Insulin therapy - abcdiabetes.co.uk

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DIABETES
CONTROL
The Alphabet Strategy
• Advice
• Blood pressure
• Cholesterol
• Diabetes control
• Eye examination
• Feet examination
• Guardian drugs
Smoking , diet , exercise
< 140/80
TC ≤ 4 , LDL : HDL ≤ 2
HbA1c ≤ 7%
Annual examination
Annual examination
Aspirin, ACEI, statins &c
Effect on diabetes complications
of HbA1c% reduction
Study name
DCCT
UKPDS
Kumamoto
Steno-2
HbA1c
 2%
 0.9%
 2%
 1.0%
Retinopathy
 63%
 17-21%
 69%
 58%
Nephropathy
 54
 24-33%
 70%
 61%
Autonomic
neuropathy
 60%
_
_
 63%
CVD
 41%
 16%
_
 53%
Reductions in HbA1c and corresponding reductions in microvascular and
macrovascular complications described in major studies of persons with T1
DM and T2 DM
Micro
albuminuria
cataract
Retinal laser
MI
micro
vasculars
0%
any diabetes
endpoints
UKPDS : HbA1c% 7.0% versus 7.9%
-5%
-10%
-15%
-20%
12%
16%
P=0.052
25%
-25%
-30%
24%
29%
P=0.046
P=0.0099
33%
P=0.0031
-35%
P<0.001
UKPDS : glycaemic control
9
HbA1c (%)
Conventional
8
Intensive
7
6.2% upper limit of normal range
6
0
0
3
6
9
12
Years from randomisation
15
Type 1 diabetes - treatment
options
Type 1 diabetes - treatment
options
• Lifestyle
• Diet, exercise
• Insulin
• Islet transplantation
Type 1 diabetes
Premixed Insulin
Basal Bolus Regime
Why pre-mixed insulins don’t work
Diagrammatic representation of physiological insulin secretion and 30/70 pre-mixed insulin time-action profile
Physiological insulin
Blood insulin levels
Pre-mixed 30/70 regimen
06.00
12.00
Breakfast
Lunch
18.00
Dinner
24.00
06.00
Type 2 diabetes - treatment
options
Type 2 diabetes - treatment
options
• Lifestyle
• Diet, exercise
• Oral monotherapy
• Oral combination therapy
• Insulin (with or without oral agents)
Primary sites of action of
hypoglycaemic agents
-glucosidase inhibitors
Stomach
Carbohydrate
Gut
Sulphonylureas
Incretin mimetics
DPP-IV inhibitors
Glucose
I
I
Adipose tissue
Insulin
Pancreas
Insulin acts on all
tissues
I
Liver
Muscle
Thiazolidinediones
Biguanides
Adapted from Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1):S32–S40.
Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329.
Oral hypoglycaemic agents
Oral hypoglycaemic agents
•
•
•
•
•
•
•
Metformin
Sulphonylureas
Acarbose
Guar gum
Postprandial glucose regulators
Thiazolidinediones
Dipeptidyl peptidase-IV inhibitors
By injection
•
Incretin mimetics
Metformin : history
• French Lilac or Goat’s Rue (Galega
officianalis) - a traditional remedy for diabetes
- is rich in guanidine
Metformin : history
•
•
•
•
•
Used by mediaeval monks
1920s : guanidine derivatives introduced, then
forgotten
1957 : metformin, phenformin
1970s : phenformin withdrawn
1994 : metformin obtained FDA approval in USA
Metformin : efficacy
•  FPG 2 - 4,  HbA1c 1 - 2%
• Effect depends on the presence of insulin
• Hypoglycaemia unlikely with monotherapy
• Weight neutral
• Small improvement in lipid profile
• Reduced cardiovascular events
UKPDS : metformin in overweight subjects
0
Diabetes-related
endpoints
Diabetes-related
deaths
All-cause
mortality
Myocardial
infarction
Risk reduction (%)
5
10
15
20
25
30
35
p = 0.0023
p = 0.011
40
45
p = 0.01
p = 0.017
p values in comparison to conventional treatment group
United Kingdom Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352: 854–865.
Metformin : use
• First – line monotherapy in obese and non•
•
obese
Combination with other oral agents : effects
additive
Combination with insulin
Metformin : contraindications
Metformin : contraindications
• Impaired renal function
• Cardiac or respiratory insufficiency
• Liver disease, alcohol abuse
• History of metabolic acidosis
• Severe sepsis
• Use of IV contrast media
Metformin : adverse effects
Metformin : adverse effects
• Lactic acidosis:
•
•
• 0.03 cases / 1000 patient years
• 50% mortality
GI symptoms
B12 malabsorption
Sulphonylureas : history
• 1940s : sulphonamides noted to cause
•
•
•
•
•
hypoglycaemia.
1950s : carbutamide, tolbutamide
1960s : tolazamide, chlorpropamide
1970s : ? detrimental cardiovascular effects
1970s – 1980s : glibenclamide, glipizide,
gliclazide
1990s : glimepiride
Sulphonylureas : efficacy
•  FPG 2 - 4,  HbA1c 1 - 2%
• Only effective if beta-cell still functioning.
• Can initiate insulin release when plasma
•
glucose < 5.
Maximum glucose lowering effect may be
achieved below maximum permitted dose.
