Vildagliptin

vildagliption vs gliptin vs OHA

1. Vildagliptin vs oha & vildagliptin vs other gliptin Dr. Khushboo Bhojwani, BDS, MSc Pharmaceutical Medicine

2. Table of content Diabetes Mellitus (DM) Pathogenesis and diagnosis of DM Pancreatic hormones mantaining glucose homeostasis Oral hypoglycemic agents (OHA) DPP4 inhibitors Vildagliptin Pharmacologic overview of vildagliptin Vildagliptin vs gliptins Comparision of various gliptins Gliptins vs OHA Overview of OHA Benefits and risk of gliptins vs OHA Vildagliptin monotherapy Vildagliptin combination therapy Adverse effects of vildagliptin vs gliptin & OHA Long term benefits of vildagliptin References

3. DIABETES MELLITUS Type 2 diabetes mellitus (T2DM) is a heterogeneous disease with multiple underlying pathophysiological processes characterized by hyperglycemia due to a progressive insufficiency of pancreatic β-cells in maintaining adequate regulatory levels of insulin secretion against backdrop of insulin resistance. Virtually all forms of DM are due to either a decrease in the circulating levels of insulin (insulin deficiency) or a decrease in the response of target tissue to insulin (insulin resistance). The hallmarks of DM are three polyps Polyuria - excessive urine production Polydipsia - excessive thirst Polyphagia - excessive eating

4. Pathogenesis and diagnosis of DM

5. Pancreatic cells secreting hormones maintaining glucose homesostasis Pancreas has both endocrine and exocrine functions. Scattered amongst the exocrine portion of the pancreas are million of tiny clusters of endocrine tissue called pancreatic islets or islets of langerhans which contain four type of cells secreting hormones Alpha cells Beta cells Delta cells F cells Glucagon and insulin are the two important endocrine hormones that maintain the glucose homesostasis .

6. ORAL HYPOGLYCEMIC AGENTS Oral hypoglycemic agents are used to treat type 2 DM as they have potential to decrease blood glucose to subnormal levels and also promote insulin relase from pancreatic B cells

7. Dipeptidyl Peptidase 4 inhibitors The DPP-4 inhibitor class of oral anti-diabetic agents selectively inhibits the DPP-4 enzyme that rapidly degrades two major incretin hormones, glucagon-like peptide-1 (GLP-1) and glucosedependent insulinotropic polypeptide (GIP) As a result, GLP-1 levels are increased and its actions prolonged. Consequently these drugs: Increase insulin secretion Decrease glucagon release Delay gastric emptying Suppress appetite

8. VILDAGLIPTIN The introduction of vildagliptin , a dipeptidyl peptidase-4 (DPP-4) inhibitor for the treatment of type 2 diabetes mellitus (T2DM) in 2007 provided clinicians with a novel and effective treatment option for lowering blood glucose , which neither caused weight gain nor increased the risk of hypoglycaemia . It is a potent, selective and orally active 2nd generation inhibitor of DPP-4, with a reversible and competitive mechanism of action (MOA) that binds and forms a complex with DPP-4, causing its inhibition. This results in improved glycemic control as determined by glycosylated haemoglobin (HbA1c) and fasting plasma glucose (FPG) levels plus an enhancement of pancreatic a-and β-cell function.

9. Pharmacologic overview of vildagliptin Vildagliptin has demonstrated ability to inhibit DPP-4, increase plasma concentrations of intact GLP-1 and GIP, reduce FPG and postprandial glucose (PPG ) and suppress plasma glucagon in clinical trials in T2DM patients. The drug improves hyperglycemia primarily by prolonging the half-lives of GLP-1 and GIP, thus enhancing their action on islet cells and promoting glucose-dependent insulin secretion and suppression of inappropriate glucagon secretion. Vildagliptin appears to attenuate the decline in glucosedependent β-cell function and improve insulin sensitivity, and also to enhance the sensitivity of α-cells to glucose Drug is quickly absorbed after oral administration, reaching peak plasma concentrations ( Cmax ) achieved in a time ( tmax ) of 1.5–1.7 hours after administration.43-45 Although the tmax is delayed to 2.5 hours and Cmax reduced by 19% when drug is administered with a high-fat meal, however these effects are not thought to be of any clinical significance and drug can be taken with any type of meal.

