Management of Type 2 Diabetes · Presentation • Insidious onset (asymptomatic many yrs) •...
Transcript of Management of Type 2 Diabetes · Presentation • Insidious onset (asymptomatic many yrs) •...
Pathophysiology
• Insulin resistance and relative insulin deficiency/ defective secretion
• Not immune mediated• No evidence of β cell destruction• Increased risk with age, obesity and ↓
physical activity• Strong genetic predisposition
Adapted from 2. Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483; 3. Buchanan TA Clin Ther 2003;25(suppl B):B32–B46; 4. Powers AC. In: Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill, 2005:2152–2180; 5. Rhodes CJ Science 2005;307:380–384.
The pathophysiology of type 2 diabetes
HyperglycaemiaLiver
Insulin deficiency
Excess glucose output Insulin resistance (decreased glucose
uptake))
Pancreas
Muscle and fat
Excess glucagon
Islet
Diminishedinsulin
Diminishedinsulin
Alpha cellproduces excess glucagon
Beta cellproduces less insulin
Presentation
• Insidious onset (asymptomatic many yrs)• generally not ketosis• Tendency to be obese• Macrovascular/microvascular complications
at presentation• Not insulin dependent but may be insulin
requiring
Current Treatment Type 2 Diabetes
Diet, Lifestyle change and Metformin
Sulphonlyurea
Poglitazone
Metformin Intolerant
Or
HbA1C ≥ 7 %
Add
On Triple Therapy
Insulin Regimens
New Therapy
New Therapy
Problems With Existing Therapies
• Sulphonlyurea Therapy
• Glitazone Therapy
• Insulin combinations
• Weight gain 2.6kg (UKPDS 1998)
• Weight gain 4.5 kg (obesity review 2007)
• 43 % ↑ Myocardial Infarction (NEJM 2007)
• Weight Gain 4 kg (UKPDS 1998)
Treatment of Type 2 Diabetes
• First line– Diet and lifestyle changes and Metformin
• Second line– Sulphonlyura– Gliptins– Glitazone
• Third line– Add on any of above– Basal Insulin– BD Insulin
Metformin
• First line drug in all patients regardless of weight• Mechanism of action is reduction in hepatic
glucose output and increased insulin sensitivity• Not associated with hypoglycaemia• Start small dose (500mg) and titrate upwards
– With or after food to reduce side effects– Slow release metformin
• Sulphonlyurea, Glitazone, Gliptins and Insulin can be added to metformin therapy
• Renal failure
Sulphonlyurea Therapy
• Add on to Metformin• Lowers blood glucose by stimulating insulin
release• Can induce hypoglycaemia• Timing of dose not crucial but consider 30
min before breakfast (↓ plasma levels)• Role of sulphonlyureas in management is
changing
Glitazone Therapy
• New class of drug• Decreases glucose output by liver and
decreases peripheral insulin resistance• Two licensed at present which is restricted
– Rosiglitazine– Pioglitazone
• Time to effect ≈ 8 weeks• Contraindicated in liver disease and CCF
Rosiglitazone vs Pioglitazone
• Recent evidence rosiglitazone is associated with significant increase risk of MI and death from cardiovascular causes
• No such effect with Pioglitazone• Pioglitazone lower risk of deaths from MI,
stroke• Position statement risk vs benefits
Insulin Secretagogues
• Post prandial glucose regulators• Second line drugs• Rapid onset of action and short duration• Avoidance of hypoglycaemia• Nateglinide or Repaglinide
α Glucosidase Inhibitors
• Inhibit glucose absorption in small bowel• Effective in control of post prandial
hypoglycaemia• Cause GI upset
GLP-1 effects in humans
Adapted from 1Nauck MA, et al. Diabetologia 1993;36:741–744; 2Larsson H, et al. Acta Physiol Scand 1997;160:413–422; 3Nauck MA, et al. Diabetologia 1996;39:1546–1553; 4Flint A, et al. J Clin Invest 1998;101:515–520; 5Zander et al. Lancet 2002;359:824–830.
GLP-1 secreted upon the ingestion of food
1.β-cell:enhances glucose-dependent
insulin secretion in the pancreas1
3.Liver:reduces hepatic glucose
output2
2.α-cell:suppresses postprandial
glucagon secretion1
4.Stomach:slows the rate of
gastric emptying3
5.Brain:promotes satiety and
reduces appetite4,5
Incretins and glycaemic control
Adapted from 7. Drucker DJ. Cell Metab. 2006;3:153–165. 8. Miller S, St Onge EL. Ann Pharmacother 2006;40:1336-1343.
