pharmevo diabetes & dpp-4 inhibitors workshop 2013
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Diabetes Updates
By
Dr.Karim KammeruddinConsultant Physician & Professor Of
MedicineBaqai University & Hospitals Karachi
Unmet clinical need associated with Abdominal Obesity
Patients with
abdominal obesity
(high waist
circumference)
often present with
one or more
additional
CV risk factors
CV risk factors in a typical patient with abdominal obesity
NHANES 1999–2000. http://www.cdc.gov/nchs/nhanes
Assess “Global Cardiovascular risk” in all hypertensive patients
91%
Rantala A, et al. J Intern Med 1999;245;163-74. Wannamethee S, et al. J Hum Hypertens 1998;12;735-41
Risk factors = Global CV risk
91% of hypertensive patients have at least 1 additional risk factor
Pre-diabetes* is a stage in the transition from normoglycaemia to diabetes
Genuth et al., for the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2003;26:3160–7
Diabetes
IGT
7.8 mmol/L 11.1 mmol/L
5.6 mmol/L
6.9 mmol/L
2 hr post-load plasma glucose
Fas
ting
plas
ma
gluc
ose
*Defined as patients with IFG and/or IGTIFG: impaired fasting glucoseIGT: impaired glucose tolerance
American Diabetes Association criteria
Normal
IFG
IGT and IFG – differences in progression.Baltimore Longitudinal Study
More than 80% of people with IGT are expected to develop type 2 diabetes over a lifetime
Herman et al. Ann Intern Med 2005;142:323–32
Simulated lifetime cumulative incidence of type 2 diabetes in the Diabetes Prevention Program cohort of 3,234 individuals with impaired glucose tolerance (IGT)
Inci
denc
e of
dia
bete
s (%
)
Time since diagnosis of IGT (years)
90
80
70
60
50
40
30
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Lifetime
3.4 y
11.1 y
8%20%
PlaceboMetforminLifestyle
Oral Monotherapies
SUs Meglitinides TZDs Metforminα-Glucosidase
Inhibitors
DPP-4 Inhibitors
Improves insulin secretion
Improves insulin resistance
Lowers hepatic glucose production
Inzucchi SE. JAMA 2002;287(3):360–372; Gallwitz B. Minerva Endocrinol. 2006;31(2):133–147.
Efficacy of Monotherapy with OHAs
DeFronzo Annals of Internal Medicine 1999;131:281-303
Nathan N Engl J Med 2002; 347:1342-1349
DrugsFastingPlasma Glucose Reduction
(mg/dl)
A1CReduction
(%)
Thiazolidinedione 35-40 0.5-1.0
Sulfonylurea 60-70 1.0-2.0
Biguanide 60-70 1.0-2.0
Meglitinide 60-70 1.0-2.0
Alpha- glucosidase inhibitor 20-30 0.5-1.0
Clinical Inertia
“Failure to Advance Therapy When Recommended”M
ean
A1C
at
Last
Vis
it* (
%)
8.2 Years
ADA Goal
Diet and Exercise
Years Elapsed Since Initial Diagnosis
Initiation of
insulin therapy
SU or metformin
Combination oral agents
8.6%8.9%
9.6%
7
8
9
10
2.5 Years 2.9 Years 2.8 Years
*Adapted from: Brown JB et al. Diabetes Care. 2004;27:1535-1540.
Early Insulin Use in Type 2 Diabetes Offers No Benefits Over Standard
Approaches
16
ORIGIN Trial Investigators. N Engl J Med. 2012;367:319-328.
Outcome Reduction With an Initial Glargine InterventionCV risk factors + prediabetes or T2DM (N=12,537)
Benefit of Intensifying Glycemic Control Diminishes with Duration of Diabetes
+
–
UKPDS
ACCORD /ADVANCE / VADT
Del Prato S. EASD 2008, Rome, Italy
1%
-18%
-13%
-16%
-17%
-28%
Cardiovascular disease
Peripheral arterialdisease
Stroke
Fatal coronaryheart disease
Coronary heart disease
ReducedRisk*
EVERY 1% reduction in HbA1c
Numberof patients
Numberof studies
7435 10
6684 6
3042 5
5962 3
3748 3
*p<0.0001
Meta-Analysis: Glycosylated Hemoglobin and Cardiovascular Disease in Diabetes mellitus
Selvin et al. Ann. Intern. Med. 2004;141:421
The relative contribution of PPG and FPG varies with HbA1c1
HbA1c Is a Combination of Both FPG and PPG
1. Monnier L, et al. Diabetes Care. 2003;26(3):881-885.
As your patients’ HbA1c level approaches the normal range, PPG takes on greater importance in determining HbA1c.