10. Plasma concentrations of vildagliptin increase in an approximately dose-dependant manner; the absolute bioavailability of the drug is 85%. Vildagliptin is primarily metabolized in the kidney to inactive cyano and amide metabolites and approximately 85% of the drug is eliminated in the urine (21–23% as the unchanged drug) and 15% into the faeces,43,45 with a terminal elimination half life of approximately 3 hours following oral administration, irrespective of drug dosage or food intake.

11. Vildagliptin VS Gliptins Although various DPP-4 inhibitors have different pharmacokineic and pharmodynamic profiles, they are remarkably similar with regards anti-hyperglycemic properties with a very safe adverse effect profile (weight neutral without causing hypoglycemia). The DPP-4 inhibitors based on their structure can be divided into those that mimic the DPP-4 molecule ( peptidomimetics , vildagliptin and saxagliptin ) and those that do not (non- peptidomimetics , sitagliptin , alogliptin , linagliptin ). They are competitive reversible inhibitors of the DPP-4 substrate acting extracellularly . The molecules have varying affinities toward the DPP-4 substrate. A list of available and expected gliptins are as follows : Sitagliptin (Merck Sharp and Dohme Corp, approvedas Januvia by US FDA in year 2006 ) Vidagliptin (Novartis, approved as Galvus by EU in year 2007 ) Saxagliptin (Bristol-Myers Squibb, approved as Onglyza by US FDA in 2010) Linagliptin ( Boerhinger Ingelheim , approved as Tradjenta by US FDA in year 2011 ) Alogliptin (developed by Takeda Pharmaceutical Company Limited, approved for use in Japan ) Dutogliptin (being developed by Phenomix Corporation ) Gemiglaptin (being developed by LG Life Science ( Sitagliptin , Vidagliptin , Saxagliptin -are-approved- foruse - in-India)

12. The mechanism of DPP-4 inhibition differs from peptidomimetics ( vildagliptin , saxagliptin ) compared to non- peptidomimetics ( sitagliptin , alogliptin , linagliptin ). Non- peptidomimetics form non-covalent extra-cellular interactions with residues in the catalytic site of the DPP-4 substrate, thereby resulting in potent, immediate inhibition . In contrast, inhibition of the DPP-4 substrate by peptidomimetics occurs in a manner that involves formation of a reversible covalent enzyme–inhibitor complex . This complex binds and dissociates from the catalytic site of the DPP-4 substrate very slowly resulting in persistent DPP-4 inhibition even after the drug has inactivated . This means that the catalytic activity remains inhibited even after the free drug has been cleared from the circulation and may help to explain why vildagliptin and saxagliptin inhibit DPP-4 activity for longer than their relatively short half-lives would suggest . Compared to the other gliptins , vildagliptin distinguishes itself by behaving like a surrogate substrate, being altered itself by the enzyme DPP-4. No head-to-head comparison clinical trials between the different gliptins are available at present, so that only indirect comparisons can be made. HbA1c lowering effects seem to be comparable over the spectrum of gliptins , whereas some studies indicate a greater reduction of fasting glycemia for sitagliptin  

