Transcript Criteria for the Diagnosis of Diabetes Mellitus

Current and Future Therapies for the
Treatment of Type 2 Diabetes Mellitus
Slide 1
Pathogenesis of Type 2 Diabetes
Major Underlying Pathologies
Beta-cell dysfunction
Pancreas
Insulin
secretion
Diabetes =
Hyperglycemia
Liver
Muscle
Hepatic glucose
production
Glucose
uptake
Adapted from American Diabetes Association Diabetes Care 2004;27(suppl 1):S5–S10; Beers MH, Berkow R, eds. Merck Manual of Diagnosis
and Therapy, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories, 1999.
Slide 2
Pathogenesis of Type 2 Diabetes
Impaired Glucose Tolerance and Development of
Diabetes
Normal
glucose
tolerance
Obesity
and
increased
insulin
resistance
“Prediabetes”
(IGT or IFG)
and beta-cell
loss
Diabetes
IGT=impaired glucose tolerance; IFG=impaired fasting glucose
Adapted from Weyer C et al Diabetes Care 2001;24(1):89–94; Hedley AA et al JAMA 2004;291:2847–2850.
Slide 3
Pathogenesis of Type 2 Diabetes
Complications of Uncontrolled Hyperglycemia
Impaired insulin release
Insulin resistance
Overproduction
of glucose
Decreased
glucose uptake
Hyperglycemia
Blood vessel wall
abnormalities
Microvascular risk
• Nephropathy
• Retinopathy
• Neuropathy
Increased
lipolysis
Increased
circulating
free fatty acids
TNF-alpha
CRP
PAI-1
Dyslipidemia
Increased platelet aggregation
Macrovascular risk
• MI
• Stroke
• PVD
TNF=tumor necrosis factor; CRP=C-reactive protein; PAI-1=plasminogen-activator inhibitor-1; MI=myocardial infarction; PVD=peripheral
vascular disease
Adapted from Inzucchi SE JAMA 2002;287(3):360–372; Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philiadelphia:
Saunders, 2003:1427–1483; Sheetz MJ, King GL JAMA 2002;288(20):2579–2588; Libby P, Plutzky J. Editorial Circulation 2002;106:2760–2763;
Kendall DM et al Coron Artery Dis 2003;14:335–348; DeFronzo RA Ann Intern Med 1999;131:281–303.
Slide 4
Current Therapies for Type 2 Diabetes
How Different Agents Regulate Hyperglycemia in
Diabetes
Pancreatic beta-cells
Liver
Sulfonylureas
Meglitinides
Stimulate insulin release
Muscle
Amelioration of
hyperglycemia
Gut
PPARs (thiazolidinediones
or glitazones)
Biguanides
Insulin
Inhibit glucose production
PPARs (thiazolidinediones
or glitazones)
Biguanides
Insulin
Stimulate glucose uptake
Alpha-glucosidase inhibitors
Retard glucose reflux into circulation
PPAR=peroxisome proliferator-activated receptor agonist
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.
Slide 5
Current Therapies for Type 2 Diabetes
Sulfonylureas: Mechanism of Action
Glucose
KATP

Sulfonylurea
site
Pancreatic beta-cell
Metabolism
K+
 ATP
ADP
VDCC
Ca2+
Proinsulin
Triggering
Insulin
K=potassium; ATP=adenosine triphosphate; ADP=adenosine phosphate; VDCC=voltage-dependent Ca2+ channel
Adapted from Siconolfi-Baez L et al Diabetes Care 1990;13(suppl 3):2–8.
Slide 6
Current Therapies for Type 2 Diabetes
Sulfonylureas: Overview
Mechanism of action
Increase insulin release
Efficacy depends on
Functioning beta-cells
Dosing
Once or twice daily
Weight gain
Side effects
Hypoglycemia
Main risk
Adapted from Siconolfi-Baez L et al Diabetes Care 1990;13(suppl 3):2–8; Riddle MC Am Fam Physician 1999;60(9):2613–2620; DeFronzo RA
Ann Intern Med 1999;131:281–303; Glynase™ prescribing information, Pharmacia Corporation, April 2002; Glucotrol™ prescribing information,
Pfizer, 2000; Glucotrol XL™ prescribing information, Pfizer, 2003.
