PHARMACOLOGICAL MANAGEMENT OF

DIABETES – OHA
Mechanism of Action: Oral Hypoglycemic Agents

SGLT2i
 Sulphonylureas and CV risk

• University Group Diabetes Program (UGDP) trial (1975):

Tolbutamide associated with increased mortality*

• UKPDS (1998): Outcome of sulfonylureas was inferior to

metformin in overweight patients.**

• RECORD(2009) trial: Incident cardiovascular events with

glibenclamide were similar to those of rosiglitazone.***

* Diabetes 1975; 24:65–184. ** Lancet 1998; 352: 837–853

*** (RECORD): a multicentre, randomised, open-label trial. Lancet 2009; 373: 2125–2135..
 Sulphonylureas and CV risk

• Glimepiride has fewer cardiac actions than

other SUs, then this would have important
implications for its preferred use in the
treatment of T2D with concurrent CAD.

J Am Coll Cardiol. 1998;31(5):950-956. doi:10.1016/S0735-1097(98)00038-2

Diabetes Care 24:738–742, 2001
 2015
Sulphonylureas and CV risk

• Not all Sulphonylureas have same CV effects

• Glimipride better than others in terms of lower Cardiovascular

and All Cause Mortality

Lancet Diabetes and Endocrinology, Vol 3, 43-51, 2015

 Effects of Thiazolidinediones

Receptor Dependent Receptor Independent Effect

Effect

PPAR  activation
Edema, bone loss, Improved insulin sensitivity,
Negative vascular
lower glucose, insulin, lipids
effects
blood pressure
Higher binding affinity to PPAR  leads to more side
effects
The relative binding affinity to PPAR : Rosi > Pio
D. L. Fienstein etal. J Bioc Pharmaco 2005;70:177-188
 Pioglitazone – Mechanism of action

Increases GLUT 4 transcription

Increases new Adipocyte formation – hence new storage site for
triglyceride and FFA –weight gain
Increases ADIPONECTIN
Decreases TNF , IL-6 , resistin
TZD – acts mainly by ADIPOCYTE recruitment and ADIPOKINE
production

Trends in Endocrinology and Metabolism 23(5):205-15 · April 2012

 Efficacy of Thiazolidinediones

Place in therapy:2nd to 3rd line agent

HBA1c reduction by 1 – 1.5 %
Helps in fasting and post prandial blood glucose
Onset of action by 4 weeks
Maximum glycemic control by 12 weeks

Prescribing Information Pioglitazone, August 2007

 Advantages of Thiazolidinediones
Favorable lipid profile: Pioglitazone decreases LDL,TG
Slight increase in HDL
Risk of hypoglycemia is low
Mechanism of action: Increases insulin sensitivity in cells
Reduces beta cell apoptosis rate
Prevention of Type 2 diabetes

Aust Prescr 2004;27:67–70

The risk of stroke or MI was lower among patients who
received pioglitazone than who received placebo

The New England Journal of Medicine, February 17, 2016

 Pioglitazone halved the risk of developing diabetes in
patients with IR and CVD

Progression to diabetes occurred less often in participants in the pioglitazone

versus placebo group: 73 (3.8%) versus 149 (7.7%) ( p value,0.0001) in the
IRIS trial.
Pioglitazone is the first medication shown to prevent both progression to
diabetes and major cardiovascular events.

Diabetes Care 2016 Jul; dc160798

Protection effects of Pioglitazone relating to various
organs
 Mechanism of action of AGIs

Voglibose exerts a good glucose-lowering effect

Expert Opin. Pharmacother. (2015) 16(13):1959-
1981
 Dual mechanism of action of AGIs/Voglibose

Insulin sparing effects

1. AGIs reduce plasma insulin and C-peptide conc. Beneficial

effect on Metabolic Syndrome
2. Combine incretin enhancement with insulin suppression, therefore, is
the treatment of choice in Type 2 diabetes.
AGIs inhibit a-glucosidase in the proximal
SI, allow large amounts of undigested
carbohydrates to reach the distal SI

Ileum, which is rich in entero-endocrine L-

cells, produces GLP-1 upon exposure to
nutrients

AGIs stimulate a long-lasting, sustained

rise in endogenous GLP-1
Expert Review of Endocrinolog
 Effect of Voglibose on Postprandial Hyperglycemia in
T2 DM Patients