13. Comparision between gliptins Sitagliptin - The recommended dose is 100 mg OD. Its absorption is unaffected by food and proven to be more effective at reducing fasting blood sugar compared to vildagliptin , but overall efficacy was similar . For patients with hepatic impairment no change in dose is recommended. Vildagliptin - The recommended dose is 50 mg BD. Its absorption is unaffected by food and extensively metabolized by the liver and has >90 % bioavailability following a single oral dose. No dosage adjustment is required for liver disease although a greater amount of inactive metabolites (30% greater) are retained in patients with severe liver disease. Linaligliptin - is recommended in the dose of 5 mg once a day. It has a favorable pharmacokinetic profile has a potential advantage over currently approved gliptins in that it primarily undergoes non-renal elimination. predominantly excreted via the enterohepatic system, with 84.7 % of the drug eliminated in the feces and only 5% eliminated via the urine. It therefore appears to be safe in patients with renal failure . Saxagliptin - The recommended dose is 5 mg once a day. Its absorption is unaffected by food . Saxagliptin is metabolized mainly by cytochrome P450. No dose adjustment is recommended for those with mild renal impairment or any degree of hepatic impairment.

14. Gliptins vs oha Metformin :   Metformin is generally the first choice for people with type 2 diabetes because of its safety, low cost and possible heart benefits. Metformin also lowers glucose production from the liver. Nausea and diarrhea are possible side effects and usually go away within 1 to 2 weeks as your body gets used to the medicine. It is associated with a low risk of hypoglycemia and does not cause weight gain. DPP-4 inhibitors:  These medications work to lower blood glucose by increasing insulin levels after meals and lowering glucagon levels (a hormone that raises blood glucose). They do not cause weight gain and are associated with a low risk of hypoglycemia. SGLT2 inhibitors:  These medications work by eliminating glucose into the urine. Side effects may include genital yeast infections, urinary tract infections, increased urination and low blood pressure. They are associated with weight loss and a low risk of hypoglycemia. Insulin secretagogues ( meglitinides , sulfonylureas ):  These medications help your pancreas release more insulin. Possible side effects include hypoglycemia and weight gain.   Thiazolidinediones :  Like metformin , these medications make the body's tissues more sensitive to insulin. Side effects include weight gain and an increased risk of heart failure and fractures.

15. Overview of OHA (MOA and drug effect)

16. Benefits and risk of Gliptins vs Other OHA

17. Vildagliptin monotherapy Vildagliptin monotherapy The efficacy of vildagliptin has been confirmed in a number of controlled trials. Most trials were designed to examine the noninferiority of vildagliptin to the comparator. However, the comparison with other active OADs not only validated its efficacy, but also revealed that it is weight-neutral and has low risk of hypoglycemia vildagliptin (50 mg bid) with a SU ( gliclazide up to 320 mg/day). Similar reductions in HbA 1c  were found (−0.5% versus −0.6%), but vildagliptin was weight-neutral and posed little risk of hypoglycemia to patients. A study where patients were randomized to accept vildagliptin (50 mg bid) or metformin (2 g daily) revealed that after 2 years of treatment, a significant HbA 1c  reduction was noticed both in the vildagliptin (−1.0%) and metformin (−1.4%) groups. However, the metformin group had a twofold higher incidence of gastrointestinal adverse events.

18. Vilagliptin combination therapy Vildagliptin as an add-on therapy to metformin : Vildagliptin can work well with metforminFirst , vildagliptin improves islet function by increasing the sensitivity of the α- and β-cells to glucose, whereas metformin reduces hepatic glucose and improves insulin resistance. . It is rational to combine an agent primarily targeting insulin sensitivity within the pancreas, like vildagliptin , with an agent primarily targeting insulin resistance, like metformin . metformin also has a positive effect on promoting endogenous intact GLP-1 levels, presumably by increasing its synthesis but not inhibiting degradation. Subjects taking vildagliptin with metformin caused about two times elevations in fasting plasma GLP-1 than in taking vildagliptin alone, Vildagliptin as an add on therapy to other antidiabetic drugs: Vildagliptin had been added to other antidiabetic drugs, such as pioglitazone , and insulin in patients inadequately controlled with monotherapy . The reduction in HbA 1c  varied from 0.5% to 1.0% with different dosages of vildagliptin . Vildagliptin posed a low risk of hypoglycemia when combined with pioglitazone or insulin, and the weight gain was more apparent in the vildagliptin /insulin group

