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Pharmacological management
Blood glucose-lowering medicines
Section 3 | Part 1 of 3
Curriculum Module III-2 | Glucose-lowering medication
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Aims of treatment
Reduce the symptoms ofhyperglycaemia
Limit adverse effects of treatment
Maintain quality of life andpsychological well-being
Prevent or delay vascularcomplications of diabetes
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UKPDS:long-term glucose control
06
7
8
9
0 3 6 9 12 15
HbA1c
(%
)
Years of treatment
Conventional
Intensive
UKPDS Study Group 1998
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Natural history of type 2 diabetes
Normal Impaired glucose
tolerance
Type 2 diabetes
Time
Insulin
resistance
Insulin
production
Glucose
level
Beta-cell
dysfunction
Henry 1998
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Mechanisms of action
Insulin secretagogues: sulphonylureasand meglitinides increase insulinproduction
Biguanides and thiazolidinedionesreduce glucose production
Thiazolidinediones and biguanides reduceinsulin resistance
Alpha-glucosidaseinhibitors slowabsorption of sucroseand starch
GLP-1 (incretins)improve response toglucose level
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Understanding the names
Chemical name relates tochemical structure
Generic name identifies a uniquecompound with therapeuticproperties
Brand name given by themanufacturer
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What are the most common oralblood glucose-lowering
medicines in your community?
What are their brand names andgeneric names?
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The principles of combinationtherapy
Two (or more) oral blood glucose-lowering medicines that have
different mechanisms of action
Two medications rather thanincrease in initial medicine to
maximum dosage Fewer side effects than mono-
therapy at higher doses
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Expected effect of bloodglucose-lowering medicines
Class of medicine Expected decrease inHbA1C in mono-therapy
Alpha-glucosidaseinhibitor
0.5-0.8%
Biguanide
Insulin sensitisersMost insulinsecretagogues
Nateglinide
1.0-1.5%
1.0-1.5%
1.0-1.5%
0.5%
Canadian Diabetes Association 2003
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Strategies to help people remember
Check that people understandhow and when to take their
medicines Clarify the benefits of treatment
Keep regimens simple
Minimize costs
Discuss adverse effects
Rubin 2005
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HbA1C Pre-meal 2 hourspost-meal
Target for people
who can achieve it(without too muchhypoglycemia)1
< 6% 4-6 mmol/L 5-8 mmol/L
Target for mostpeople withdiabetes
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Suggested starting medicine
HbA1c BMI Suggested medicine
25 Biguanide alone or in combination
9% 2 medicines from different classes
or insulin
CDA 2003
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Increasing or adding
If goals have not been reachedwithin 2-3 months, medication
should be increased or medicationfrom a different class added
Target levels should be reachedwithin 6 months
Insulin should be added ifnecessary to reach target levels
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Biguanides
Action not fully understood
Decreases glucose production inliver
Mild and variable effect onmuscle sensitivity to insulin
Side effects
Gastrointestinal (nausea,abdominal discomfort or diarrheaand occasional constipation)
Lactic acidosis
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Biguanides
Contraindications
Renal insufficiency
Liver failure
Heart failure Severe gastrointestinal disease
Advantages
Do not cause hypoglycaemiawhen used as mono-therapy
Do not cause weight gain; may
contribute to weight loss
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Biguanides
First-line treatment inoverweight or obese people
Do not cause weight gain
Have some effect onresistance at the periphery
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Biguanides
Caution
Should be discontinued 24 hours
before procedures requiringintravenous contrast dye
Can be restarted 48 hours after
the procedure if renal function isnot compromised
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Sulphonylureas
Increase insulin secretion regardless ofblood glucose levels
Many different medicines in this class
Side effects
Hypoglycaemia
Stimulate appetite and provoke weightgain
Nausea, fullness, heartburn
Occasional rash
Swelling
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Sulphonylureas
Short-acting secretagogues
Meglitinides increase insulin
secretion in response to increasingblood glucose levels (i.e. aftereating)
Side effects Hypoglycaemia (probably lessthan sulphonylureas)
Weight gain
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Sulphonylureas
Contraindications
Type 1 diabetes
Pregnancy Breastfeeding
Sulphonylureas - Use cautiouslywith liver or kidney disease
Meglitinides - Severe impairment ofliver function
l d l l d
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Sulphonylureas
Things to remember
Some sulphonylureas have sloweronset and lower peak than glyburide,
thus may provoke less hypoglycaemia
Some need to be taken only once aday, therefore may be easier toremember to take
First generation sulphonylureas, suchas chlorpropamide may accumulateand cause hypoglycaemia due to theirlong duration of action
Bl d l l i di i
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Thiazolidinediones