Slide 7
Current Therapies for Type 2 Diabetes
Meglitinides: Mechanism of Action
Glucose
KATP

Pancreatic beta-cell
Metabolism
K+
Benzamido site
 ATP
↓ ADP
VDCC
Ca2+
Proinsulin
Triggering
Insulin
Adapted from Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders, 2003:1427–1483.
Slide 8
Current Therapies for Type 2 Diabetes
Meglitinides: Overview
Mechanism of action Increase insulin release
Efficacy depends on
Functioning beta-cells
Dosing
Two, three, or four times daily
with meals
Weight gain
Side effects
Hypoglycemia
Main risk
Adapted from Williams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed. Malden, MA: Blackwell Publishing, 2004; Riddle MC Am Fam
Physician 1999;60(9):2613–2620; Del Prato S et al Diabetes Care 2003;26(7):2075–2080; Starlix™ prescribing information, Novartis
Pharmaceuticals, December 2000; DeFronzo RA Ann Intern Med 1999;131:281–303.
Slide 9
Current Therapies for Type 2 Diabetes
Biguanides (Metformin): Mechanism of Action
Metformin
Reduced hepatic
glucose production
Enhanced muscle
glucose uptake
Reduced insulin
resistance
Reduced plasma glucose
Precise mechanism of action is unknown
Adapted from DeFronzo RA Ann Intern Med 1999;131:281–303; Kirpichnikov D et al Ann Intern Med 2002;137(1):25–33; Williams G, Pickup JC,
eds. Handbook of Diabetes. 3rd ed. Malden, MA: Blackwell Publishing, 2004; Hundal RS et al Diabetes 2000;49(12):2063–2069.
Slide 10
Current Therapies for Type 2 Diabetes
Biguanides (Metformin): Overview
Mechanism of action
Primary:
Decreased hepatic glucose production
Secondary:
Increased peripheral glucose uptake
Efficacy depends on
Presence of insulin
Dosing
Once or twice daily with meals
Side effects
Nausea, anorexia, diarrhea
Main risk
Lactic acidosis
Adapted from Kirpichnikov D et al Ann Intern Med 2002;137(1):25–33; DeFronzo RA Ann Intern Med 1999;131:281–303; Glucophage™/
Glucophage XR™ prescribing information, Bristol-Myers Squibb, April 2003; Williams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed.
Malden, MA: Blackwell Publishing, 2004.
Slide 11
Current Therapies for Type 2 Diabetes
Alpha-Glucosidase Inhibitors: Mechanism of Action
Alpha-glucosidase inhibitor
Inhibition of terminal carbohydrate digestion
at intestinal brush border
Delayed carbohydrate absorption
Delayed entry of glucose into circulation, allowing beta-cells time
to augment insulin release in response to glucose influx
Adapted from 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.
Slide 12
Current Therapies for Type 2 Diabetes
Alpha-Glucosidase Inhibitors: Overview
Mechanism of action Delayed carbohydrate absorption
Efficacy depends on Functioning beta-cells
Dosing
Three times daily administered
at the beginning of meals
Side effects
Bloating, abdominal discomfort,
diarrhea, flatulence
Main risk
Elevations in liver enzymes (rare)
Adapted from Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders, 2003:1427–1483; DeFronzo RA Ann
Intern Med 1999;131:281–303; Glyset™ prescribing information, Bayer Corporation, July 2003.
Slide 13
Current Therapies for Type 2 Diabetes
PPARγ Agonists: Mechanism of Action
Modify gene
expression in
adipocytes
Modify fatty acid uptake
and lipolysis
PPARγ
Agonist
Modify
free fatty acids
Skeletal
muscle
Modify insulin-sensitizing
factor(s) (e.g., adiponectin)
Adipose
Tissue
Modify expression/action
of insulin-resistance factor(s)
(e.g., resistin/TNF)
Small, insulinsensitive adipocytes
modify visceral adiposity
Modify
insulin
action
Liver
PPARγ = Peroxisome Proliferator-Activated Receptor Gamma
Adapted from Moller DE Nature 2001;414:821–828.