<7.3 7.3-8.4 8.5-9.2 9.3-10.2 >10.2HbA1c Range (%)
Co
ntr
ibu
tio
n (
%)
100
80
60
40
20
0
PPG
FPG
GUIDELINES ON DIABETES, PRE-DIABETESAND CARDIOVASCULAR DISEASES
New ESC/EASD GuidelinesSuggested policy for the selection of glucose-lowering therapy according to the glucometabolic situation
ESC Pocket Guidelines adapted from European Heart Journal (2007) 28, 88 - 136
Breakfast Lunch Dinner 0.00am 4.00am Breakfast
Monnier L. Eur J Clin Invest 2000;30(Suppl 2):3-11.
“Our Lives are Spent in the Postprandial State”
Legend:
Postprandial state;
Postabsorptive state;
Fasting state
The damage of postprandial glucose levels is the damage of diabetes
Therapies that Preferentially Lower Postmeal Glucose
Drug Class Postmeal Glucose-lowering Effect
Delays carbohydrate absorptionα-glucosidase inhibitors
Slows gastric emptying, lowers glucagon, increases satietyAmylin analogues
Stimulates glucose-dependent insulin secretion, suppresses glucagon releaseDPP-4 inhibitors
Stimulates rapid but short-lived insulin releaseGlinides
Replaces insulin normally secreted after mealsRapid-acting insulin
analogues
Replaces insulin normally secreted after mealsBiphasic insulins
Stimulates glucose-dependent insulin secretion, suppresses glucagon release, delays gastric emptying,
increases satietyGLP-1 derivatives
DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide 1.Blevins T. Postgrad Med. 2011;123(4):135-147.
26
Standards of Medical Care in Type 2 Diabetes – 2008 ADA Weight Recommendations
• Weight loss is an important therapeutic objective1
• 85% of patients with T2DM are obese/overweight2 • Physical activity and behavior modification are important1
• Moderate weight loss (5% in short-term studies)1
• Decreased insulin resistance
• Improved measures of glycemia and lipemia
• Reduced blood pressure
• “The importance of controlling body weight in reducing risks related to diabetes is of great importance …” but sustaining weight loss is difficult1
References: 1. Diabetes Care. 2008;31(Suppl1). 2. NHANES 1999-2002
Antidiabetic Agents and Weight
• Risk of additional weight gain must be balanced against the benefits of the agent;
• Sulfonylureas may negate weight loss benefits of GLP-1 receptor agonists or metform in.• Insulin should not be withheld because of the risk of weight gain.
Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379. Rodbard HW, et al. Endocr Pract. 2009;15:540-559. Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. Stenlof K, et al. Diabetes Obes Metab 2013;15:372-382.
27
Class Agent(s) Weight EffectAmylin analog Pramlintide ↓Biguanide Metformin ↓GLP-1 receptor agonists Exenatide, exenatide XR, liraglutide ↓SGLT-2 inhibitor Canagliflozin ↓-Glucosidase inhibitors Acarbose, miglitol ↔Bile acid sequestrant Colesevelam ↔DPP-4 inhibitors Alogliptin, linagliptin, saxagliptin, sitagliptin ↔Dopamine-2 agonist Bromocriptine ↔Glinides Nateglinide, repaglinide ↑Sulfonylureas Glimepiride, glipizide, glyburide ↑
Insulin Aspart, detemir, glargine, glulisine, lispro, NPH, regular ↑↑
Thiazolidinediones Pioglitazone, rosiglitazone ↑↑
0
10
20
30
40
50
60
70
80
90
100
Blood Glucose (mg/dL)
Decreased insulin secretion
Increased glucagon, epinephrine, ACTH, cortisol, and growth hormone
Palpitation, sweatingDecreased cognition, hungerAberrant behaviorSeizures, coma
Neuronal cell death
Moghissi E, et al. Endocr Pract. 2013;Feb 20:1-33. [Epub ahead of print].
Symptoms and Signs with Progressive Hypoglycemia
GLP-1 receptor agonists
DPP-4 inhibitors
TZDs
Insulin (basal, basal-plus, premixed)
Sulfonylureas
Metformin
Less Hypoglycemia
MoreHypoglycemia
Initial Treatment Additional Treatment
Moghissi E, et al. Endocr Pract. 2013;Feb 20:1-33. [Epub ahead of print].
Hypoglycemia Risk With Antihyperglycemic Agents Added to Metformin
Incretin Actions
GIP GLP-1
•Stimulates insulin secretion•Expansion of beta cell mass •Min effect on gastric emptying•No effect on glucagon secretion•Normal GIP secretion in T2DM•Defective GIP reponse in T2DM•No effect on Satiety
• Stimulates insulin secretion.• Expansion of B cell mass. • Inhibits gastric emptying• Inhibits glucagon secretion
• ↓ GLP1 secretion in T2DM• GLP1 reponse in T2DM
Normal • Stimulates Satiety - Inhibits
food intake and weight gain
Ahrén. Diabetes Care. 2003;26:2860.Farilla. Endocrinology. 2002;143:4397.
