Pharmacological management
Blood glucose-lowering medicines
Slides current until 2008
Blood glucose-lowering medicines
Aims of treatment
Curriculum Module III-2
Slide 2 of 41
• Reduce the symptoms of
hyperglycaemia
• Limit adverse effects of treatment
• Maintain quality of life and
psychological well-being
• Prevent or delay vascular
complications of diabetes
Slides current until 2008
Blood glucose-lowering medicines
UKPDS: long-term glucose control
HbA1c (%)
9
Curriculum Module III-2
Slide 3 of 41
Conventional
8
Intensive
7
6
0
0
3
9
6
Years of treatment
12
15
UKPDS Study Group 1998
Slides current until 2008
Blood glucose-lowering medicines
Natural history of type 2 diabetes
Curriculum Module III-2
Slide 4 of 41
Insulin
resistance
Glucose
level
Beta-cell
dysfunction
Insulin
production
Time
Normal
Impaired glucose
tolerance
Type 2 diabetes
Henry 1998
Slides current until 2008
Blood glucose-lowering medicines
Mechanisms of action
Curriculum Module III-2
Slide 5 of 41
GLP-1 (incretins)
improve response to
glucose level
Biguanides and thiazolidinediones
reduce glucose production
Insulin secretagogues: sulphonylureas
and meglitinides increase insulin
production
Alpha-glucosidase
inhibitors slow
absorption of sucrose
and starch
Thiazolidinediones and biguanides reduce
insulin resistance
Slides current until 2008
Blood glucose-lowering medicines
Understanding the names
Curriculum Module III-2
Slide 6 of 41
• Chemical name relates to
chemical structure
• Generic name identifies a unique
compound with therapeutic
properties
• Brand name given by the
manufacturer
Slides current until 2008
ACTIVITY
Blood glucose-lowering medicines
Curriculum Module IV-1
Slide 7 of 41
• What are the most common oral
blood glucose-lowering
medicines in your community?
• What are their brand names and
generic names?
Slides current until 2008
Blood glucose-lowering medicines
The principles of combination
therapy
Curriculum Module III-2
Slide 8 of 41
• Two (or more) oral blood glucoselowering medicines that have
different mechanisms of action
• Two medications rather than
increase in initial medicine to
maximum dosage
• Fewer side effects than monotherapy at higher doses
Slides current until 2008
Blood glucose-lowering medicines
Expected effect of blood
glucose-lowering medicines
Class of medicine
Alpha-glucosidase
inhibitor
Curriculum Module III-2
Slide 9 of 41
Expected decrease in
HbA1C in monotherapy
0.5-0.8%
Biguanide
1.0-1.5%
Insulin sensitisers
1.0-1.5%
Most insulin
secretagogues
1.0-1.5%
Nateglinide
0.5%
Canadian Diabetes Association 2003
Slides current until 2008
Blood glucose-lowering medicines
Curriculum Module III-2
Slide 10 of 41
Strategies to help people remember
• Check that people understand
how and when to take their
medicines
• Clarify the benefits of treatment
• Keep regimens simple
• Minimize costs
• Discuss adverse effects
Rubin 2005
Slides current until 2008
Blood glucose-lowering medicines
Curriculum Module III-2
Slide 11 of 41
Targets for blood glucose
HbA1C
Target for people
who can achieve it
(without too much
Pre-meal
2 hours
post-meal
< 6%
4-6 mmol/L
5-8 mmol/L
<7%
4-7mmol/L1
5-10mmol/L1
90-130mg/dl*2
<180mg/dl2
<6.0mmol/L
<8.0mmol/L
<110mg/dl
<145mg/dl
hypoglycemia)1
Target for most
people with
diabetes
IDF Global guideline
for Type 2 diabetes3
<6.5%
1CDA
2003, 2ADA 2004,
3
IDF 2005
Slides current until 2008
Blood glucose-lowering medicines
Suggested starting medicine
HbA1c
<9%
>9%
Curriculum Module III-2
Slide 12 of 41
BMI
Suggested medicine
>25
Biguanide – alone or in combination
<25
1 or 2 agents from different classes
2 medicines from different classes
or insulin
CDA 2003
Slides current until 2008
Blood glucose-lowering medicines
Increasing or adding
Curriculum Module III-2
Slide 13 of 41
• If goals have not been reached
within 2-3 months, medication
should be increased or medication
from a different class added
• Target levels should be reached
within 6 months
• Insulin should be added if
necessary to reach target levels
Slides current until 2008