Changes in plasma glucose (A) and insulin (B) concentrations before (O) and
after ( • ) 4 weeks of therapy with voglibose. Results are means ± SE. *P <
0.05 vs. before treatment. **P < 0.01 vs. before treatment.
Kawagishi T. Diabetes Care, Volume 20, Number 10, October 1997.
Glycemic parameters of Voglibose

Br J Med Health Res. 2016;3(5)

 DPP-4 Inhibitors corrects the Basic
Pathophysiological defects of T2DM
Ingestion
of food Glucose dependent
 Insulin Insulin
from beta cells increases
(GLP-1 and GIP) peripheral
glucose
GI tract Release of Pancreas uptake
incretins from
the gut
β-cells
α-cells Improved
GLP-1, GIP Hyperglycemia
Physiologic
Glucose Control

X
DPP-4
Enzyme Glucagon
↑ Insulin and
↓ Glucagon
from alpha cells reduce hepatic
DPP-4 (GLP-1) glucose
Inhibitor Glucose dependent output
Inactive
incretins DPP-4 = dipeptidyl peptidase 4

Adapted from Brubaker PL, Drucker DJ Endocrinology 2004;145:2653–2659; Zander M et al Lancet 2002;359:824–830; Ahrén B Curr
Diab Rep 2003;3:365–372; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483.
 DPP4i: Pleiotropic Benefits

Cardiovascular effect of dipeptidyl peptidase-4 (DPP4)/incretin axis 30

Circ Res. 2015 Apr 10;116(8):1491-504.
 Several clinical trials have now
shown an excellent safety
profile of gliptin therapy in
cardiovascular risk patients.

Based on the available studies,

DPP4 inhibitors seem to
represent a promising
therapeutic approach for the
treatment of vascular diseases
Potential therapeutic implications of
in addition to glucose control
pharmacological dipeptidyl peptidase 4
inhibition
 DPP-4 Inhibitors in the market for treatment of
T2DM
Pharmacological Action Dosage (mg) Dosing
Agent Frequency

Vildagliptin Short Acting 50 Twice daily

Sitagliptin Short Acting 100 Once Daily
Linagliptin Short Acting 5 Once Daily
Saxagliptin Short Acting 2.5-5 Once Daily
Teneligliptin Short Acting 20-40 Once Daily
Gemigliptin Short Acting 50 Once Daily
Alogliptin Short Acting 25-50 Once Daily
Anagliptin Short Acting 100 Once Daily
Omarigliptin Long Acting 25 Once weekly
Trelagliptin Long Acting 25-100 Once weekly
Curr Opin Lipidol. 2016 Oct;27(5):484-92
 24-Hour DPP- 4 inhibition with Gliptins

≥80% DPP4 inhibition?

Vildagliptin 100 mg/day Yes

Sitagliptin Yes

Saxagliptin ~70%
Linagliptin Yes

Gemigliptin Reference: Scheen etal,~70%

Expert Opin Pharmacother (2012) 13(1): 81-99
Roberta Baetta and Alberto Corsini , Drugs 2011; 71 (11): 1441-1467