Slide 14
Current Therapies for Type 2 Diabetes
PPARγ Agonists : Overview
Mechanism of action Enhance tissue response to insulin
Efficacy depends on Presence of insulin
Dosing
Once or twice daily
Side effects
Weight gain, edema, anemia
Main risk
Congestive heart failure;
Need to monitor liver enzymes
Adapted from Actos™ prescribing information, Takeda Pharmaceuticals, December 2003; Avandia™ prescribing information, GlaxoSmithKline,
May 2004; DeFronzo RA Ann Intern Med 1999;131:281–303; Williams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed. Malden, MA: Blackwell
Publishing, 2004.
Slide 15
Current Therapies for Type 2 Diabetes
Insulin: Mechanism of Action
Insulin
Reduced hepatic
glucose production
Enhanced glucose
uptake by muscle and fat
Reduced plasma glucose
Adapted from Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders, 2003:1427–1483.
Slide 16
Current Therapies for Type 2 Diabetes
Insulin: Overview
Mechanism of action
Decreased hepatic glucose production
Increased glucose uptake
Efficacy depends on
Exogenous source for subcutaneous
injections
Dosing
Once daily to continuous
Side effects
Weight gain, hypoglycemia
Main risk
Hypoglycemia
Adapted from Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders, 2003:1427–1483.
Slide 17
Therapies in Development
Dual PPARα/γ Agonists: Rationale
Gamma
Alpha
Insulin
resistance
Dual
PPARα/γ
agonist action
Dyslipidemia:
TG, HDL-C
Hyperglycemia
Macrovascular disease:
MI, stroke, PVD
Microvascular complications:
retinopathy, nephropathy
• Dual PPAR-alpha/gamma agonists reduce hyperglycemia and improve
the lipid profile
HDL-C=high-density lipoprotein cholesterol; TG=triglycerides
Adapted from Doebber TW et al Biochem Biophys Res Comm 2004;318:323–328.
Slide 18
Therapies in Development
Dual PPARα/γ Agonists: Mechanism of Action
PPAR selectivity (alpha/gamma zone)
Alpha
Gamma
pioglitazone rosiglitazone
fenofibrate
alpha/gamma
O
F
F
Improved lipid control
 Fatty acid oxidation
 Total cholesterol
 TG
S
N
H
O
O
F
Effects of
dual PPARs
O
N
H
Improved glucose control
 Insulin sensitivity
 Glucose
 Free fatty acids
Adapted from Doebber TW et al Biochem Biophys Res Comm 2004;318:323–328; Guo Q et al Endocrinology 2004;145(4):1640–1648; Hegarty BD
et al Endocrinology 2004;145(7):3158–3164.
Slide 19
Therapies in Development
Dual PPARα/γ Agonists: Overview
Mechanism of action
Increased insulin sensitivity
Increased fatty acid uptake
Potential side effects
Weight gain, peripheral edema,
fluid retention, which may lead to
or exacerbate congestive heart failure
Potential benefits
Reduced microvascular and cardiovascular
risk in patients with metabolic syndrome
and type 2 diabetes
Note: Agents in this class are not currently approved
Adapted from Doebber TW et al Biochem Biophys Res Comm 2004;318:323–328; Guo Q et al Endocrinology 2004;145(4):1640–1648;
Hegarty BD et al Endocrinology 2004;145(7):3158–3164; Bristol-Myers Squibb Research and Development Review, 2004; Verges B Diabetes
Metab 2004;30(1):7–12.
Slide 20
Therapies in Development
GLP-1 Therapies: Rationale
Glucose-dependent insulinotropic
effects (low risk of hypoglycemia)
Increased insulin release
GLP-1
Functional improvements in beta-cell
beta-cell
? in
humans
Beta-cell neogenesis
Long-term improvements
in beta-cell function?
GLP-1=glucagon-like peptide 1
Adapted from Drucker DJ Expert Opin Invest Drugs 2003;12(1):87–100; Evans DM IDrugs 2002;5(6):577–585; Holz GG, Chepurny OG Curr Med
Chem 2003;10(22):2471–2483; Knop FK et al Diabetes Care 2003;26(9):2581–2587; Xu G et al Diabetes 1999;48(12):2270–2276.