Sulphonylureas : use
• Not preferred in obese subjects
• Monotherapy
• Combination with other oral agents : effects
•
additive
? Combination with insulin
Sulphonylureas : adverse effects
Sulphonylureas : adverse effects
• Hypoglycaemia
• Weight gain : 1 - 4 KGm in 6 months
• Sensitivity reactions
Postprandial glucose regulators
• Nateglinide, repaglinide
• Reduce postprandial glucose spikes by
•
•
•
•
•
•
restoring early phase insulin release
Reduce HbA1c% by 0.5-2.0%
Main use in combination with metformin
Meal time flexibility
? Less weight gain than with sulphonylureas
Gastrointestinal side-effects, hypoglycaemia
No outcome data
Glitazones : history
• 1980s : effect first described
• 1997 : troglitazone introduced – and
•
•
•
withdrawn
1999 : rosiglitazone (Avandia  , GSK) and
pioglitazone (Actos  , Takeda) introduced.
2005 : PROactive Study – small reduction in
CV events with pioglitazone.
2007 : does rosiglitazone increase CV
events?
Glitazones : efficacy
•  FPG 2 - 3,  HbA1c around 1 %
• Effect depends on the presence of insulin
• Full expression of dose may not be apparent
•
for 3 months
Not all patients respond
Glitazones : adverse effects
Glitazones : adverse effects
• Fluid retention : oedema , heart failure ,
•
•
•
anaemia
Weight gain : 1 – 4 KGm in 6 months
Hypoglycaemia in combination with other
oral agents
? Unforeseen chronic effects
Glitazones : contraindications
Glitazones : contraindications
• Heart failure
• Oedema
• Anaemia
• ? Insulin therapy
• ? Impaired liver function
New agents for T2D
•
CB1 receptor antagonist
• Rimonabant
•
Glucagon-like peptide-1 (GLP-1) receptor agonists
(incretin mimetics)
• Exenatide
• Liraglutide
•
Dipeptidyl peptidase-4 (DPP-4) inhibitors (incretin
enhancers)
• Sitagliptin
• Vildagliptin
UKPDS : glycaemic control
9
HbA1c (%)
Conventional
8
Intensive
7
6.2% upper limit of normal range
6
0
0
3
6
9
12
Years from randomisation
15
UKPDS : decline of -cell function
over time
-cell function (%)
100
Start of treatment
80
60
40
20
0
–10 –9 –8 –7 –6 –5 –4 –3 –2 –1
1
2
3
4
5
6
Time from diagnosis (years)
HOMA model, diet-treated
n = 376
Adapted from Holman RR. Diabetes Res Clin Pract 1998; 40 (Suppl.):S21–S25.
Insulin : history
• 1921
• 1940s
• 1980s
• 1990s
: Banting and Best
: protamine and zinc
: human insulin
: insulin analogues
Insulin : mechanisms
Increases :
Reduces :
•
•
•
•
•
•
•
•
•
•
Glucose uptake by
cells
Glycogen synthesis
Fatty acid synthesis
Cholesterol & LDL
synthesis
Amino acid transport
Protein synthesis
Glycogen breakdown
Gluconeogenesis
Lipolysis
Protein breakdown
Insulin : use
Insulin : use
• Type 1 diabetes
• Improved metabolic control in type 2 diabetes
• Oral therapies contraindicated or not tolerated
• Post-myocardial infarction (DIGAMI)
• Severe intercurrent illness , surgery
• Gestational diabetes not controlled by diet
Insulin : adverse effects
Insulin : adverse effects
• Hypoglycaemia
• Weight gain
• Allergy
• Lipohypertrophy and lipoatrophy
• Transient deterioration of retinopathy
• Insulin neuritis
Control versus hypos : DCCT
Weight gain with insulin : UKPDS
Change in weight (kg)
10.0
7.5
Intensive (Insulin)
5.0
2.5
Conventional
0
0
3
6
9
Years from randomisation
12
15
Insulin preparations
Short acting
onset 30 mins
peak 2-4 hours
duration 8 hours
Humulin S
Actrapid
Intermediate
onset 1-2 hours
peak 4-12 hours
duration 16-24 hours
Insulatard
Humulin I
Long acting
onset 1-2 hours
peak 4-12 hours
duration 20-35 hours
Human Ultratard
Humulin Zn
Analogue
onset 0-15mins
peak 1-2 hours
duration 4-6 hours
Humalog (Lispro)
Novorapid (Aspart)
duration 24 hours
Glargine , Levemir
How many do you need ?
How many do you need ?
• Novorapid
• NPH
• Glargine
• Detemir
• Novomix 30
Insulin regimes
• Twice daily mixture
• Once daily long acting
• Basal - plus
• Four times a day basal bolus
• ? Inhaled insulin
• Continuous Subcutaneous Insulin Infusion
Basal insulin* & oral combination
therapy in insulin naïve T2DM
Mean A1C level during study
N=756
Mean A1C (%; ± SE)
9
8.6
8.5
8
7.5
7.5
7.1
6.9*
7
6.5
0.5
0
8
Time (weeks)
* Basal insulin therapy studied was either Lantus (n=367) or NPH (n=389)
12
18
Basal bolus regime
Insulin : combination therapies
• Metformin
• Sulphonylureas
• Glitazones
EASD/ADA Algorithm (2006)
Bailey C et al (2006) Br J Diab Vasc Dis 6: 147
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