Early Treatment to Manage Hyperglycemia :

Do We Have Enough Option ?

Dr. Olly Renaldi, SpPD-KEMD

SYMPTOM , SIGN , AND DIAGNOSTIC DIABETES

Symptoms and Signs of Diabetes

Fauci AS, et al, eds. Chapter 338. Diabetes mellitus. In: Harrison’s Online. McGraw-Hill.

www.accessmedicine.com. Accessed August 1, 2010;

South-Paul JE, et al. Chapter 34. Diabetes mellitus. In: Current Diagnosis & Treatment in

Family Medicine. 2nd edition. McGraw-Hill. www.accessmedicine.com.

Accessed August 1, 2010.

Central• Polydipsia• Polyphagia• Lethargy• Stupor

Systemic• Weight loss

Respiratory• Kussmaul breathing

(hyperventilation)

Eyes• Blurred vision

Breath• Smell of acetone

Gastric• Nausea• Vomiting• Abdominal pain

Urinary• Polyuria• GlycosuriaMore common in T1DM

Diagnostic Criteria for Diabetes

Mellitus

Fauci AS, et al, eds. Chapter 338. Diabetes mellitus. In: Harrison’s Online. McGraw-Hill.

www.accessmedicine.com. Accessed August 1, 2010;

American Diabetes Association. Diabetes Care. 2010;33(suppl 1): S11-S61.

Type of

Diabetes

Normal

Glucose

Tolerance

(NGT)

Hyperglycemia

Prediabetes Diabetes Mellitus

Impaired fasting

plasma glucose

(FPG) or impaired

glucose tolerance

(IGT)

Not

insulin requiring

Insulin required for

control

Insulin required for

survival

Type 1

Type 2

Other specific types

Gestational diabetes

Time (years)

FPG <5.6 mmol/L

(100 mg/dL)

5.6-6.9 mmol/L

(100-125 mg/dL)

≥ 7.0 mmol/L

(126 mg/dL)

2-h postprandial

glucose (PPG) (75-g

oral glucose

tolerance test

[OGTT])

<7.8 mmol/L

(140 mg/dL)

7.8-11.1 mmol/L

(140-199 mg/dL)

≥11.1 mmol/L

(200 mg/dL)

HbA1c < 5.7% 5.7%-6.4% ≥6.5%

PATHOPHYSIOLOGY OF T2DM

The Pathophysiology of Type 2 Diabetes

Includes 3Main Defects

6

Adapted from Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483; Buchanan TA Clin Ther 2003;25(suppl B):B32–B46; Powers AC. In: Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill, 2005:2152–2180;

Rhodes CJ Science 2005;307:380–384.

HyperglycemiaLiver

Insulin deficiency

Excess glucose output Insulin resistance (decreased glucose uptake)

Pancreas

Excess glucagon

Islet

Diminishedinsulin

Diminishedinsulin

Alpha cell

produces excess

glucagon

Beta cell

produces less insulin

Muscle

Fat

1

2 3

More player in the progression of diabetes……

Type 2 diabetes is a chronic condition with

progressive loss of β-cell function across time

Holman RR, et al. Diab Res Clin Pract. 1998;40(Suppl):S21–S25.UKPDS Study Group. Diabetes. 1995;44:1249–1258.

HOMA = homeostasis model assessment

?

β-cell function

= 50% of normal

–10 –9 –8 –7 –6 –5 –4 –3 –2 –1 0 1 2 3 4 5 6Years

100

80

60

40

20

0

β-c

ell f

un

ctio

n(%

of

no

rmal

by

HO

MA

)

Time of diagnosis~50% of β-cell

function was

already lost at

the time of

diagnosis in

UKPDS

UKPDS 16 Study

Etiology of -Cell Dysfunction in

T2DM Is Multifactorial

DeFronzo RA. Diabetes. 2009;58:773-795.