Active GLP-1 and GIP
Release of incretin gut hormones
Pancreas
Bloodglucose control
GI tract
Glucagon from alpha cells
(GLP-1)Glucose dependent
Alpha cells
Increased insulin and decreasedglucagon reduce hepatic glucose output
Glucose dependentInsulin
from beta cells(GLP-1 and GIP)
Beta cells
Insulinincreases peripheral glucose uptake
Ingestion of food
DPP-4enzyme rapidly
degrades incretins
Therapeutic Agents using the GLP-I Pathway
• GLP-1 receptor agonists– Exenatide (naturally occurring but bioengineered)
– Liraglutide (GLP-1 analogue)
• DPP-IV Inhibitors– Sitagliptin – Vidagliptin– Saxagliptin
GLP-1• BYETTA® was authorised by the European Medicines
Evaluation Agency (EMEA) in November 2006• BYETTA® is indicated for the treatment of type 2 diabetes
mellitus in combination with metformin, and/or sulphonylureain patients who have not achieved adequate glycaemic control on maximally tolerated doses of these oral therapies
Exenatide Summary of Product Characteristics 2006Fixed dose, pre-filled pens
Overall incidence ≥5% and incidence of Exenatide > placeboBYETTA® (exenatide) US Prescribing Information, February 2007, data on file.
Results of 30-week exenatide studies
Placebo (N = 483)
Exenatide 5 µg and 10 µg BD
(N = 963)Nausea 18% 44%Vomiting 4% 13%Diarrhoea 6% 13%Feeling jittery 4% 9%Dizziness 6% 9%Headache 6% 9%Dyspepsia 3% 6%
Adverse events
Sitagliptin (DPP-4 inhibitor)• Sitagliptin is an orally administered DPP-4
inhibitor
• Improvement in glycaemic control is mediated by increasing the levels of active incretin hormones (GLP-1, GIP) leading to
• Decreased glucagon
• Increased insulin
• Sitagliptin improves glycaemic control as monotherapy or add on therapy to metformin or pioglitazone
Adverse Events
UncommonVomiting
UncommonDiarrhoea
UncommonAbdominal Pain
CommonNausea
commonUncommonHypoglycaemia
Sitagliptin and Pioglitazone
Sitagliptin and Metformin
D I A G N O S I S
A n d / O r
L I F E S T Y L E I N T E R V E N T I O N
A N D
M E T F O R M I N
c o n s id e r
A d d to
o r
O r
Y E S
A d dP IO G L IT A Z O N E
A d dP IO G L IT A Z O N E
O rS U L P H O N L Y U R E A P I O G L I T A Z O N E
S I T A G L I P T I N
M E T F O R M IN
P IO G L IT A Z O N E
S U L P H O N L Y U R E A
M E T F O R M IN
IN T O L E R A N T
H b A 1 C ≥ 7 %
O rO rS U L P H O N L Y U R E A P I O G L I T A Z O N E
S I T A G L I P T I N
M E T F O R M IN
P IO G L IT A Z O N E
S U L P H O N L Y U R E A
M E T F O R M IN
IN T O L E R A N T
H b A 1 C ≥ 7 %
O r
A d dB A S A L I N S U L I N
H b A 1 C ≥ 7 %
S to p S I T A G L IP T I N
tr ip le th e r a p yO r
A d d it io n o f s u lp h o n ly u r e a a n d /o r b a s a l in s u l in
O rIn te n s ife d in su l in r e g im e n e g
b a sa l p lu sA d d E x e n a t id e to S u lp h o n ly u r e a a n d
o r M e tfo rm in
H b A 1 C ≥ 7 %
H b A 1 C ≥ 7 %
A d dB A S A L I N S U L I N
A d dB A S A L I N S U L I N
H b A 1 C ≥ 7 %H b A 1 C ≥ 7 %
S to p S I T A G L IP T I N
tr ip le th e r a p yO r
A d d it io n o f s u lp h o n ly u r e a a n d /o r b a s a l in s u l in
O rIn te n s ife d in su l in r e g im e n e g
b a sa l p lu s
S to p S I T A G L IP T I N
tr ip le th e r a p yO r
A d d it io n o f s u lp h o n ly u r e a a n d /o r b a s a l in s u l in
O rIn te n s ife d in su l in r e g im e n e g
b a sa l p lu sA d d E x e n a t id e to S u lp h o n ly u r e a a n d
o r M e tfo rm inA d d E x e n a t id e to S u lp h o n ly u r e a a n d
o r M e tfo rm in
H b A 1 C ≥ 7 %
H b A 1 C ≥ 7 %
L ife s ty le c h a n g e a n d M e tfo rm in
D ia g n o s is
A d dP I O G L IT A Z O N E
H b A 1 C ≥ 7 %
Y E S
Summary
• Type 1 diabetes requires diet and insulin treatment
• Type 2 requires diet, oral hypoglycaemic agents and or insulin
• Choice is agent depends on many factors weight, co morbidities and ability to tolerate drug
Male Age 50 Years
• Presented with symptoms confirmed diagnoses of type 2 diabetes
• BMs 10-17mmol/l• HbA1c 10 %• What treatment, if any
would you choose?
• Diet• Role of Metformin• Role of Glitazone• Would you give a
sulphonlyurea?• Why/why not?
Female Age 56 Years
• Type 2 diabetes for 10 years
• HbA1c 9%• Diet , metformin and
sulphonlyurea• BMI 35• Previous MI
• What options are available to you?
• How would you proceed?
• Review diet/ exercise• Review treatments
Male Age 35 Years
• Type 2 Diabetes 3 years
• BMI 40• HbA1c 10%• On sulphonlyurea and
pioglitazone• HGV License• eGFR 40 mls/min
• How would you proceed with this patient?
• Would you use Metformin ???
• What are your treatment options?