Transcript Slide 1
Page 1: Baker IDI
Update on therapies for type 2 diabetes
Treatment algorithms for type 2 diabetes
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Management Algorithm for Blood Glucose Control in Type 2 Diabetes in Australia Lifestyle Modification
•
diet modification
•
weight control
•
physical activity Metformin Sulphonylurea Acarbose DPP-4 inhibitor # Glitazone* Insulin Basal Premixed Basal Bolus insulin
• The algorithm includes only therapeutic agents available through the PBS.
• If
HbA1c >7% consider intensifying treatment provided hypoglycaemia is not a problem.
# Authorised only as dual therapy with metformin or sulphonylurea where combination metformin and sulphonylurea is contraindicated or not tolerated
.
* Rosiglitazone is not authorised for triple therapy or for use with insulin (from February 1, 2009) but is approved only as dual therapy with metformin or sulphonylurea where combination metformin and sulphonylurea is contraindicated or not tolerated.
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Targets for type 2 diabetes in Australia
• • • •
Glycaemic control
–
HbA1c <7.0% Blood pressure*
–
<130/80 mmHg
–
<125/75 mmHg in the presence of proteinuria Lipids*
–
LDL >2.5 mmol/l – consider statin
–
TG >2.0 mmol/l – consider fibrate Aspirin for those with prior CVD, and those with other CVD risk factors
* NHMRC 2005
ADA/EASD algorithm 2009
a Sulfonylureas other than glybenclamide (glyburide) or chlorpropamide.
b Insufficient clinical use to be confident regarding safety.
Nathan et al.
Diabetes Care
2009
32:193-203
Stepwise Use of Medication
Monotherapy Combination OHA Insulin + OHA HbA1c > 7.0%
Metformin Sulphonylurea 2 or more of: Metformin Sulphonylurea Acarbose Glitazone Glinide GLP1 DPPIV Glitazone
Thiazoledinediones – Australian PBS restrictions
• Dual therapy, ie. rosiglitazone or pioglitazone, when SU or metformin contra-indicated or causes adverse event • Triple oral therapy NOW pioglitazone only!
• Can be combined with insulin NOW pioglitazone only!
• HbA1c must be >7.0% at initiation • Precautions: fluid retention, bone loss, (?coronary events with rosigltazone)
Insulin initiation in type 2 diabetes
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2.5
Quick-acting insulins
Humalog NovoRapid Apidra Regular Insulin (Actrapid,Humulin R) 0.5
Hours after Injection 10 12
2.5
Long-acting insulins
Protaphane Humulin NPH Lantus Levemir 0.5
4 2 8 4 12 6 Hours after Injection 16 8 20 24 Hours after injection
Management Algorithm for Blood Glucose Control in Type 2 Diabetes in Australia Lifestyle Modification
•
diet modification
•
weight control
•
physical activity Metformin Sulphonylurea Acarbose DPP-4 inhibitor # Glitazone* Insulin Basal Premixed Basal Bolus insulin
• The algorithm includes only therapeutic agents available through the PBS.
• If
HbA1c >7% consider intensifying treatment provided hypoglycaemia is not a problem.
# Authorised only as dual therapy with metformin or sulphonylurea where combination metformin and sulphonylurea is contraindicated or not tolerated
.
* Rosiglitazone is not authorised for triple therapy or for use with insulin (from February 1, 2009) but is approved only as dual therapy with metformin or sulphonylurea where combination metformin and sulphonylurea is contraindicated or not tolerated.
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Consensus statement EASD ADA 2008
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Insulin initiation trials
Diabetes Care 2003, Riddle et al.
Diabetes Care 2005, Raskin et al.
Minor hypoglycaemia 43% vs. 16% BiAsp vs. Glargine
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Why new treatments?
What’s wrong with the old treatments?
New treatments - why new treatments?
• • • • Beta cell preservation – Prevent relentless progression of type 2 diabetes Hypoglycaemia ? harmful CV morbidity and mortality – – ACCORD and other CV outcome trials Glitazone controversies Weight loss as a priority – Recognized as a major factor in morbidity Page 22: Baker IDI
Incretins
•
GLP 1 analogues
• • • Exenatide Liraglutide Once weekly GLP – 1 analogues •
DPP 4 inhibitors
• Sitagliptin Page 23: Baker IDI
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The Incretin Effect Demonstrates the Response to Oral vs IV Glucose Oral Glucose IV Glucose 11 2.0
* 1.5
5.5
* * * Incretin Effect * * 1.0
* 0.5
0 0 1 0 2 60 120 Time (min) 180 0.0
0 1 0 2 60 120 Time (min) 180 Mean ± SE; N = 6; *p
.05; 0 1 -0 2 = glucose infusion time.