Slide 21
Therapies in Development
GLP-1 Therapies: Mechanism of Action
Pancreas
Augments glucose-induced insulin
release; increases insulin biosynthesis;
inhibits glucagon secretion; may
potentially promote beta-cell
differentiation
Liver
Muscle
Hyperglycemia
Inhibits glucose
production
Gut
Improves glucose
uptake
Slows gastric emptying;
promotes satiety;
reduces food intake
Adapted from Holz GG, Chepurny OG Curr Med Chem 2003;10(22):2471–2483; Drucker DJ Endocrinology 2001;142(2):521–527; Evans DM
Drugs 2002;5(6):577–585; Schirra J et al J Endocrinol 1998;156(1):177–186; Gutzwiller JP et al Am J Physiol 1999;76(5 pt 2):R1541–1544;
DeFronzo RA Ann Intern Med 1999;131:281–303.
Slide 22
Therapies in Development
GLP-1 Analogs: Overview
Mechanism of action
Multiple pathways
Route of administration Injectable
Potential benefits
Preservation or restoration
of beta-cell function
Durable glucose control
Note: Agents in this class are not currently approved
Adapted from Holz GG, Chepurny OG Curr Med Chem 2003;10(22):2471–2483; Drucker DJ Endocrinology 2001;142(2):521–527; Drucker DJ
Expert Opin Invest Drugs 2003;12(1):87–100.
Slide 23
Therapies in Development
DPP-IV Inhibitors: Rationale
Mixed
meal
Intestinal
GLP-1
release
GLP-1 (7-36)
active
DPP-IV
DPP-IV
inhibitor
GLP-1 (9-36)
inactive
DPP-IV=dipeptidyl peptidase IV
Adapted from Drucker DJ Expert Opin Invest Drugs 2003;12(1):87–100; Ahrén B Curr Diab Rep 2003;3:365–372.
Slide 24
Therapies in Development
DPP-IV Inhibitors: Mechanism of Action
Delayed gastric emptying
Other potential substrates
(e.g., GIP, GLP-2, PACAP)
Active GLP-1
• Increased insulin biosynthesis and
secretion (glucose dependent)
• Decreased glucagon
• Potentially improved beta-cell function
DPP-IV
inactive metabolites
Inactive GLP-1
Decreased
food intake
GIP=glucose-dependent insulinotropic peptide; PACAP=pituitary adenylate cyclase activating polypeptide
Adapted from Ahrén B Curr Diab Rep 2003;3:365–372; Schirra J et al J Endocrinol 1998;156(1):177–186; Meier JJ et al Clin Endocrinol Metab
2003;88(6):2719–2725; Holz GG, Chepurny OG Curr Med Chem 2003;10(22):2471–2483; Drucker DJ Expert Opin Invest Drugs 2003;12(1):
87–100; Gutzwiller J-P et al Am J Physiol 1999;76(5 pt 2):R1541–1544; Drucker DJ Endocrinology 2001;142(2):521–527.
Slide 25
Therapies in Development
DPP-IV Inhibitors: Overview
Mechanism of action
Inhibit degradation of incretins (e.g., GLP-1)
resulting in
• Increased insulin release
• Decreased glucagon secretion
• Delayed gastric emptying
• Reduced food intake
• Potentially improved beta-cell function
Route of administration
Oral
Potential benefits
Preservation or restoration of beta-cell function
Durable glucose control
Note: Agents in this class are not currently approved
Adapted from Ahrén B Curr Diab Rep 2003;3:365–372; Schirra J et al J Endocrinol 1998;156(1):177–186; Meier JJ et al Clin Endocrinol Metab
2003;88(6):2719–2725; Holz GG, Chepurny OG Curr Med Chem 2003;10(22):2471–2483; Drucker DJ Expert Opin Invest Drugs 2003;12(1):
87–100; Gutzwiller JP et al Am J Physiol 1999;76(5 pt 2):R1541–1544; Drucker DJ Endocrinology 2001;142(2):521–527; Holst JJ, Deacon CF
Diabetes 1998;47(11):1663–1670.
