DPP-4 inhibitors work by inhibiting the breakdown of the incretin hormones GLP-1 and GIP, prolonging their effects and enhancing insulin secretion. They reduce blood glucose levels with a low risk of hypoglycemia and are weight neutral. Several DPP-4 inhibitors are available or in development for treating type 2 diabetes, including sitagliptin, saxagliptin, and linagliptin. DPP-4 inhibitors offer an effective treatment either alone or in combination with other drugs, with advantages like fewer side effects, safety in hepatic or renal impairment, and possible cardiovascular benefits. More research is still needed to fully evaluate their long-term safety profile.

1. DPP – 4 Inhibitors :
Mechanism of Action& Role
in DM - 2 Management
Dr. Arun Sharma

2. BRIEF INTRODUCTION : T2DM
 Prevalent chronic healthcare disease with a significant
global disease burden.
 Achieving specific glycemic goals substantially
reduces morbidity & have made the effective treatment
of hyperglycemia a top priority.
 Intensive glycemic control has a powerful beneficial
effect on diabetes-specific complications.
 Development of new classes of blood glucose-
lowering medications has increased the number of
treatment options.

3. DPP-4 Inhibitors : A Novel
approach in T2DM Management
 DPP 4 inhibitors inhibit the breakdown of Incretin peptide hormones
and increase the Incretin effect in patients with type 2 DM.
 Their development was based on observations that factors
secreted from gut participated in regulation of pancreatic endocrine
secretion.These gut factors were termed “Incretins”.
 Two Incretin peptide hormones have been identified in
humans,namely Glucose dependent insulin releasing polypeptide
(GIP) and Glucagon like peptide -1 (GLP-1)
 Incretins are rapidly inactivated by dipeptidyl peptidase-4 (DPP-4).
The DPP-4 inhibitors prolong the action of endogenous incretins,
enhancing the first-phase insulin response.

4. Incretins and glycemic
control
Adapted from 7. Drucker DJ. Cell Metab. 2006;3:153–165. 8. Miller S, St Onge EL. Ann Pharmacother 2006;40:1336-1343.
Active
GLP-1 and GIP
Release of
incretin gut
hormones
Pancreas
Blood
glucose
control
GI tract
 Glucagon
from alpha cells
(GLP-1)
Glucose
dependent
Alpha cells
Increased insulin
and decreased
glucagon
reduce
hepatic
glucose output
Glucose dependent
 Insulin
from beta cells
(GLP-1 and GIP)
Beta cells
Insulin
increases
peripheral
glucose
uptake
Ingestion
of food
DPP-4
enzyme
rapidly
degrad
es
incretins

5. Functions of Incretins

6. DPP – 4 Inhibitors in Clinical
Practice
A list of available and expected gliptins :
 Sitagliptin (Merck Sharp and Dohme Corp, approved as 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)
 Gemigliptin (being developed by LG Life Sciences)
 Linagliptin has recently been approved in India.
 In clinical trials,most of these drugs have been shown to reduce HbA1c significantly when used
either as monotherapy or in combination with Metformin, Sulphonylureas or a combination of
both.
 They are also associated with lower rates of hypoglycemia and have also been shown to be
weight neutral.

7. Comparative Pharmacokinetic
Profile

8. Advantages of Using DPP – 4
Inhibitors
 As Monotherapy : Shown to be equally efficacious as compared to other
antidiabetic agents with added advantage of lesser incidence of
hypoglycemia and being weight neutral.
 As Initiation Therapy : Can be safely coupled with Metformin as an Inititaion
therapy as per the latest guidelines (ADA guideline)
 Insulin dose can be reduced if given with gliptins as a combination therapy.
 No significant drug – drug interaction with other drugs so can be given
safely with anti-hypertensives,anti-hyperlipidemics & antibiotics.
 Cardiac friendly profile :Studies suggest that DPP-4 inhibitors have a
cardiovascular friendly profile. Preclinical studies have suggested
endothelial benefit, anti-atherosclerotic effects and blood pressure lowering
effects.

9. Advantages of Using DPP – 4
Inhibitors : Continued
 Safe in Hepatic Inefficiency : For patients with hepatic
insufficiency, except for vildagliptin, no dose adjustment
is necessary for gliptins.
 Safe in Renal Insufficiency :Linagliptin is safe in renal
insufficiency.Other gliptins can be used safely with dose
adjustments.
 Well Tolerated in most people with not much significant
adverse event profile.

10. Conclusion
 Need for newer medications in T2DM
Management.
 DPP - 4 Inhibitors offer a promising treatment
modality in T2DM.
 Need for continued research to evaluate long
term safety and adverse event profile in
patients.

11. References
 Indian Journal Of Endocrinology &
Metabolism 2011 Oct-Dec; 15(4): 298–308.
 www.Diabetesincontrol.com
 www.diabetesjournals.org
 www.qjmed.oxfordjournals.org

12. THANK YOU
Dr. Arun Sharma
M.B.B.S.