GLP-1 Effects in HumansUnderstanding the Natural Role of Incretins
Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553Adapted from Drucker DJ. Diabetes. 1998;47:159-169
Stomach: Helps regulate gastric emptying
Promotes satiety and reduces appetite
Liver: Glucagon reduces hepatic glucose outputBeta cells:
Enhances glucose-dependent insulin secretionDecreased apoptosisBeta cell regeneration
Alpha cells: Postprandialglucagon secretion
GLP-1 secreted upon the ingestion of food
Beta-cellworkload
Beta-cellworkload
Beta-cellresponse
Beta-cellresponse
GLP-1 levels are decreased in DM 2
Degradation of GLP-1
1 2 3 30
GLP-1
Des-HA-GLP-1 (inactive)
Enzymatic cleavage of GLP-1 by DPP-4 inactivates GLP-1
1 2 3 30
DPP-4
Two possible solutions to utilize GLP-1 action therapeutically:1) Long-acting DPP-4-resistant GLP-1 analogues/incretin mimetics.2) DPP-4 inhibitors / incretin enhancers.
Mentlein et al. Eur J Biochem. 1993; Gallwitz et al. Eur J Biochem. 1994
*
GLP-1 Levels Are Decreased in Type 2 Diabetes
** *
*
**
Control (n=33)Type 2 diabetes (n=54)
0
5
10
15
20
0 60 120 180 240
GL
P-1
(p
mo
l/L
)
*p<0.05, type 2 diabetes vs control
Adapted from Toft-Nielsen M-B et al. J Clin Endocrinol Metab. 2001;86:3717–3723.
Meal Started
Meal Finish
ed
(10–15)
Time after start of meal, minutes
BUT, the levels are never ZERO
DPP4 activity increases in
Hyperglycemia
0
5
10
15
20
25
30
T2DM T2DM-ND IGT NGT
T2DM
T2DM-ND
IGT
NGT
Mannucci et al, Diabetologia April 2005
Incretin-based Therapy for DMT2
GLP-1- based therapies exert unique glucose-lowering effects; Improve islet beta and alpha cell function. Unique effects on body weight (vs. other glucose lowering therapies).
GLP-1 Analogs DPP-4 Inhibitors
• HbA1c reduction -0.8%-1.9%• Significant and sustained weight loss• Injected therapy• GI side effects• Low rates of hypoglycemia• Multiple mechanism of action;
↑Insulin secretion, ↓ glucagon release, ↓Food intake, slows gastric emptying
• HbA1c reduction 0.5%-1.1%• Weight neutral• Oral administration• No significant GI side effects• Low rates of hypoglycemia• Improves islet function;
• ↑Insulin secretion, ↓ glucagon release, β cell regeneration and hypertrophy with reduced apoptosis
HbA1c Reduction with Sitagliptin
Pooled Results from all Phase III studies of Sitagliptin
100mg monotherapyGlycemic endpoints analyzed by duration of type 2 diabetes
Influence of Measures of Beta Cell Function on Efficacy of Sitagliptin in Patients with Type 2 Diabetes – pooled analysis of data from 4 phase III placebo controlled studies of Sitagliptin 100 mg monotherapy, involving 1691 patients. Poster by Harvey L. Katzeff et al. at ADA 2008.
Pla
ce
bo
ad
just
ed
LS
mea
n c
ha
ng
e
fro
m b
ase
lin
e H
bA
1c,%
, (9
5%
CI)
Pla
ceb
o a
dju
sted
LS
mea
n c
han
ge
fro
m
bas
elin
e F
PG
mg
/dl,
(95
% C
I)
Pla
ceb
o a
dju
sted
LS
mea
n c
han
ge
fro
m
bas
elin
e 2-
h P
PG
mg
/d)
(95%
CI)
*Significant reduction of A1c across all duration
Long-Term Efficacy with Sitagliptin as Monotherapy or Add-On Therapy to Metformin
ADA 2009 Abstract 540-P
Sitagliptin Is the Most Widely Dispensed DPP-4 Inhibitor With the Most Approved Uses of Any DPP-4
Inhibitor
Sitagliptin: Powerful efficacy and proven experience as an adjunct to diet and exercise
As initial therapy for appropriate patients (Monotherapy)
As initial therapy in combination with metformin
As initial therapy in combination with thiazolidinedione
In combination with metformin
In combination with sulfonylurea
In combination with thiazolidinedione
In combination with insulin
In combination with sulfonylurea + metformin
In combination with thiazolidinedione + metformin
In combination with insulin + metformin
Earlier and Appropriate Intervention May Improve Patients’ Chances of Reaching Goal
OAD=oral antidiabetic agent.Adapted from Del Prato S et al. Int J Clin Pract. 2005;59(11):1345–1355. Copyright © 2005. Adapted with permission of Blackwell Publishing Ltd.
Published Conceptual Approach
HbA
1c G
oal
Mean HbA1c
of patients Duration of Diabetes
OAD monotherapy
Diet andexercise
OAD combination
OAD up-titration
OAD + multiple dailyinsulininjections
OAD + basal insulin
Conventional stepwisetreatment approach
Earlier and more aggressive intervention approach
6
7
8
9
10
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