:520-528 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.