established and novel pharmacological therapies for type 2 diabetes mcgill first canadian summit on...
Post on 25-Dec-2015
216 Views
Preview:
TRANSCRIPT
Established and Novel Pharmacological Therapies
for Type 2 Diabetes
McGill First Canadian Summit onSurgery for Type 2 Diabetes
Montréal, QuébecMay 6, 2010
David C.W. Lau, MD, PhD, FRCPCProfessor of Medicine and Biochemistry
Julia McFarlane Diabetes Research CentreUniversity of Calgary
Email: dcwlau@ucalgary.ca
Disclosures
• Research funding:CIHR, AHFMR, Alberta Cancer Board, AstraZeneca, BMS, Dainippon, GSK, Eli Lilly, Pfizer and sanofi-aventis
• Consultant or advisory board member: Abbott, Allergan, AstraZeneca, Bayer, Boehringer-Ingelheim, GSK, Eli Lilly, Merck, Novartis, Novo Nordisk, Pfizer, Roche, sanofi-aventis, Sepracor
• Speaker bureau:CDA, HSFC, AstraZeneca, Abbott, Bayer, Boehringer-Ingelheim, Eli Lilly, GSK, Merck, Novo Nordisk, Pfizer sanofi-aventis and Sepracor
Overview
• Glycemic control and vascular complications • Pathophysiology of type 2 diabetes• 2008 CDA Clinical Practice Guidelines on the
management of type 2 diabetes• Pharmacotherapy for type 2 diabetes• Novel and emerging therapies for type 2 diabetes
1 Fong DS, et al. Diabetes Care. 2003; 26 [Suppl. 1]:S99–S102.2 Molitch ME, et al. Diabetes Care. 2003; 26 [Suppl.1]:S94–S98.3 Kannel WB, et al. Am Heart J. 1990; 120:672–676.4 Gray RP & Yudkin JS. In Textbook of Diabetes. 1997.5 Mayfield JA, et al. Diabetes Care. 2003;26 [Suppl. 1]:S78–S79.
DiabeticretinopathyLeading causeof blindness in working-age adults1
DiabeticnephropathyLeading cause of end-stage renal disease2
Cardiovasculardisease
Stroke2- to 4-fold increase in cardiovascular mortality and stroke3
DiabeticneuropathyLeading cause of non-traumatic lower extremity amputations5
8/10 diabetic patients die from CV events4
Diabetes is a Serious Chronic Disease
P Hossain et al. N Engl J Med 2007;356:213-215
Global Increase 180 472 million!
Global Prevalence of Diabetes in 2000 and Projections for 2030
Obesity as the Major Cause of Diabetes
IDF. Diabetes Atlas. Second Edition 2003
Glycemic Control and Complications
DCCT: Type 1 diabetes followed for 6.5 years A1C 7% versus 9% 60% reduction in microvascular
complications 1
DCCT-EDIC 17-year follow-up 57% reduction in major CVD outcomes 2
UKPDS: Type 2 diabetes followed for 10 yrs A1C 7% versus 7.9% 25% reduction in microvascular
complications 3
Each 1% decrease in A1C ~30% reduction in microvascular complications in both Type 1 and Type 2 diabetes
1. DCCT Research Group. N Engl J Med 1993;329:977-862. DCCT/EDIC Research Group. N Engl J Med 2005;353:2643-533. Holman RR et al. N Engl J Med 2008;359:1577-1589
UKPDS: Long-term Glycemic ControlCross-sectional, median values
UKPDS, Lancet 1998;352:837-853
06
7
8
9
0 3 6 9 12 15
HbA
1c (
%)
Years from randomisation
Conventional
Intensive
6.2% upper limit of normal range
8
A1C
7
Years 2 6 10
Stratton IM, et al. UKPDS 35. BMJ 2000;321:405–12
Perc
enta
ge in
crea
se in
rela
tive
risk
corr
espo
ndin
g to
a 1
% ri
se in
HbA
1C
**
Any diabetes-related
endpoint
21%
**
Diabetes-related death
21% **
All cause
mortality
14%*
Stroke
12%
**
Peripheral vascular disease†
43%
**
Myocardial infarction
14%
**
Micro-vascular disease
37%
**
Cataract extraction
19%
† Lower extremity amputation or fatal PVD* P = 0.035; **P < 0.0001
