Dpp 4 inhibitors

Dpp 4 inhibitors

• 5.
   These areantidiabetic drugs that improve glycaemic control without causing weight gain or increasing hypoglycaemic risk in patients with type 2 diabetes mellitus (T2DM).  The eight available DPP-4 inhibitors, includes: Alogliptin Anagliptin Gemigliptin Linagliptin Saxagliptin Sitagliptin Teneligliptin Vildagliptin
• 6.
   Dipeptidyl peptidase-4inhibitors may be classified into:  Peptidomimetic (i.e., sitagliptin, teneligliptin, vildagliptin, saxagliptin, and anagliptin)  Non-peptidomimetic (i.e., alogliptin and linagliptin) subtypes (Fig).
• 7.
  Table 1 Clinicalpharmacokinetic and pharmacodynamics properties of selective DPP-4 inhibitors Continue..
• 8.
  Table 1 (continued)
• 9.
  DPP-4 inhibitors suppressthe enzymatic activity of DPP-4, resulting in an increase in incretin levels (GLP-1 and GIP), which subsequently inhibit glucagon release and glucose production in the liver and increase insulin secretion and glucose uptake in skeletal muscle. Consequently, it leads to a decrease in blood glucose level. GLP- 1, glucagon-like peptide 1; GIP, gastric inhibitory polypeptide.
• 10.
  • Alogliptin selectivelyinhibits DPP-4 with an IC50 of 7 nmol/L and has exhibited more than 14 000-fold selectivity over the related serine proteases DPP-8 and DPP-9. • Anagliptin Potent inhibitor for DPP-4, with an IC50 of 3.4 nmol/L. • Gemigliptin is a potent, competitive, reversible, long-acting DPP-4 inhibitor (IC50 = 16 nmol/L) with over 3000- fold selectivity over other DPP-2, DPP-8, DPP-9, elastase, trypsin, urokinase, and cathepsin G • Linagliptin has greater potency than other DPP-4 inhibitors (IC50 = ~1 nmol/L for linagliptin vs 19, 62, 50 and 24 nmol/L for sitagliptin, vildagliptin, saxagliptin and alogliptin, respectively. • Teneliigliptin with IC50 of 1.75 nmol/L • Vildagliptin is a potent, competitive, and reversible inhibitor for DPP-4, with an IC50 of 3.5 nmol/L. Diabetes, Obesity and Metabolism 13: 7–18, 2011
• 11.
   ALOGLIPTIN -Takeda Pharmaceuticals (Osaka, Japan), FDA approval January 2013  Alogliptin selectively inhibits DPP-4 with an IC50 of 7 nmol/L and has exhibited more than 14 000-fold selectivity over the related serine proteases DPP-8 and DPP-9.  Single-dose administration of alogliptin to healthy subjects resulted in a peak inhibition of DPP-4 within 2–3 h after dosing.  Single doses of alogliptin from 25 to 800 mg produced peak DPP-4 inhibition ranging from 93.3% to 98.8%.  FDA of the US approved the drug in three formulations: as a standalone, in combination with metformin (Kazano) or with pioglitazone (Oseni). Clinical and Experimental Pharmacology and Physiology (2015) 42, 999–1024
• 12.
   ANAGLIPTIN- wasdeveloped by Sanwa Kagaku Kenkyusho Co. (Mie, Japan) and approved by the PMDA of Japan in September 2012.  Potent inhibitor for DPP-4, with an IC50 of 3.4 nmol/L  oral dose of 100 mg in healthy subjects were 98.2 % recovered within 168 h, with 73.2% in urine and 25.0% in faeces  Peak plasma is achieved within 1.8 hr of postdose  Mean fraction of the dose absorbed was > 73%. Clinical and Experimental Pharmacology and Physiology (2015) 42, 999–1024
• 13.
