Download Insulin - Minerva

The therapeutics of diabetes
Simon Heller
Outline
 Treating Type 1 diabetes
 Type 2 diabetes
– Role of current oral agents and new
injectables
– Approaches to insulin treatment
 Treating DKA
Current insulins

Short acting insulins
– Conventional human soluble
• Actrapid, Humulin S
– Rapid Acting insulin analogues
• Insulin aspart, insulin lispro, insulin glulisine

Medium acting insulins
– Conventional human isophane (NPH)
• Human insulatard, Humulin I
– Long acting insulin analogues
• Insulin glargine, insulin detemir

Pre-mixed insulins
– Conventional human insulin
• Mixtard, Humulin M3 (30% sol, 70% NPH)
– Insulin analogues
• Humalog Mix25 (25% humalog 75% NPH), Novomix 30
(30% aspart, 70% NPH)
Benefits and risks of tight glucose control
14
Retinopathy per 100 patient years
12
10
8
6
4
2
0
100
Severe hypoglycaemia per 100 patient years
16
Hypoglycaemia
Retinopathy
80
60
Intensive group
40
20
0
5
DCCT Group, Diabetes 1996
6
7
8
9
10
Haemoglobin A1c
11
12
13
14
Conventional plasma insulin profile
Plasma insulin (pmol/l)
450
Normal free insulin levels
(Mean)
Estimated s.c. injected
soluble human insulin + NPH
300
Meals
150
0
0600 0900
1200
1500
1800
2100 2400 0300
Time of day
Breakfast Lunch
Adapted from Rizza 1981, Polonsky et al. 1988
Dinner
NPH
0600
Treatment of Type 1 diabetes
First choice for everyone is to “restore” the physiology of the beta
cell

Insulin treatment
– Separate basal insulin secretion and meal related insulin by giving:
Meal related insulin-pre meal quick acting insulin)
Background-twice daily medium acting insulin (NPH) or once or
twice daily long acting analogues (glargine or detemir)



Measure CHO intake (CHO counting)
Eat freely and flexibly with pre-meal monitoring to decide correct
dose of quick acting insulin
Awareness of blood glucose lowering effect of exercise
All combined to keep blood glucose close to normal (and so
prevent diabetic complications)
For those who are unable to cope with this intensive therapy, then
twice daily pre-mixed insulin with occasional monitoring is a less
good but common option
Most people with Type 1 diabetes fail to achieve
tight glycaemic control
 Risk of hypoglycaemia
 Too arduous a treatment
 Risk of weight gain
 Interference with lifestyle
New educational approaches encouraging
effective self-management by intensive skills
training are now standard treatment across
the UK
Type 2 diabetes
 Perhaps the greatest non-infective threat to
global health
 4% prevalence in Sheffield
 15-20% prevalence in many developing
countries
 Currently affects 150 million (set to double by
2020)
 A disease of ‘western industrialised lifestyle’
– Obesity
– Lack of physical exercise
Prevalence (millions)
Increasing Prevalence of T2D Globally
WHO database, 2003
140
120
100
80
60
40
20
0
2000
2030
Type 2 diabetes-pathophysiology
 Metabolic defects
– Insulin resistance
– Impaired insulin secretion and progressive
-cell damage
– Excessive hepatic glucose output
– Increased counterregulatory hormones
including glucagon
On the background of excessive energy
intake
Principles of treatment







Control of symptoms
Identification and prevention of long-term
microvascular complications
No evidence yet that glucose control reduces
cardiovascular events (confirmed by 2 recent clinical
trials, ACCORD, ADVANCE) in the short-term
But longterm follow-up indicates a modest reduction
in MI from tight glucose control if started at diagnosis
HbA1c <7.5% (as low as possible in those not on
insulin or sulphonylureas)
Negative urine tests
Fasting blood glucose <7mM
Treatment in Type 2 diabetes
in reality
 Ideally consists of weight loss and exercise which
if substantial will reverse hyperglycaemia
but most of those with Type 2 diabetes have been
making the ‘wrong’ lifestyle choices all their lives
and rarely respond to std approaches
 At present, management usually consists of
medication to control BP, blood glucose and lipids
Metformin
a biguanide,the drug of choice in the obese with NIDDM
– modest improvement in control (around 1-1.5%
in HbA1c)
– opposes insulin resistance
– no weight gain
– may improve lipids
– reduces cardiovascular risk (UKPDS)
risk of lactic acidosis if renal function impaired
–
–
(don’t prescribe if creatinine >150mcmol/l)
s/e of diarrhoea reduced by gradual increase in
dose and taking tablets with food.
 Sulphonylureas (gliclazide, glibenclamide,
gliquidone)
– stimulate insulin release by binding to -cell
receptors
– Improve glycaemic control (1-2% in HbA1c) at the
expense of significant weight gain.
– Do not prevent the gradual failure of insulin
secretion
– Can cause hypoglycaemia (occasionally
prolonged and fatal, particularly in the elderly)
– Use gliclazide in most people and avoid
glibenclamide in the over 60s

