sitagliptin-phosphate and Edema

Sitagliptin and vildagliptin represent a new class of anti-diabetic agents that enhance the action of incretin hormones through inhibition of dipeptidyl peptidase-4 (DPP-4), the enzyme that normally inactivates incretin hormones. Because of their distinct mechanism of action, DPP-4 inhibitors can be used as add-on therapy to other classes of drugs for treatment of type 2 diabetes. The objective of this review is to critically evaluate clinical trials of sitagliptin and vildagliptin in combination with pioglitazone. The addition of either sitagliptin or vildagliptin to ongoing pioglitazone therapy is associated with reduction in average hemoglobin A1c (HbA1c) levels of approximately 0.7% compared with placebo and 1% compared with baseline after 24 weeks. When started concomitantly in drug-naïve patients, the combination of pioglitazone 30 mg and vildagliptin 100 mg qd reduces HbA1c by 1.9% after 24 weeks, compared with 1.1% with pioglitazone monotherapy. In general, the addition of DPP-4 inhibitors to pioglitazone was well tolerated, did not increase the incidence of hypoglycemia, and did not substantially worsen the weight-gain induced by pioglitazone. The combination of sitagliptpin or vildagliptin with pioglitazone can be a useful therapeutic approach in patients with type 2 diabetes who cannot tolerate metformin or a sulfonylurea.

Topics: Adamantane; Blood Glucose; Body Weight; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Edema; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Lipids; Nitriles; Pioglitazone; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Thiazolidinediones; Treatment Outcome; Triazoles; Vildagliptin

Substance P (SP), an undecapeptide belonging to the tachykinin family, is released during the activation of sensory nerves, and causes vasodilation, edema and pain through activation of tissular Neurokinin 1 receptors. SP proinflammatory effects are terminated by angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP), while the aminopeptidase dipeptidylpeptidase IV (DPPIV) can also play a role. The aim of this randomized, crossover, double-blind study was to assess the cutaneous vasoreactivity (flare and wheal reaction, burning pain sensation) to intradermal injection of ascending doses of SP in six volunteers receiving a single therapeutic dose of the DPPIV inhibitor sitagliptin or a matching placebo. Cutaneous SP challenges produced the expected, dose-dependent flare and wheal response, while eliciting mild to moderate local pain sensation with little dose dependency. However, no differences were shown in the responses observed under sitagliptin compared with placebo, while the study would have been sufficiently powered to detect a clinically relevant increase in sensitivity to SP. The results of this pilot study are in line with proteolytic cleavage of SP by ACE and NEP compensating the blockade of DPPIV to prevent an augmentation of its proinflammatory action.

Topics: Capsaicin; Carbonated Beverages; Cross-Over Studies; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug Eruptions; Edema; Erythema; Humans; Injections, Intradermal; Male; Pain; Pyrazines; Sitagliptin Phosphate; Skin; Substance P; Triazoles; Vasodilation

Topics: Aged, 80 and over; Blood Sedimentation; C-Reactive Protein; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Edema; Humans; Male; Sitagliptin Phosphate; Synovitis

To validate the potential anti-inflammatory and analgesic role of sita- and vildagliptin, five different experimental models were used in mice: i) mustard oil-induced ear edema, ii) neutrophil accumulation, iii) mechanical and iv) thermal touch sensitivity in complete Freund's adjuvant-induced arthritis and v) capsaicin-induced plasma extravasation in the urinary bladder. For the complete examination period in i) the dose of 10mg sitagliptin as well as 1-10mg vildagliptin was found to significantly decrease ear edema as compared to positive control (p<0.05, n=8/group). All doses of sitagliptin provided an anti-inflammatory effect p<0.005 (n=10/group) in test ii) and an analgesic effect in iii) except 3mg. Vildagliptin was similarly effective in test ii) (p<0.005, n=10/group) as sitagliptin, but it failed to affect mechanical touch sensitivity. Unlike mechanical touch sensitivity, both gliptins could beneficially act on the thermal threshold (p<0.05, n=10/group). And only in tests v) could both gliptins reverse inflammation. Further studies are needed to support the suggestion that the utilization of these beneficial effects of gliptins may be considered in the treatment of Type 2 diabetic patients.

Topics: Adamantane; Allyl Compounds; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Capsaicin; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Freund's Adjuvant; Isothiocyanates; Male; Mice; Nitriles; Pyrrolidines; Sitagliptin Phosphate; Temperature; Urinary Bladder; Vildagliptin

Sitagliptin is a recent oral antidiabetic drug for type 2 diabetes patients. This report is the first case of a severe drug reaction with eosinophilia and systemic symptoms (DRESS), which resolved with systemic corticosteroids. However, vigilance is necessary during the prescription of these compounds.

Topics: Acute Kidney Injury; Aged; Back; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Ear; Edema; Eosinophilia; Exanthema; Female; Glucocorticoids; Humans; Prednisone; Pyrazines; Sitagliptin Phosphate; Triazoles