Slide 26
Differences among Current and Developing Therapies
Effects on Beta-Cells
Class
Effects on beta-cells
Sulfonylureas
Stimulation of insulin release;
beta-cell exhaustion over long-term exposure
Meglitinides
Stimulation of insulin release;
beta-cell exhaustion over long-term exposure
Biguanides (metformin)
No direct effects
PPARγ agonists
Indirect effects via improved insulin sensitivity;
evidence of recovery of function
Alpha-glucosidase
inhibitors
Allow beta-cells time to augment insulin release;
no direct effects
Not currently approved:
Dual PPARs
Unknown
GLP-1 analogs
Potential preservation or restoration of function (animal data)
DPP-IV inhibitors
Potential preservation or restoration of function (animal data)
Adapted from Buchanan TA et al Diabetes 2002;51:2796–2803; Ovalle F, Bell DS Diabetes Obes Metab 2002;4(1):56–59; Wolffenbuttel BH,
Landgraf R Diabetes Care 1999;22(3):463–467; DeFronzo RA Ann Intern Med 1999;131:281–303; Ahrén B Curr Diab Rep 2003;3:365–372;
Drucker DJ Expert Opin Invest Drugs 2003;12(1):87–100; Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia:
Saunders, 2003:1427–1483; Skrumsager BK et al J Clin Pharmacol 2003;43(11):1244–1256.
Slide 27
Differences among Current and Developing Therapies
Therapeutic Effects and Limitations
Class
Primary
therapeutic
effect
Limitations
Sulfonylureas
 HbA1c
Hypoglycemia, weight gain
Meglitinides
 PPG
Hypoglycemia, weight gain
Biguanides (metformin)
 HbA1c
GI adverse effects, lactic acidosis (rare)
PPARs
 HbA1c
Weight gain, edema, anemia, potential for liver
toxicity
Alpha-glucosidase inhibitors
 PPG
GI adverse effects
Insulin
 HbA1c
Injectable route, hypoglycemia, weight gain
Not currently approved:
Dual PPAR-alpha/gamma
agonists
 HbA1c
More data needed
GLP-1 analogs
 HbA1c
Injectable route, more data needed
DPP-IV inhibitors
 HbA1c
More data needed
Adapted from DeFronzo RA Ann Intern Med 1999;131:281–303; Williams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed. Malden, MA:
Blackwell Publishing, 2004; Holz GG, Chepurny OG Curr Med Chem 2003;10(22):2471–2483; Meneilly GS Diabetes Care 2003;26(10):
2835–2841; Ahrén B et al Diabetes Care 2002;25(5):869–875; Moller DE Nature 2001;414:821–828.
Slide 28
Current and Developing Therapies for Type 2 Diabetes
Summary and Conclusions
• Type 2 diabetes is characterized by:
– Deficient insulin production and release (beta-cell dysfunction)
– Loss of sensitivity to the actions of insulin (insulin resistance)
• Each class of medication acts by a unique mechanism to improve
hyperglycemia
• These unique mechanisms also determine the drug’s other actions
– Adverse effects
– Effects on lipid abnormalities
– Potential disease-modifying effects (i.e., effects on beta-cell
function)
• Therapeutic choices will require consideration of the potential
mechanism-based effects of the drug in the individual patient
Adapted from DeFronzo RA Ann Intern Med 1999;131:281–303; Inzucchi SE JAMA 2002;287(3):360–372; Doebber TW et al Biochem
Biophys Res Comm 2004;318:323–328; Holz GG, Chepurny OG Curr Med Chem 2003;10(22):2471–2483.
Slide 29
Bibliography
Please see notes page.
Slide 30
Bibliography (continued)
Please see notes page.
Slide 31
Current and Future Therapies for the
Treatment of Type 2 Diabetes Mellitus
Before prescribing, please consult
the manufacturers’ prescribing information.
Merck does not recommend the use of any product
in any different manner than as described in
the prescribing information.
All rights reserved.
Copyright © 2005 Merck & Co., Inc., Whitehouse Station, NJ, USA.
2-06 MK431 2004-W-7001-SC
VISIT US ON THE WORLD WIDE WEB AT http://www.merck.com
Printed in USA
Slide 32