Warn and document the risks of
hypoglycaemia
Thiazolidinediones (pioglitazone - ACTOS)
 Bind to the nuclear receptor PPAR
(peroxisome proliferator-activated receptor)
 Activate genes concerned with glucose
uptake and utilisation and lipid metabolism
 Improve insulin sensitivity
 Need insulin for a therapeutic effect
 Glitazones are now less popular
– Rosiglitazone increased cardiovascular events
and is now withdrawn
– Increase weight
– Increase the risk of heart failure
– Increase the risk of fractures
An ideal drug in Type 2 diabetes
 Would:
–
–
–
–
Reduce appetite and induce weight loss
Preserve -cells and insulin secretion
Increase insulin secretion at meal time
Inhibit counterregulatory hormones which increase
blood glucose such as glucagon
– Not increase the risk of hypoglycaemia during
treatment
’Incretin’ concept
 Enteral glucose (or
food) causes greater
secretion of insulin
than glucose given
IV
 Many potential
molecules
 GIP/GLP-1 are the
dominant peptides
responsible for this
effect
Holst, 1999
Effects of GLP-1
Summary
Native GLP-1 is rapidly degraded
by DPP-IV
DPP-IV
7
9
37
enzymatic cleavage
high clearance (renal)
T½ =1-2 minutes (i.v.)
Exendin 4(exenatide)
 Naturally occurring
39AA GLP-1R
agonist from salivary
venom of Gila
monster
 53% homology with
GLP-1
 Resistant to DPP-IV
Extending the duration of action of GLP-1
 Exenatide(BYETTTA)
 Liraglutide (VICTOZA)
 DPP-IV inhibitors
– Vildagliptin (GALVUS)
– Sitagliptin (JANUVIA)
Therapeutic effect of GLP-1 in
Type 2 diabetes
 Reduces
– energy intake
– blood glucose
– weight
– HbA1c
Is this the holy grail of therapy in Type 2
diabetes?
Comparing GLP1 with DPP-IV inhibitors
Exenatide/Liraguti
de
DPP-IV Inh.
sc
Orally
- 1-2%
-0.7%
Up to 4 years
Up to one year
With
sulphonylureas
With
sulphonylureas
Weight effect
Reduction
No effect
Side effects
Mainly GI
Well tolerated
Administration
HbA1c reduction
HbA1c
maintenance
Hypoglycaemia
Oral agents - conclusions
 Sulphonylureas are still the second line
agents of choice
 GLP1 analogues and DPP-IV inhibitors
starting to replace
 Sales of glitazones are declining
are
Proportion of Type 2 patients eventually
needing insulin
100
80
% 60
Insulin
Oral Agents
40
20
0
0
5
10
Duration of diabetes (yr)
Choices of insulin therapy in Type 2 diabetes
 Oral agent/insulin combinations
 Bedtime long-acting (NPH or new long acting
analogues (glargine or detemir))
 Twice daily pre-mixed insulin containing
either soluble or rapid acting insulin analogue
 Basal bolus-twice daily background (NPH)
and pre-meal quick acting
 Weight gain during insulin therapy occurs
because:
– the decrease in energy loss as glycosuria ceases
is not compensated for by a comparable reduction
in energy intake.
– ? increase in appetite with an anabolic hormone
 Combinations of bedtime background
insulin(NPH) and oral agents seem to
produce comparable improvement in
glycaemic control but less weight gain.
Insulin in Type 2 diabetes
 The best insulin combination in terms of longterm glycaemic control, hypoglycaemia,
weight gain is probably basal overnight
medium acting insulin (NPH, glargine,
detemir)
 Metformin and sulphonylureas should
continue
 Overnight insulin is simple, acceptable to
patients who can contribute to dose
adjustment
Bariatric Surgery
 Can produce profound weight loss and may
also alter secretion of incretin hormones
 Two main operations
– Gastric banding
– Gastric bypass
 Can ‘cure’ Type 2 diabetes in up to 70% even
in those treated with insulin
 Currently limited to those with BMI >40
 Will become more common
Type 2 diabetes - Conclusions

This is not ‘mild’ diabetes - high risk of premature
vascular death and other vascular complications

The ‘best’ treatment, weight loss and increased
exercise is rarely achieved



Needs multiple medications, many of which are
probably not taken
The challenge is to engage the patient in the
management of their own condition
Is only really treatable by changing the culture (health
education and prevention)
 Definition
Diabetic Ketoacidosis
– Hyperglycaemia (use capillary sample but confirm with lab test)
– Venous bicarbonate less than 15 mmol/l
– Ketonaemia (if in doubt about cause of acidosis test urine or
plasma with ketostix)
 Causes
– older age groups- infections
– < 30y omission of insulin
 Mortality
– 5-10% ?lower in specialist centres
– Causes
• Elderly associated co-morbidity and late diagnosis
• Young
– severe DKA recognised late
– a failure to monitor patients and follow guidelines
– rare and poorly understood condition of cerebral oedema
in children
Pathophysiology (1)
 lack of insulin and/or rising levels of glucagon,
adrenaline, cortisol leads to rising glucose levels
from gluconeogenesis
 lipolysis raises NEFA and glycerol.
Liver oxidises
NEFA to form acetyl coA and then ketone bodies
 High glucose overcomes capacity of the kidney to
reabsorb glucose, glycosuria inhibits water
reabsorption and losses of potassium, sodium +
other electrolytes
 Compensation for urinary losses by drinking
maintains circulating blood volume
Pathophysiology (2)
 Rise in ketones and increasing acidaemia leads
to anorexia and vomiting, a critical point
 Circulating blood volume falls due to obligatory
urinary losses from osmotic effect of urinary
glucose