UKPDS 35: Decreased Risk of Diabetes-related complications with 1% in A1C
Glucose Lowering (A1C 0.9%) and Non-fatal MIs
Ray KK et al. Lancet 2009;373:1765-1672
17%
Glucose Lowering (A1C 0.9%) and CAD
Ray KK et al. Lancet 2009;373:1765-1672
15%
The (DCCT/EDIC) Study Research Group. N Engl J Med 2005;353:2643-2653
DCCT/EDIC in DM1: 17-yearCumulative Incidence of First CV Event
Legacy effect; benefit of
early aggressive glycemic control on
CVD outcomes
DCCT/EDIC Research Group. N Engl J Med 2005;353:2643-53
ACE42%
CVD
57%
Holman RR, et al. N Engl J Med 2008;359:1577-1589
UKPDS 10-year Follow-up:Kaplan-Meier Curves for Outcomes
Legacy effect; benefit of
early aggressive glycemic control on
CVD outcomes
Holman RR, et al. N Engl J Med 2008;359:1577-1589
Ins-SU
End-pt9%
MI15%
Micro24%
Death13%
Met
End-pt21%
MI33%
MicroNS
Death27%
STENO-2 13-year Follow-up:Kaplan-Meier Curves of the Risk of Death and CV Events
All cause 45%
CVD
57%
Defining Glycemic Control
Parameter Target Rationale
A1C ≤ 7% (0.070 lab value)
A1C levels >7% are associated with significantly increased risk of microvascular and macrovascular complications
FPG 4.0–7.0 mmol/L FPG levels are a major contributor to A1C values of >8.5%
2h PPG 5.0–10.0 mmol/L(or 5.0–8.0 mmol/L)
In A1C levels approaching ≤7%, there is a greater contribution from postprandial glucose levels; if A1C targets are not met, lowering PPG to 5.0–8.0 mmol/L can be considered
2008 CDA CPGs. Can J Diabetes 2008;32(Suppl 1):S29–S31
A1C = glycated hemoglobin FPG = fasting plasma glucose PPG = postprandial plasma glucose
Targets for Glycemic Control
• In most people with type 1 or type 2 diabetes, A1C ≤ 7% should be targeted to reduce microvascular complications [Grade A, Level 1A]
• In type 2 diabetes, A1C ≤ 6.5% may be considered to further lower the risk of nephropathy [Grade A, Level 1A]
Can J Diabetes 2008;32(Suppl 1):S29-S31
Intestine:Glucose Absorption
Liver: Glucose Production
Muscle
Fat
PeripheralGlucoseUptake
Pancreas
InsulinSecretion
+
- +
Brain &Nervous System
BLOOD GLUCOSE
Control of Blood Glucose
Diminishedinsulin
HyperglycemiaLiver
1. Insulin deficiency
2. Excess glucose output 3. Insulin resistance
Pancreas
Muscle and fat
Excess glucagon
Islet
Diminishedinsulin
α-cell produces excess glucagon
β-cell produces less insulin
Pathophysiology of Type 2 DiabetesThree Main Defects
Adapted from Williams G, Pickup JC, eds. Handbook of Diabetes, 3rd ed. Malden, MA: Blackwell Publishing, 2004. DeFronzo RA. Ann Intern Med. 1999;131:281–303; Buse JB, et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders, 2003;1427–1483.
Pancreatic β-cells Sulfonylureas, meglitinides
↑ insulin release
Gut
α-glucosidase inhibitors glucose
absorption
Muscle
Liver
Biguanides Thiazolidinediones
Insulin glucose production
ThiazolidinedionesBiguanides
Insulin ↑ glucose uptake
Oral Anti-diabetic agents: Mechanisms of action
Amelioration of hyperglycemia
Insulin Secretion Profiles in Type 2 Diabetes and Non-Diabetic Subjects
K Polonsky et al. New Engl J Med 318:1231-1239, 1998
Pa
ncre
atic
Insu
lin S
ecr
etio
n (
pm
ol/m
in)
Clock Time (hours)
No Diabetes
Type 2 diabetes
Meals (9 am, 1pm, 6pm)
800
700
600
500
400
300
200
100
6:00 am 10:00 2:00 pm 6:00 10:00 2:00 am
β-ce
ll fu
nctio
n (%
)
Years
100
75
50
25
00 1 2 3 4 5 6
β-cell function declines, while . . .