Blood glucose-lowering medicines
Biguanides
Curriculum Module III-2
Slide 14 of 41
• Action not fully understood
• Decreases glucose production in
liver
• Mild and variable effect on
muscle sensitivity to insulin
Side effects
• Gastrointestinal (nausea,
abdominal discomfort or diarrhea
and occasional constipation)
• Lactic acidosis
Slides current until 2008
Blood glucose-lowering medicines
Biguanides
Curriculum Module III-2
Slide 15 of 41
Contraindications
• Renal insufficiency
• Liver failure
• Heart failure
• Severe gastrointestinal disease
Advantages
• Do not cause hypoglycaemia
when used as mono-therapy
• Do not cause weight gain; may
contribute to weight loss
Slides current until 2008
Blood glucose-lowering medicines
Curriculum Module III-2
Slide 16 of 41
Biguanides
First-line treatment in
overweight or obese people
• Do not cause weight gain
• Have some effect on
resistance at the periphery
Slides current until 2008
Blood glucose-lowering medicines
Curriculum Module III-2
Slide 17 of 41
Biguanides
Caution
• Should be discontinued 24 hours
before procedures requiring
intravenous contrast dye
• Can be restarted 48 hours after
the procedure if renal function is
not compromised
Slides current until 2008
Blood glucose-lowering medicines
Sulphonylureas
Curriculum Module III-2
Slide 18 of 41
• Increase insulin secretion regardless of
blood glucose levels
• Many different medicines in this class
Side effects
• Hypoglycaemia
• Stimulate appetite and provoke weight
gain
• Nausea, fullness, heartburn
• Occasional rash
• Swelling
Slides current until 2008
Blood glucose-lowering medicines
Sulphonylureas
Curriculum Module III-2
Slide 19 of 41
Short-acting secretagogues
Meglitinides – increase insulin
secretion in response to increasing
blood glucose levels (i.e. after
eating)
Side effects
• Hypoglycaemia (probably less
than sulphonylureas)
• Weight gain
Slides current until 2008
Blood glucose-lowering medicines
Sulphonylureas
Curriculum Module III-2
Slide 20 of 41
Contraindications
• Type 1 diabetes
• Pregnancy
• Breastfeeding
Sulphonylureas - Use cautiously
with liver or kidney disease
Meglitinides - Severe impairment of
liver function
Slides current until 2008
Blood glucose-lowering medicines
Sulphonylureas
Curriculum Module III-2
Slide 21 of 41
Things to remember
• Some sulphonylureas have slower
onset and lower peak than glyburide,
thus may provoke less hypoglycaemia
• Some need to be taken only once a
day, therefore may be easier to
remember to take
• First generation sulphonylureas, such
as chlorpropamide may accumulate
and cause hypoglycaemia due to their
long duration of action
Slides current until 2008
Blood glucose-lowering medicines
Thiazolidinediones
Curriculum Module III-2
Slide 22 of 41
• Improve sensitivity to insulin in muscle,
adipose tissue and liver
• Reduce glucose output from liver
• Changes fat distribution by decreasing
visceral fat and increasing peripheral fat
Side effects
• Weight gain, fluid retention
• Upper respiratory infection and
headache
• Decrease in haemoglobin
Slides current until 2008
Blood glucose-lowering medicines
Thiazolidinediones
Curriculum Module III-2
Slide 23 of 41
Contraindications
• Liver disease, heart failure or
history of heart disease
• Pregnancy and breast feeding
They are not contraindicated in
renal insufficiency
Potential benefits
• Reduced levels of LDLcholesterol and increased level
of HDL-cholesterol
Slides current until 2008
Blood glucose-lowering medicines
Alpha glucosidase inhibitors
Curriculum Module III-2
Slide 24 of 41
• Slow digestion of sucrose and starch
and therefore delay absorption
• Slow post-meal rise in blood glucose
Side effects
• Flatulence, abdominal discomfort ,
diarrhoea
• As mono-therapy will not cause
hypoglycaemia
• Hypoglycaemia when used with other
medicine (e.g. a sulphonylurea)
Slides current until 2008
Blood glucose-lowering medicines
Alpha glucosidase inhibitors
Curriculum Module III-2
Slide 25 of 41
Contraindications
• Intestinal diseases, such as
Crohn’s