A viscious spiral follows with renal loss of water,
electrolytes, increasing glucose and worsening
acidosis
 Death within hours from severe acidosis and
circulatory collapse
Principles of DKA management
a potentially lethal condition, treatment should
be started with 30 min of admission
1.
2.
3.
Restore circulating blood volume
Replace lost electrolytes
Return blood glucose towards normal while
giving sufficient insulin to inhibit hepatic
production of ketones
Acidosis will correct itself if the above
treatment is delivered appropriately
Investigations
Venous blood for:
Urea and electrolytes
Blood glucose
Full blood count
Venous bicarbonate
Blood cultures
 Consider:
Arterial blood gases- only if you suspect
hypoxia.
Chest X-ray
ECG (always do in anyone over 30)
 1.
EARLY MANAGEMENT
IV Fluids
– 1 litre of normal saline over the first hour.
If there is hypotension give plasma volume
expander (eg, haemaccel or blood)
– Rate of fluid administration thereafter
depends upon age and fitness of patient.
– Typical rates are 1 litre in next 2h, then 1
litre in 4h and 1 litre every 6h from then on.
Reduce rates in the elderly or in cardiac
disease
– Be guided by urine output (>60ml/h)
– Rapid IV infusion rates increase the risk of
serious complications especially
respiratory distress syndrome.
Early Management
2. Potassium
Serum potassium is often normal or high
initially but total body potassium is low. Add
potassium to the IV infusion only when first
plasma potassium is known as follows:
Serum potassium (mmol/l)
Action
over 5.5
omit and check in 2h
below 5.5
use 40mmol/litre
in pre-filled bag
Early management
3.Insulin
Add 50 units of Actrapid insulin to 50 ml N
saline in a syringe. Infuse intravenously,
using a syringe driver and start rate at 6
units an hour.
Check venous blood glucose after 2h-if
blood glucose has not fallen, check pump
is working and IV connections then
increase rate to 12u/h.
Further management
Measure blood glucose hourly
Start 10% Glucose 1L 8 hourly once BG ≤ 14
mmol/L; continue sodium chloride 0.9% separately if
still volume deplete
Typical insulin infusion rate
Blood glucose (mmol/l); Infusion rate (units/h)
<4 stop pump, check IV fluid
4-7
1
>7-11
2
>11-17
4
>17
6
Target blood glucose is between 11 and 17 mmol/l at
4u/h insulin
Insulin levels need to remain high to inhibit ketogenesis
Other measures
1.Measure venous glucose, K+. Na+, bicarbonate
every 2h for 6h, thereafter frequency depends
upon clinical state.
2.Monitor ECG for potassium changes.
3.Consider urinary catheter if no urine passed
after 2h
4.Consider n/g tube and aspiration if patient is
comatose (only after airway is supported)
5.Give antibiotics only if there is evidence of
infection.
6.Give oxygen if arterial pO2 less than 11kPa
(80mmHg)
7.Give 10 units of Actrapid insulin IM if there is a
delay in starting intravenous insulin.
Other points
 Bicarbonate Generally not helpful and
potentially dangerous. Consider only after
discussion with senior colleagues
 Abdominal pain and tenderness common in
DKA and serum amylase often high in the
absence of pancreatitis.
 White cell counts as high as 30 x 109/L occur
in the absence of infection.
Hyperosmolar Non-Ketotic Coma
(HONK)
Definition
 Hyperglycaemia (blood glucose is
usually over 50 mmol/l)
 Hyperosmolality (usually over
350mosmoles/l)
 Serum bicarbonate over 20mmol/l
Management
Similar to DKA but :
1. Patients are usually elderly, have Type
2 diabetes and have decompensated
slowly
Mortality is high
2. Plasma sodium is usually over 150
mmol/l, but normal saline is still the fluid
of choice
3. Give enoxaparin 40mg once daily
unless C/I, as dehydration is usually
severe and high risk of venous
thrombosis
4. Most patients can eventually be
managed with sulphonylureas or diet.
Final comments
The commonest mistakes in treating
hyperglycaemic emergencies:
1.Failure to chase biochemistry and
act on the results, particularly K+
2.Failure to appreciate its severity
(especially in the elderly in whom
the mortality rate is over 50%)
3.Trying to correct the abnormal
metabolism too quickly.