Insulin Resistance

Age

-CellDysfunction

Genetics(TCF 7L2)

Lipotoxicity

↑ Free Fatty Acid (FFA)Glucose

Toxicity

Amyloid(Islet Amyloid Polypeptide)Deposition

↓ Incretin

Effect

Ramlo-Halsted BA, Edelman SV. Prim Care 1999; 26: 771-789.Nathan DM. N Engl J Med 2002; 347: 1342-1349.

Sekresi Insulin

Type 2 diabetes

Tahun dari

terdiagnosa

0 5-10 -5 10 15

Pre-diabetes

Onset Diagnosis

Resistensi Insulin

Glukosa setelah makan

Komplikasi makrovascular

Glukosa puasa Komplikasi mikrovascular

Perjalanan Penyakit DM Tipe 2

10

INCRETIN

Inhibition of DPP-4 (DPP-4i)

Increases Active GLP-1

IN ActiveGLP-1

(>80% of pool)

ActiveGLP-1

Meal

DPP-4

IntestinalGLP-1 release

GLP-1 t½=1–2 min

DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1

Adapted from Rothenberg P, et al. Diabetes. 2000; 49(suppl 1): A39. Abstract 160-OR.

Adapted from Deacon CF, et al. Diabetes. 1995; 44: 1126-1131.

Clinical characteristics of DPP-4 inhibitors

* Without limitations in renal or hepatic impairment: please consult the label before prescribing

Characteristics Linagliptin Sitagliptin Vildagliptin Saxagliptin

One dose fits all*

No dose adjustment in renal impairment

No reports of decrease in renal function1

No drug-related monitoring of renal

function

No dose adjustment in hepatic impairment

No liver toxicity1

No dose adjustment based on

drug-drug-interactions

No skin toxicity in pre-clinical studies1

1. Linagliptin, Sitagliptin, Saxagliptin US PI. Other sources: Vildagliptin EU SmPC

MANAGEMENT & TREATMENTOf

T2DM

(ADA)

Lessons from Large Clinical Intervention Trials:

Better Control Means Fewer Complications

Stratton IM, et al. BMJ. 2000;321:405-412.

*P<0.0001

Risk of complicationsBenefits of lowering hemoglobin HbA1c

0

4

8

12

16

6 7 8 9 10 11 12

Hemoglobin HbA1c (%)

Rel

ativ

e R

isk

of

com

plic

atio

ns

Adapted from UKPDS 33: Lancet 1998;352:837-853.Adapted from DCCT Study Group. N Engl J Med 1993;329:977.

Average Glucose

mg/dl120 150 180 210 240 270 300

Diabetesdiagnosis

Glucose

Need for multiple add-on pharmacological interventions

Diabetes complications

Weight

Cardiovascular risk

Hypoglycaemia

Beta-function

Pre-diabetes Diabetes

Type 2 diabetes progression is a multifactorial challenge

Additional factors of type 2 diabetes

progression

Parameters of carbohydrate metabolism

Time

Barriers to Goal Achievement in

Diabetes

ADA/EASD position statement 2012

Insulin (MDI)

Inzucchi et al. Diabetologia 2012;55:1577–96

ADA, American Diabetes Association; EASD, European Association for the Study of Diabetes; MDI, multiple daily injections; MET, metformin

Healthy eating, weight control, increased physical activity

Not at target HbA1c

after ~3 months

Two-drug combinations

Three-drug combinations

MET

SU

TZDDPP-4i

GLP-1RAInsulin

TZD

SUDPP-4i

GLP-1RAInsulin

DPP-4i

SUTZD

Insulin

GLP-1RA Insulin

TZDDPP-4i

GLP-1RA

SUTZD

Insulin

More complex strategies

Initial monotherapy

Not at target HbA1c after 3-6 months combination therapy with insulin

Not at target HbA1c

after ~3 months

GLP-1RA

Hypoglycaemia - Why is this important?