• Autonomic neuropathy
affecting the gastro-intestinal
tract
Must be taken just before a
meal
Slides current until 2008
Blood glucose-lowering medicines
GLP-1 (incretin mimetic agent)
Curriculum Module III-2
Slide 26 of 41
• Improves beta-cell responsiveness to
increasing glucose levels
• Decreases glucagon secretion
• Slows gastric emptying
• Results in a feeling of fullness
• Must be injected subcutaneously twice a
day, within 30-60 minutes before a meal
• Reduces HbA1c by ~1%
Side effects
• Nausea
• Weight loss
• Diarrhoea
• Risk of hypoglycaemia when used with a
sulphonylurea
Slides current until 2008
Blood glucose-lowering medicines
GLP-1 (incretin mimetic agent)
Curriculum Module III-2
Slide 27 of 41
Contraindications
• End-stage kidney disease or
renal impairment
• Pregnancy
• Severe gastrointestinal disease
Slides current until 2008
Blood glucose-lowering medicines
Curriculum Module III-2
Slide 28 of 41
DPP-4 Inhibitors
A new class of medications called DPP-4 inhibitors help improve A1C
without causing hypoglycemia.
They work by by preventing the breakdown of a naturally occuring
compound in the body, GLP-1.
GLP-1 reduces blood glucose levels in the body, but is broken down very
quickly so it does not work well when injected as a drug itself. By
interfering in the process that breaks down GLP-1, DPP-4 inhibitors allow
it to remain active in the body longer, lowering blood glucose levels only
when they are elevated.
DPP-4 inhibitors do not tend to cause weight gain and tend to have a
neutral or positive effect on cholesterol levels. Sitagliptin(Januvia),
saxagliptin(Onglyza) and Vidagliptin(Galvus) are currently DPP-4
inhibitors on the market .
ADA
Slides current until 2008
Blood glucose-lowering medicines
Older people with diabetes
Curriculum Module III-2
Slide 29 of 41
Beware of the possible reductions in
• General good health (with other
concomitant conditions)
• Kidney function (and increased risk of
hypoglycaemia)
• Family support and monitoring
• Vision
• Flexibility and activities of daily living
Remember also
• Poly-pharmacy increases the risk of
medicine-related adverse events
• To review all medication and
complementary therapies
Slides current until 2008
Blood glucose-lowering medicines
Older people with diabetes
Curriculum Module III-2
Slide 30 of 41
• Always start with the lowest dose
of any blood glucose-lowering
medicine and increase gradually
• Using shorter-acting medicines
reduces the risk of hypoglycaemia
• Hypoglycaemia may increase the
risk of falls and heart attack in
older people
Slides current until 2008
Blood glucose-lowering medicines
Older people with diabetes
Curriculum Module III-2
Slide 31 of 41
Remember the possibility of
• Forgetfulness
• Poor motivation
• Depression
• Cognitive deficits
• Poly-pharmacy
• Reduced manual dexterity
These impact on the ability to maintain
self-care and achieve maximum benefits
from blood glucose-lowering medicines.
Slides current until 2008
Blood glucose-lowering medicines
Ineffectiveness of blood glucoselowering medicines
Curriculum Module III-2
Slide 32 of 41
If oral blood glucose-lowering
medicines are ineffective
• Check diet and exercise
• Consider adding intermediate or
long-acting insulin at bedtime
• Maintain metformin
• Consider reducing or stopping
the morning sulphonylurea
Slides current until 2008
Blood glucose-lowering medicines
ACTIVITY
Curriculum Module IV-1
Slide 33 of 41
Class of medicine
Likely to cause
weight gain
Likely to cause
hypoglycaemia
Target postmeal glucose
Sulphonylureas
Biguanide
Glitazones
Meglitinides
Alpha-glucosidase
inhibitors
Incretin mimetic
agent & DPP
Inhibitors
Slides current until 2008
Blood glucose-lowering medicines
ACTIVITY
Curriculum Module IV-1
Slide 34 of 41
Case study
• AB has had type 2 diabetes for two years
• 51-year-old truck driver
• BMI of 32, blood pressure at 150/95
• HbA1C 9.5%
• No medication
• AB says he has no time for exercise and
will not change his meal pattern
What medication do you think should be
started and why?
