early treatment to manage hyperglycemia: do we have enough option dr olly trajenta
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Early Treatment to Manage Hyperglycemia : Do We Have Enough Option PIT VII IDI Kota Bogor, 1-2 November 2014TRANSCRIPT
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