   GEMIGLIPTIN- LGLife Science (Seoul, Korea) and Double-Crane Pharmaceutical Co. (Beijing, China).  Approval from Korea Food & Drug Administration in June 2012.  Gemigliptin is a potent, competitive, reversible, long-acting DPP-4 inhibitor (IC50 = 16 nmol/L) with over 3000-fold selectivity over other DPP-2, DPP-8, DPP-9, elastase, trypsin, urokinase, and cathepsin G  At oral dose of ≥ 200 mg of gemigliptin inhibited plasma DPP-4 activity by > 80% over a 24-h dosing interval in healthy subject.  Gemigliptin exhibited linear kinetic properties over the range of 50–400 mg Clinical and Experimental Pharmacology and Physiology (2015) 42, 999–1024
• 14.
   LINAGLIPTIN –Develop by Tradjenta & Trajenta;was approved by the FDA in May 2011  It is used as a monotherapy or in combination with metformin (Jenadueto).  Linagliptin has greater potency than other DPP-4 inhibitors (IC50 = ~1 nmol/L for linagliptin vs 19, 62, 50 and 24 nmol/L for sitagliptin, vildagliptin, saxagliptin and alogliptin, respectively)  peak plasma concentrations of linagliptin occurred at approximately 1.5 h postdose.  Linagliptin shows modest oral bioavailability, but is rapidly absorbed.  The absolute bioavailability of linagliptin is around 30%.  Following oral administration, the majority (about 90%) of linagliptin is excreted unchanged. Clinical and Experimental Pharmacology and Physiology (2015) 42, 999–1024
• 15.
   SAXAGLIPTIN (Onglyza);co-developed by Bristol-Myers Squibb and AstraZeneca was approved by the FDA in July 2009.  It is also used in combination with metformin (Kombiglyze XR).  Cmax and AUC values of saxagliptin and its active metabolite increased proportionally in the 2.5–400 mg dose range.  Single oral dose of 5 mg saxagliptin, the mean plasma t½b for saxagliptin and its active metabolite was 2.5 and 3.1 h, respectively Clinical and Experimental Pharmacology and Physiology (2015) 42, 999–1024
• 16.
   SITAGLIPTIN isthe first DPP-4 inhibitor developed by Merck & Co. , approved by the FDA in October 2006.  50 mg sitagliptin and 500 or 1000 mg metformin was approved by FDA in April 2007.  Sitagliptin markedly and dose-dependently inhibited ~80% of plasma DPP-4 activity over 24 h.  Peak plasma concentrations occurring 1–4 h postdose.  Single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 µmol/L per h, Cmax was 950 nmol/L, and apparent t½ß was 12.4 h. Clinical and Experimental Pharmacology and Physiology (2015) 42, 999–1024
• 17.
   TENELIGLIPTIN wasdeveloped by Mitsubishi Tanabe Pharma (Osaka, Japan) and gained approval from the PMDA of Japan in September 2012.  Teneligliptin significantly inhibited human plasma DPP-4 and recombinant human DPP-4 activity, with IC50 of 1.75 nmol/L and 0.889 nmol/L (Ki = 0.406 nmol/L), respectively.  In human, teneligliptin is metabolized to five metabolites, M1, M2, M3, M4, and M5, which all show some DPP-4 inhibitory activity.  Plasma Cmax on oral administration of 10 or 20 mg once daily for 4 weeks was 125.0 and 274.5 ng/mL, respectively, with a Tmax of 1.0 h in both groups and a mean t1/2b of 20.8 and 18.9 h, respectively Clinical and Experimental Pharmacology and Physiology (2015) 42, 999–1024
• 18.
   VILDAGLIPTIN, gainedapproval from the European Medicines Agency (EMEA) in February 2008.  Its approval in the US is still pending. In the meantime, the EMEA has also approved a combination use of vildagliptin with metformin (brand name: Eucreas).  Vildagliptin is a potent, competitive, and reversible inhibitor for DPP-4, with an IC50 of 3.5 nmol/L.  Its oral bioavailability was 85%, peak plasma concentrations 1.7 hr, plasma protein binding 9.3% , mean volume of distribution (Vss) was 70.5 L  Following oral administration of [14C] vildagliptin, ~85% of the dose was excreted into the urine and 15% of the dose is recovered in the faecesClinical and Experimental Pharmacology and Physiology (2015) 42, 999–1024
• 20.