Nauck MA, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986;63:492-498. Copyright 1986, The Endocrine Society.
The Incretin Effect Is Reduced in Patients With Type 2 Diabetes 80 Control Subjects 80 Intravenous Glucose Oral Glucose Patients With Type 2 Diabetes 60 60 40 40 20
* * * * * * *
20
* * *
0 0 30 60 90 120 150 180 Time (min) 0 0 30 *p≤.05 compared with respective value after oral load. Nauck MA, et al. Diabetologia. 1986;29:46-52. Reprinted with permission from Springer Verlag © 1986.
60 90 120 150 180 Time (min)
GLP-1 Effects in Humans: Understanding the Glucoregulatory Role of Incretins GLP-1 secreted upon the ingestion of food Beta cells: Enhances glucose dependent insulin secretion Promotes satiety and reduces appetite Alpha cells: ↓ Postprandial glucagon secretion Liver: ↓ Glucagon reduces hepatic glucose output Stomach: Helps regulate gastric emptying Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520.; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.; Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553.; Adapted from Drucker DJ. Diabetes. 1998;47:159-169.
Development of Exenatide: An Incretin Mimetic
Exenatide (Exendin-4) • Synthetic version of salivary protein found in the Gila monster • Approximately 50% identity with human GLP-1 Binds to known human GLP-1 receptors on cells
in vitro
Resistant to DPP-4 inactivation
Exenatide
GLP-1 Human H
G
E G T F T S D
L
S
K Q M
E
E E
A
V R L
F I
E
W L
K N
G
G P S S G A P P P S – NH 2
H A E G T F T S D V S S Y L E G Q A A K E F I A W L V K G R – NH 2
Site of DPP-4 Inactivation Adapted from Nielsen LL, et al. Regulatory Peptides. 2004;117:77-88. With permission from Elsevier for English use only.; Drucker DJ. Diabetes Care. 2003;26:2929-2940.; Ahrén B. Best Pract Res Clin Endocrinol Metab. 2007;21:517-533.
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Exenatide once weekly
• • • • Once weekly vs bd exenatide, 30 week study Patients were drug naive or treated with 1 or more oral glucose lowering therapies (~15% diet/exercise, ~45% 1 OAD, ~40% 2 OADs).
Starting HbA1c 8.3
±1.0% HbA1c decreased in both groups , 1.9% ±0.08 vs 1.5%± 0.08 (P=0.002) in once weekly vs bd • • 22 week extension study LAR for all patients after first 30 weeks At 52 weeks decrease HbA1c by 2.0% both groups, 4.1 kg wt loss , 80% patients lost weight BP decreased 4-6 mmHg Page 31: Baker IDI
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DPP 4 inhibitors
Ingestion of food GI tract Release of gut hormones — incretins * Active GLP-1 & GIP Pancreas Glucose-dependent Insulin from β cells (GLP-1 and GIP) β cells α cells DPP-4 enzyme Glucose dependent Glucagon from α cells (GLP-1) Inactive GLP-1 Inactive GIP *Incretins are also released throughout the day at basal levels.
Glucose uptake by muscles Glucose production by liver Blood glucose in fasting and postprandial states Adapted from Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913; Ahrén B. Curr Diab Rep. 2003;2:365–372; Drucker DJ. Diabetes Care. 2003;26:2929–2940; Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441.
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Clinical experience with sitagliptin
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Effective for dual , triple therapy and with insulin
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Low side effect profile
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Weight neutral
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No hypoglycaemia in combination with metformin or glitazone
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Safe and effective in older patients
Januvia -PBS restrictions in Australia
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Dual therapy for combination with metformin or a sulphonylurea agent
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HbA1c > 7.0% at initiation
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Treatment with metformin or sulphonylurea as a second agent is either contraindicated or not tolerated
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(private script $100 per month)
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Other new agents
• SGLT 2 inhibitors • Glucokinase activators • Glucagon receptor antagonists