19. Adverse Effect vildagliptin vs gliptins & oha Dipeptidyl peptidase 4 inhibitors are generaly well tolerated. Their strength lies in the fact that they are weight neutral do not cause any significant hypoglycemia. A metaanalysis suggested an increased risk of nasopharyngitis (6.4 % for DPP4 inhibitor { sitagliptin > vildagliptin } vs. 6.1 % for comparator) headache (5.1% for DPP4 inhibitor ( vildagliptin > sitagliptin } vs 3.9% for comparator), urinary tract infection (3.2% for DPP4 inhibitor { sitagliptin = vildagliptin } vs 2.4% for comparator). Although rare an increased incidence of extremity pain was seen with DPP- 4 inhibitors. No increased incidences in gastro-intestinal side-effects were observed. Saxagliptin use has been linked with a reduction in lymphocyte count . Post-marketing surveillance has identified isolated rare cases of pancreatitis with use of DPP-4 inhibitors. For patients with hepatic insufficiency except for vildagliptin no dose adjustment is necessary for gliptins . Vildagliptin is not recommended for patients with alanine aminotransferase or aspartate aminotransferase more than three times the upper limit of normal . A meta-analysis comparing the risk of congestive heart failure between antihyperglycemic therapies found an increased risk with TZDs and DPP-4 inhibitors (driven by higher risk with saxagliptin ). Gastrointestinal side effects are more common with metformin , alpha glucosidase inhibitors, GLP-1 receptor agonists and orlistat than with other agents. Metformin is also associated with an approximate 2-fold increased incidence of vitamin B12 deficiency  and vitamin B12 levels should be measured periodically in people taking metformin or with signs or symptoms of deficiency (such as impaired proprioception or peripheral neuropathy). GLP-1 receptor agonists and, less commonly, DPP-4 inhibitors can cause nausea and GLP-1 receptor agonists can also cause diarrhea

20. Long term benefits of vildagliptin Vildagliptin showed long-term benefit for type 2 diabetes by preserving β-cell function and normalizing the lipid profile. Effect of vildagliptin on β-cell function: Studies of vildagliptin in patients with type 2 diabetes demonstrated improvements in meal-test derived markers of β-cell function The homeostatic model assessment-β was increased while the proinsulin to insulin ratio was decreased by vildagliptin Clinical trials have also demonstrated that the insulin demand was brought down by adding vildagliptin , which achieved a negative caloric balance Effect of vildagliptin on plasma lipids: The lipid profile is an important determinant of cardiovascular risk in type 2 diabetes. It is conceivable that glucose-lowering agents have a positive impact on the lipid profile due to the close relationship between glucose and lipid metabolism. A meta-analysis showed that vildagliptin significantly reduced the total cholesterol level.

21. references Gupta, V., & Kalra , S. (2011). Choosing a gliptin .  Indian journal of endocrinology and metabolism ,  15 (4), 298–308. doi:10.4103/2230-8210.85583 Pi- Sunyer FX, Schweizer A, Mills D, Dejager S. Efficacy and tolerability of vildagliptin monotherapy in drug-naïve patients with type 2 diabetes. Diabetes Res Clin Pract . 2007;76:132–8 Scheen AJ. Pharmacokinetics of dipeptidylpeptidase-4 inhibitors. Diabetes Obes Metab . 2010;12:648–58. Diagnosis and Classification of Diabetes Mellitus (2004) American Diabetes Association Diabetes Care 27: S1. Monami M, Iacomelli I, Marchionni N, Mannucci E. Dipeptidyl peptidase-4 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis. 2010;20(4):224–35. Kim NH, Sung YA, Ahn CW, et al. Efficacy and safety of add-on vildagliptin to metformin in comparison to uptitrating metformin therapy.Diabetes . 2012;61( Suppl 1):A297.