Data not from the same study, only for overview

24-hours DPP4 inhibition1

Teneligliptin 20 mg 53.9
33
Teneligliptin 40 mg 59.8%
1. PMDA - Report on the Deliberation Results: Review Report – Teneligliptin Hydrobromide Hydrate.
Submitted by Mitsubishi Tanabe Pharma Corporation. Published on April 5, 2012
Absolute HbA1c reduction at different FPG levels
with DPP-4 inhibitors
FPG 150
Vildagl Alogli Sitagli Saxagli Linagli
A1c iptin ptin ptin ptin ptin
7.6 -0.86 -0.79 -0.74 -0.65 -0.48
7.8 -0.92 -0.88 -0.83 -0.74 -0.59
8.0 -1.06 -0.96 -0.92 -0.84 -0.68
8.2 -1.16 -1.06 -1.01 -0.94 -0.77
8.4 -1.24 -1.16 -1.1 -1.03 -0.86
8.6 -1.34 -1.26 -1.21 -1.12 -0.96
8.8 -1.42 -1.35 -1.31 -1.23 -1.06
FPG 160
Vildagl Alogli Sitagli Saxagli Linagli
A1c iptin ptin ptin ptin ptin
7.6 -0.76 -0.69 -0.64 -0.55 -0.38
7.8 -0.82 -0.78 -0.73 -0.64 -0.49
8.0 -0.96 -0.86 -0.82 -0.74 -0.58
8.2 -1.06 -0.96 -0.91 -0.84 -0.67
8.4 -1.14 -1.06 -1 -0.93 -0.76
8.6 -1.24 -1.16 -1.11 -1.02 -0.86
8.8 -1.32 -1.25 -1.21 -1.13 -0.96
FPG 170
Vildagl Alogli Sitagli Saxagli Linagli
A1c iptin ptin ptin ptin ptin
7.6 -0.66 -0.59 -0.54 -0.45 -0.28
7.8 -0.72 -0.68 -0.63 -0.54 -0.39
8.0 -0.86 -0.76 -0.72 -0.64 -0.48
8.2 -0.96 -0.86 -0.81 -0.74 -0.57
8.4 -1.04 -0.96 -0.9 -0.83 -0.66
8.6 -1.14 -1.06 -1.01 -0.92 -0.76
8.8 -1.22 -1.15 -1.11 -1.03 -0.86

FPG 180
FPG 190
Vildagli Aloglip Sitagli Saxagli Linagli
Vildagl Alogli Sitagli Saxagli Linagli
A1c ptin tin ptin ptin ptin
A1c iptin ptin ptin ptin ptin
7.6 -0.56 -0.49 -0.44 -0.35 -0.18
7.6 -0.46 -0.39 -0.34 -0.25 -0.08
7.8 -0.62 -0.58 -0.53 -0.44 -0.29
7.8 -0.52 -0.48 -0.43 -0.34 -0.19
8.0 -0.76 -0.66 -0.62 -0.54 -0.38
8.2 -0.86 -0.76 -0.71 -0.64 -0.47 8.0 -0.66 -0.56 -0.52 -0.44 -0.28
8.4 -0.94 -0.86 -0.8 -0.73 -0.56 8.2 -0.76 -0.66 -0.61 -0.54 -0.37
8.6 -1.04 -0.96 -0.91 -0.82 -0.66 8.4 -0.84 -0.76 -0.7 -0.63 -0.46
8.8 -1.12 -1.05 -1.01 -0.93 -0.76 8.6 -0.94 -0.86 -0.81 -0.72 -0.56
8.8 -1.02 -0.95 -0.91 -0.83 -0.66

Reduction with Vildagliptin is highest across all baseline

of HbA1c & FPG BMJ Open 2015;5:e005892.
 CV Trials with Gliptins
Gliptin Study name RR (95% CI) for RR (95% CI) for
MACE HF

Sitagliptin TECOS 1 [0.908 - 1.101] 0.997 [0.832;

1.194]

Saxagliptin SAVOR-TIMI-53 0.998[0.896 - 1.112] 1.257 [1.060;

1.491]

Alogliptin EXAMINE 0.957 [0.826 - 1.110] 1.067 [0.789;

1.443]

Vildagliptin McInnes G. et al 0.82 (0.61-1.11) 1.08 (0.68-1.70)

2015 (Meta-analysis of 40
studies)
Schweizer A, et al. (Meta- 0.84 (0.62–1.14) -
analysis of 25 studies)
Bekiari et al. (Meta-analysis 0.91 (0.73 to 1.14) 0.77 (0.46-
of 9 studies) 1.30)

Teneligliptin No data available - -

Gemigliptin No data available - -
 2015
DPP-4 Inhibitors and CV risk
TECOS (Sitagliptin): Summary of Results
• For the primary composite cardiovascular outcome
(CV death, nonfatal MI, nonfatal stroke, or hospitalization for
unstable angina) sitagliptin, compared with placebo, was
noninferior, and not superior
• For the secondary composite cardiovascular outcome
(CV death, nonfatal MI, or nonfatal stroke) sitagliptin, compared
with placebo, was noninferior, and not superior
• The rate of hospitalization for heart failure did not differ
between sitagliptin and placebo treatment groups

Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

 Right selection of Gliptin matters
• DPP-4 inhibitors have revolutionized the management of type 2
diabetes mellitus (T2DM).

