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 thecatalytic 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

14. 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.

16. 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.

17. OVERVIEW OF OHA
(MOA AND DRUG EFFECT)

18. BENEFITS AND RISK OF GLIPTINS VS OTHER OHA

19. 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
HbA1c 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 HbA1c 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.

20. 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 HbA1c 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

21. 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

22. 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.

23. 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.