• Hypoglycaemia is associated with cognitive dysfunction and delayed recovery in the elderly6

• Hypoglycaemia is linked to cardiac arrythmias1

• Up to 38% of people with type 2 diabetes experience symptomatic hypoglycaemia2

o It is believed that many incidences of hypoglycaemia go unreported to healthcare professionals3

• Hypoglycaemia results in reduced quality of life, treatment satisfaction and therapy adherence2,4

• Hypoglycaemia is a barrier to optimal insulin dose titration and the achievement of glycaemic control5

• Hypoglycaemia is associated with increased anxiety7 1. Nordin C. Diabetologia 2010; 53: 1552–612. Alvarez Guisasola F et al. Diab Obes Metab 2008; 10 Suppl 1: 25−323. Leiter LA et al. Can J Diab 2005; 29: 186−924. Jermendy G et al. Health Qual Life Outcomes 2008; 6: 885. Briscoe VJ et al. Clin Diab 2006; 24: 115−216. Zammitt N et al. Diabetes 2008; 57: 732−6 7. Labad J et al. Diabetologia 2010; 53: 467−71

OAD OF DIABETES

Matching Pharmacology to Pathophysiology

Benefits and Limitations of T2DM Treatment Options

Adapted from: Rodbard HW, et al. Endocr Pract. 2009;15:540-559.

DPP-4iSULFONILUREA BIGUANIDE GLINIDE TZD AGI

GLP-1 AGONIST INSULIN

FPG+ ++ ++ + ++ Neutral + +++

PPG++ ++ + ++ + ++ +++ +++

Level of Risk

HypoglycaemiaNeutral Moderate Neutral Mild Neutral Neutral Neutral

Moderate to severe

Weight gainNeutral Mild Benefit Mild Moderate Neutral Benefit

Mild to Moderate

CV eventNeutral Neutral

Contraindicated in CHF

NeutralContraindi

cated in CHF

Neutral Neutral Neutral

Drugsinteraction

Neutral Moderate Neutral Moderate Neutral Neutral Neutral Neutral

Range of weight change(kg) in response to diabetes medications

Mitri J, Hamdy O. Expert Opin Drug Saf. 2009;8:573-84.

Range of weight change (kg)

Sulphonylureas

Glinides

Thiazolidinediones

Insulin

-6 -4 -2 0 2 4 6 8 10

DPP-4 inhibitor

Metformin

GLP-1 receptor agonist (exenatide)

Glucose-lowering medications and weight profile

Type 2 diabetes treatment efficacy

Change in body weight (kg)

Change in HbA1c (%)

SUs High Gain

GLP-1RAs High Loss

TZDs High Gain

DPP-4is Intermediate Neutral

Insulin Highest Gain

Inzucchi et al. Diabetologia 2012;55:1577–96

Risk of hypoglycaemia

Moderate

Low

Low

Low

High

Mechanisms of Action of Major Oral Monotherapies

Oral Monotherapies

SUs Meglitinides TZDs Metformin

α-Glucosidase

Inhibitors DPP-4i

Improves insulin secretion

Improves insulin resistance

Lowers hepatic glucose production

SUs=sulfonylureas; TZD=thiazolidinediones; DPP-4=dipeptidyl peptidase 4.

1. Inzucchi SE. JAMA 2002;287(3):360–372; 2. Gallwitz B. Minerva Endocrinol. 2006;31(2):133–147.

Key

Def

ects

Do Not Target All 3 Core Defects in Type 2 Diabetes1,2

The idealintervention

Weight

Diabetes complications

Glucose

Cardiovascular risk

Beta-cell function

Hypoglycaemia

An ideal intervention would directly address all the key elements of disease progression

Time

Need for multiple add on pharmacological interventions

Additional factors of type 2 diabetes

progression

Parameters of carbohydrate metabolism

Normal range

THE OPTION COMBINATION THERAPY IN T2DM

Target site Action MetforminDPP-4

inhibitors

Enhances glucose-dependent insulin

secretion

Suppresses glucagon secretion

Lowers hepatic glucose production

Improves insulin resistance

Safety and

tolerability

Low risk of hypoglycaemia

No additional weight gain

Pancreatic β-cell

Metformin + DPP-4 inhibitors: Combinations of oral glucose lowering agents with complementary mechanisms of action

Pancreatic α-cell

Drucker DJ, Nauck MA. Lancet. 2006;368:1696–1705.