• These agents have a distinct place in therapy, by virtue of the

advantage of weight neutrality and low risk of hypoglycemia.

• DPP-4 inhibitors therapy is associated with:

– Clinically significant decrease in HbA1c maintained throughout
treatment
– Good CV safety profile
– Proven renal safety
– No increased risk of bone fracture
– Pancreatitis no longer an issue
 SGLT2i: Novel Insulin independent AHA
Most AHAs SGLT2i
Insulin dependent Insulin-independent
1 Insulin action
•Thiazolidinediones
•Metformin

Adipose tissue, muscle and liver

2 Insulin release
•Sulphonylureas
•GLP-1R agonists*
•DPP4 inhibitors* Pancreas
•Meglitinides
3 Insulin replacement
•Insulin
Excess Glucose excretion
Caloric loss - weight loss*
Glucose utilisation BP reduction#
*In addition to increasing insulin secretion, which is the major mechanism of action, GLP-1 agonists and DPP4 inhibitors also act to decrease glucagon secretion.
DDP4, dipeptidyl peptidase-4; GLP-1R, glucagon-like peptide-1 receptor; SGLT2, sodium-glucose co-transporter-2.
1. Washburn WN. J Med Chem 2009;52:1785–94; 2. Bailey CJ. Curr Diab Rep 2009;9:360–7; 3. Srinivasan BT, et al. Postgrad Med J 2008;84:524–31; 4. Rajesh R, et al. Int J
Pharma Sci Res 2010;1:139–47.
*Not indicated for weight loss; #Not indicated for hypertension
 SGLT2i: Novel Insulin independent AHA
Most AHAs SGLT2i
Insulin dependent Insulin-independent
1 Insulin action
•Thiazolidinediones
•Metformin

Adipose tissue, muscle and liver

2 Insulin release
•Sulphonylureas
•GLP-1R agonists*
•DPP4 inhibitors* Pancreas
•Meglitinides
3 Insulin replacement
•Insulin
Excess Glucose excretion
Caloric loss - weight loss*
Glucose utilisation BP reduction#
*In addition to increasing insulin secretion, which is the major mechanism of action, GLP-1 agonists and DPP4 inhibitors also act to decrease glucagon secretion.
DDP4, dipeptidyl peptidase-4; GLP-1R, glucagon-like peptide-1 receptor; SGLT2, sodium-glucose co-transporter-2.
1. Washburn WN. J Med Chem 2009;52:1785–94; 2. Bailey CJ. Curr Diab Rep 2009;9:360–7; 3. Srinivasan BT, et al. Postgrad Med J 2008;84:524–31; 4. Rajesh R, et al. Int J
Pharma Sci Res 2010;1:139–47.
*Not indicated for weight loss; #Not indicated for hypertension
 Treatment with an SGLT2 inhibitor:
Clinical benefits in type 2 diabetes
mellitus

1Holman RR, et al. N Engl J Med 2008;359:1577-89; 2Neumiller JJ. Drugs 2010;70:377-85; 3Lo MC, et al. Am J Ther 2010 [Epub ahead of
print].
Powerful HbA1c reduction:
As suggested by NICE guidelines
 EMPA-REG OUTCOME®: Summary
• Empagliflozin reduced hospitalisation for heart failure by 35%

• Empagliflozin reduced CV death by 38%

• Empagliflozin improved survival by reducing all-cause

mortality by 32%

42 CV, cardiovascular
 SGLT2i as a class have benefits on
various CV risk factors

BP1
Glucose1
Arterial
Insulin1
stiffness1

Weight1
HDL-C1
Visceral
Triglycerides1
adiposity1
Potential
& Novel
pathways of
CV effects of
Uric Acid1
Albuminuria 1 SGLT2i1
Magnesium4

Mild Ketonemia
Natriuresis/ Oxidative
SNS activity (Thrifty
(?) 1 Blood Substrate
stress1
Volume1,3 Hypothesis)2
1. Diab Vasc Dis Res. 2015 Mar; 12(2): 90–100
2. Diabetes Care 2016;39:1108–1114
3. Heerspink HJ, et al. Circulation. 2016 Sep 6;134(10):752-72. SNS: Sympathetic Nervous System
4. Tang H, et al. Diabetologia. 2016 Sep 15. [Epub ahead of print]