   1768 patientsreceive alogliptin 12.5 mg, alogliptin 25 mg, or placebo once daily for 26 week.  25 mg alogliptin group (n = 128) had a reduction of - 0.6% HbA1C, with 44% of HbA1C ≤ 7.0% at week 26.  Alogliptin 12.5 and 25 mg have significant improvements of HbA1C and fasting plasma glucose (FPG) compared to placebo at week 26
• 21.
   A totalof 109 patients were randomized to 100 mg (n=37) or 200 mg (n=33) anagliptin twice daily or placebo (n=39).  100 mg and 200 mg shows reductions in HbA1c (-0.50 ± 0.45 % and -0.51 ± 0.55%, respectively).  Placebo treatment resulted in an increase in HbA1c by 0.23 ± 0.62 %.  >75% and >90% inhibitions were observed during the meal tolerance tests with 100 mg and 200 mg anagliptin, respectively. Endocrine Journal 2015, 62 (5), 449-462
• 22.
   145 T2DMpatients treated with 50,100 or 200 mg gemigliptin for 12 week.  All three doses of gemigliptin significantly reduced the HbA1C from baseline compared to the placebo group (- 0.06 vs - 0.98, - 0.74 and - 0.78% in the placebo and 50, 100 and 200 mg groups, respectively)
• 23.
   336 T2DMpatients treated with 5 mg once daily linagliptin for 24 week.  47.1 % Patients treated with linagliptin achieve a reduction in HbA1c of ≥0.5% vs placebo arm 19.0%.  Fasting plasma glucose improved by -1.3 mmol/l (p < 0.0001) with linagliptin vs. placebo  Monotherapy with linagliptin produced a significant, clinically meaningful and sustained improvement in glycaemic control Diabetes Obes Metab. 2011 Mar;13(3):258-67.
• 24.
  No evident associationbetween the application of saxagliptin and the incidence of gastrointestinal adverse events, infections, hypersensitivity, pancreatitis, skin lesions, lymphopenia, thrombocytopenia, hypoglycaemia, bone fracture, severe cutaneous adverse reactions, opportunistic infection, angioedema, malignancy, and worsening renal function, the patients still need to be cautious to initiate the saxagliptin treatment.
• 25.
   Metanalysis of14 trials containing 3415 people taking sitagliptin at range of 25 mg – 200 mg daily.  Sitagliptin lowers HBA1c by 0.7% in sitagliptin versus placebo trials.  Cochrane review show that the drug is well tolerated, causes no hypoglycaemia and is weight neutral. No specific signals of concern for the safety of sitagliptin have so far arisen in the pooled database. Clinical Medicine: Therapeutics 2009: 1
• 26.
   324 T2DMpatients were treated with placebo, 10 mg, 20 mg, or 40 mg teneligliptin for 12 week.  10, 20, and 40 mg teneligliptin reduced the HbA1C levels 0.77%, 0.80%, and 0.91%, respectively.
• 27.
   632 T2DMwere treated with 50 mg qd, 50 mg bid, or 100 mg qd for 24 week.  HbA1c reduced to greater extent in patients receiving vildagliptin 50 mg qd (Delta=-0.8+/-0 .1%), 50 mg bid (Delta=-0.8+/-0.1%), or 100 mg qd (Delta=-0.9+/- 0.1%,for all groups VS. placebo).  Vildagliptin monotherapy decreases HbA1c in drug-naïve patients without weigh gain and is well tolerated with minimal hypoglycemia. Horm Metab Res. 2007 Mar;39(3):218-23.
• 28.
   DPP-4 inhibitorsare distinctive in their metabolic properties, excretion, recommended dosage, and daily dosage, and head-to-head clinical trials comparing the various DPP-4 inhibitors are scarce, the available data regarding indirect comparisons suggest that all available DPP-4 inhibitors have nearly the same efficacy and safety profile.  The DPP-4 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 a- and b-cell function, leading to an improved profile of glucagon and insulin secretion patterns after meal. Clinical and Experimental Pharmacology and Physiology (2015) 42, 999–1024