Del Prato S, et al. Int J Clin Pract. 2005; 59:1345–1355.

Inzucchi SE. JAMA. 2002;287:360–372.

Rationale for use of a DPP-4 inhibitor + metformin as initial combination therapy in type 2 diabetes

• Metformin + DPP-4 inhibitor have complementary

mechanisms of action1,2

• Metformin reduces hepatic glucose output and

improves insulin sensitivity in liver and muscle

• DPP-4 inhibitors increase GLP-1 levels and thereby

stimulate insulin secretion and inhibition of glucagon

secretion

1. Migoya EM, et al. Clin Pharmacol Ther. 2010;88(6):801–808; 2. Ahrén B. Vasc Health Risk Manag. 2008;4(2):383–394.

Synergistic effects of metformin and linagliptin

Metformin Linagliptin

AMPK activation

Liver

Gluconeogensis

Gut GLP-1

productionDPP4

inhibition GLP-1

Inactivation

GLP-1

Pancreas

GIP

Insulin Glucagon

Hyperglycaemia (fasting and post-prandial

(Glucose dependent)

AMPK: AMP activated protein kinase; DPP4: Dipeptidyl peptidase; GIP: Glucose-dependent insulinotropic polypeptide; GLP-1:

Glucagon-like peptide 1

Source: Scheen AJ. Expert Opin Drug Metab Toxicol. 2013;9:363–377.

Linagliptin improves

beta-cell function

and increases insulin

synthesis and

release.

Linagliptin reduces HGO through

suppression of glucagon from alpha

cells.Metformin decreases HGO by

targeting the liver to decrease

gluconeogenesis and

glycogenolysis.

Metformin has insulin-

sensitizing properties.

(liver > muscle, fat)

Beta-Cell Dysfunction

Hepatic Glucose Overproduction (HGO)

Insulin Resistance

Linagliptin and Metformin Target the Core

Metabolic Defects of Type 2 Diabetes

Initial combination of linagliptin (Trajenta®)and metformin was superior to the respective monotherapy arms

LIN, linagliptin; MET, metformin.*** p < 0.0001, combination therapy versus respective monotherapy.1. Randomized arm: mean (SE); full analysis set, last observation carried forward. 2. Open-label arm in patients with poor glycaemic control: mean (SE); full analysis set, observed cases (n = 48).Source: Haak T, et al. Diab Obes Metab. 2012;14:565–574.

-1.0

-1.5

-2.0

-3.0

-3.5

-1.3-1.2-0.8-0.6

-3.7

0

-1.7

-0.5

8.7135

8.7141

8.5138

8.7137

8.7140

11.866

Lin 2.5 BID + Met 1,000 mg

BID

Lin 2.5 BID + Met 1,000 mg

BID Met 1,000 mg

BIDMet 500 mg

BIDLin 5 mg QD

Lin 2.5 BID +Met 500 mg

BID

Randomized arm1 (placebo-corrected), Week 24 Open-labelarm2

Baseline HbA1c, %Patients, n

Ch

ang

e in

Hb

A1c

fro

m

bas

eli

ne

,%

***

***

-1.0

-2.0

-3.0

-4.0Both combination regimens were superior to the respective metformin monotherapy arms

Summary

• The goals of hyperglycemia management in T2DM are to :

• Reduce HbA1C to minimize risk for diabetes complications

• In some, avoid weight gain and hypoglycemia

• DPP-4 inhibitors have a complementary mechanism of action to metformin

• Combining metformin with a DPP-4 inhibitor earlier provides the improved glycaemic control

required, along with:

• Low risk of hypoglycaemia

• No additional weight gain

• By addressing the core pathophysiological mechanisms of type 2 diabetes, the addition of a DPP-4

inhibitor to metformin delivers comprehensive therapeutic advantages.

• By DPP-4i and metformin have complementary mechanisms of action that target the 3 core defects of type 2 diabetes.

Targeting the 3 core defects may result in improvements in HbA1c, fasting plasma glucose and postprandial glucose

Thank You For The Attention