Slides current until 2008
Blood glucose-lowering medicines
Curriculum Module III-2
Slide 35 of 41
Summary
• Lifestyle changes first
• Start medicine as soon as
needed
• Add a different kind
• No delay starting insulin
Slides current until 2008
Blood glucose-lowering medicines
Review question
Curriculum Module III-2
Slide 36 of 41
1. Which of the following adverse
reactions are most likely due to
metformin therapy?
a. Oedema
b. Diarrhea
c. Heart failure
d. Weight gain
Slides current until 2008
Blood glucose-lowering medicines
Review question
Curriculum Module III-2
Slide 37 of 41
2. Which of the following statements
best describes alpha-glucosidase
inhibitors?
a. Likely to cause weight gain
b. Should be taken with first bite of
the meal
c. Commonly associated with
hypoglycaemia
d. Well tolerated, few side effects
Slides current until 2008
Blood glucose-lowering medicines
Review question
Curriculum Module III-2
Slide 38 of 41
3. Which statement is FALSE?
a. All oral medicines used to treat diabetes
should be discontinued once insulin is
started
b. In most people, blood glucose-lowering
medicines become less effective over time
c. Blood glucose-lowering medicines from
different classes are often used in
combination to reach target blood glucose
d. It is important to be physically active and
follow a prescribed meal plan in addition to
blood glucose-lowering medicines
Slides current until 2008
Blood glucose-lowering medicines
Review question
Curriculum Module III-2
Slide 39 of 41
JL is a 45-year-old man. He has been taking
5 mg glyburide and 500 mg metformin at
breakfast and supper. His fasting blood
glucose ranges from 5.3–6.7mmol/L but he
has been experiencing hypoglycaemia most
days at 3 or 4 pm.
4. What is the likely cause of JL’s low blood
sugars?
a. Breakfast metformin
b. Supper metformin
c. Breakfast glyburide
d. Supper glyburide
Slides current until 2008
Blood glucose-lowering medicines
Review question
Curriculum Module III-2
Slide 40 of 41
5. When filling his prescription for a
sulphonylurea, what is the most
important thing to discuss with John?
a. What and when to eat
b. When to take the medication
c. How to recognize and treat
hypoglycaemia
d. When to see his doctor again
Slides current until 2008
Blood glucose-lowering medicines
Curriculum Module III-2
Slide 41 of 41
Answers
1. b
2. b
3. a
4. c
5. c
Slides current until 2008
Blood glucose-lowering medicines
References
1.
2.
3.
4.
5.
6.
7.
8.
Curriculum Module III-2
Slide 42 of 41
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose control with
sulphonylureas or insulin compared with conventional treatment and risk of
complications in person with diabetes with type 2 diabetes (UKPDS 33). Lancet 1998;
352: 837-53.
Ahmann AJ, Riddle MC. Current blood glucose lowering medicines for type 2 diabetes.
Postgrad Med 2002; 111(5): 32-46.
Henry RR. Type 2 diabetes care: the role of insulin-sensitizing agents and practical
implications for cardiovascular disease prevention. Am J Med 1998; 105(1A): 20S-26S.
Luna B, Feinglos MN. Blood glucose-lowering medicines in the management of type 2
diabetes mellitus. Am Fam Physician 2001; 63(9): 1747-56.
Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Clinical
Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J
Diab 2003; 27(supple 2).
Yki-Jarvinnen H, Ryysy L, Nikkila K, et al. Comparison of bedtime insulin regimen in
person with diabetes with type 2 diabetes mellitus; a randomized control trial. Annals
Intern Med 1999; 130(5): 89-96.
Amylin Pharmaceuticals Inc and Eli Lilly & Co. Byetta (cited 2005July 25) (16 screens).
(Available from: http://www.byetta.com)
Rubin Rr. Adherence to pharmacologic therapy in patients with type 2 diabetes
mellitus. Am J Med 2005; 118(5A): 275-345.
Slides current until 2008