UK Prospective Diabetes Study Group. Diabetes 1995;44:1249–1258
Years0 1 2 3 4 5 6
9
10
8
7
6
5
HbA
1C
. . . hyperglycemiaincreases
Progressive Impairment in β-cell FunctionDiet/conventional Rx (n=376)Metformin (n=159)Sulfonylurea/intensive (n=511)
Food intake
Stomach
GI tract
Intestine
Increases and prolongs GLP-1 effect on alpha-cells:
Alpha-cells
Pancreas
Insulin release
Net effect: Blood glucose
Beta-cells
Increases and prolongs GLP-1 and GIP effects on beta-cells:
DPP-4 inhibitor
Glucagon secretion
Incretins
DPP-4
DPP-4 Inhibitors Enhance Incretin and Insulin Secretion
Adapted from: Barnett A. Int J Clin Pract 2006;60:1454-70 Drucker DJ, Nauck MA. Nature 2006;368:1696-705Idris I, Donnelly R. Diabetes Obes Metab 2007;9:153-65
Lifestyle Intervention
A1C ≥9%
• Initiate pharmacotherapy immediately
• Consider initiating metformin concurrently with another agent from a different class;
• Initiate insulin
Symptomatic hyperglycemia with metabolic decompensation
Initiate insulin ± metformin
A1C <9%
Initiatemetformin
If not at target
2008 CDA CPGs. Can J Diabetes 2008;32(Suppl 1):S1–201
2008 CDA CPGs Treatment Algorithm
Initiate metformin
Initiate pharmacotherapy immediately without waiting for effect from lifestyle interventions: Consider initiating metformin concurrently with another agent from a different class; or insulin Initiate insulin
± metformin
If not at target
Add an agent best suited to the individual:
• Alpha-glucosidase inhibitor
• Incretin agent: DPP-4 inhibitor
• Insulin
• Insulin secretagogue: Meglitinide, Sulfonylurea
• TZD
• Weight loss agent
If not at target:
• Add another drug from a different class; or
• Add bedtime basal insulin to other agent(s); or
• Intensify insulin therapy
2008 CDA Clinical Practice GuidelinesClinical Assessment - Lifestyle intervention (Nutrition therapy and physical activity)
A1C < 9.0% A1C ≥ 9.0% Symptomatic hyperglycemia with metabolic decompensation
2008 CDA CPGs. Can J Diabetes 2008;32(Suppl 1):S53–S61
2008 CDA CPGs. Can J Diabetes 2008;32(suppl 1):S53-S61
* Less hypoglycemia in the context of missed meals
2008 CDA Clinical Practice Guidelines:Drug Therapy for Type 2 Diabetes
0 6 12 18 24 30 38 46 54 62 70 78 91 1046
6.5
7
7.5
8
8.5
9
Sitagliptin and Metformin Combination Therapy
24-Week Phase Continuation Phase Extension Phase
A1C
(LS
mea
n ch
ange
%)
Time (weeks)Sita 100 mg qd (n=50) Met 500 mg bid (n=64)
Met 1000 mg bid (n=87) Sita 50 mg bid + Met 500 mg b.i.d. (n=96)
Sita 50 mg bid + Met 1000 mg bid (n=105)
Adapted from Qi Daniel S, et al. 73-OR, EASD 2008Sita = sitagliptin; Met = metformin
Exenatide Monotherapy:A1C Change from Baseline
0
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
0.04 8 12 16 24
Study Week
LS M
ean
(SE
)
in A
1C (
%)
*
*
*
*
*
*
*
*
ITT patients. Analysis using mixed-models repeated measures. Mean baseline A1C values (%): exenatide 5 g: 7.9%;exenatide 10 g: 7.8%; placebo: 7.8%. *P ≤ 0.001 vs. placebo. ITT=intent-to-treat. LS=least-squares. SE=standard error.
Adapted from Moretto TJ, et al. Clin Ther. 2008;30(9):1448-1460.
Exenatide 5 µg (n=76)Exenatide 10 µg (n=76)Placebo (n=75)
Exenatide Monotherapy: Weight Change from Baseline
-4.0
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.00 4 8 12 16 24
LS M
ean
(SE
)
in W
eigh
t (kg
)
Study Week
†
*
†
*
*
*
Exenatide 5 µg (n=77)Exenatide 10 µg (n=76)Placebo (n=76)
ITT patients. Analysis using mixed-model repeated measures. Mean baseline weights: 85 to 86 kg.Statistical comparisons are vs. placebo. *P ≤ 0.007. †P ≤ 0.027. ITT=intent-to-treat. LS=least-squares. SE=standard error
Adapted from Moretto TJ, et al. Clin Ther. 2008;30(9):1448-1460.
Kahn SE et al. N Engl J Med 2006;355:2427-2443
ADOPT: Kaplan-Meier Estimates of the Cumulative Incidence of Monotherapy Failure at 5 Years
SGLT2 Inhibitor
• Sodium–glucose cotransporter-2 (SGLT2) reabsorbs glucose in the proximal tubule
• Dapagliflozin induces glucosuria by inhibiting sodium–glucose cotransporter-2
• Insulin-independent glucose lowering
• Lowers A1C by 0.6-0.8%• 2-3% body weight loss
Komoroski B et al. Clinical Pharm & Therapeutics 2009;85:513–519
Glucokinase Activators
Glucokinase Activators
• Glucokinase serves as a glucose sensor of the pancreatic islet β cells‐
• Controls the conversion of glucose to glycogen in the liver and regulates hepatic glucose production
• Lowers glucose by stimulating insulin release and glucose uptake in liver
• Can be used in combination with other OHAsMatchinski F Nature Rev Drug Discovery 2009;8;399-416
Pharmacotherapy for Type 2 Diabetes
• Glycemic control is an integral component of optimal diabetes management
• Metabolic control also reduces cardiovascular disease risk in people with diabetes
• Availability of effective and safe drugs that lower glucose without significant adverse effects will add to current armamentarium
Thank you
Questions?
top related