Improve sensitivity to insulin in muscle,adipose tissue and liver
Reduce glucose output from liver
Changes fat distribution by decreasingvisceral fat and increasing peripheral fat
Side effects
Weight gain, fluid retention Upper respiratory infection and
headache
Decrease in haemoglobin
Bl d l l i di i
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ThiazolidinedionesContraindications
Liver disease, heart failure orhistory of heart disease
Pregnancy and breast feeding
They are not contraindicated inrenal insufficiency
Potential benefits
Reduced levels of LDL-cholesterol and increased level
of HDL-cholesterol
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Alpha glucosidase inhibitors
Slow digestion of sucrose and starchand therefore delay absorption
Slow post-meal rise in blood glucose
Side effects
Flatulence, abdominal discomfort ,diarrhoea
As mono-therapy will notcausehypoglycaemia
Hypoglycaemia when used with othermedicine (e.g. a sulphonylurea)
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Alpha glucosidase inhibitors
Contraindications
Intestinal diseases, such as
Crohns Autonomic neuropathy
affecting the gastro-intestinaltract
Must be taken just before ameal
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GLP-1 (incretin mimetic agent)
Improves beta-cell responsiveness toincreasing 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
Blood glucose lowering medicines
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GLP-1 (incretin mimetic agent)
Contraindications
End-stage kidney disease or
renal impairment Pregnancy
Severe gastrointestinal disease
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Older people with diabetes
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 ofmedicine-related adverse events
To review all medication and
complementary therapies
Blood glucose lowering medicines
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Older people with diabetes
Always start with the lowest doseof any blood glucose-lowering
medicine and increase gradually Using shorter-acting medicines
reduces the risk of hypoglycaemia
Hypoglycaemia may increase therisk of falls and heart attack inolder people
Blood glucose lowering medicines
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Older people with diabetes
Remember the possibility of
Forgetfulness
Poor motivation
Depression
Cognitive deficits
Poly-pharmacy
Reduced manual dexterity
These impact on the ability to maintainself-care and achieve maximum benefitsfrom blood glucose-lowering medicines.
Blood glucose lowering medicines
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Ineffectiveness of blood glucose-lowering medicines
If oral blood glucose-loweringmedicines are ineffective
Check diet and exercise Consider adding intermediate orlong-acting insulin at bedtime
Maintain metformin Consider reducing or stoppingthe morning sulphonylurea
Blood glucose lowering medicines
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Class of medicine Likely to causeweight gain
Likely to causehypoglycaemia
Target post-meal glucose
Sulphonylureas
Biguanide
Glitazones
Meglitinides
Alpha-glucosidaseinhibitors
Incretin mimeticagent
Blood glucose-lowering medicines
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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 andwill not change his meal pattern
What medication do you think should bestarted and why?
Blood glucose-lowering medicines
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Summary
Lifestyle changes first
Start medicine as soon asneeded
Add a different kind
No delay starting insulin
Blood glucose-lowering medicines
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Review question
1. Which of the following adversereactions are most likely due tometformin therapy?
a. Oedema
b.Diarrhea
c. Heart failure
d.Weight gain
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Review question
2. Which of the following statementsbest describes alpha-glucosidaseinhibitors?
a. Likely to cause weight gain
b. Should be taken with first bite ofthe meal
c. Commonly associated withhypoglycaemia
d. Well tolerated, few side effects
Blood glucose-lowering medicines
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Review question
3. Which statement is FALSE?
a. All oral medicines used to treat diabetesshould be discontinued once insulin is
startedb. In most people, blood glucose-lowering
medicines become less effective over time
c. Blood glucose-lowering medicines fromdifferent classes are often used incombination to reach target blood glucose
d. It is important to be physically active andfollow a prescribed meal plan in addition toblood glucose-lowering medicines
Blood glucose-lowering medicines
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Review question
JL is a 45-year-old man. He has been taking5 mg glyburide and 500 mg metformin atbreakfast and supper. His fasting bloodglucose ranges from 5.36.7mmol/L but he
has been experiencing hypoglycaemia mostdays at 3 or 4 pm.
4. What is the likely cause of JLs low bloodsugars?
a. Breakfast metformin
b. Supper metformin
c. Breakfast glyburide
d. Supper glyburide
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Review question
5. When filling his prescription for asulphonylurea, what is the mostimportant thing to discuss with John?
a. What and when to eat
b. When to take the medication
c. How to recognize and treat
hypoglycaemiad. When to see his doctor again
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Answers
1. b
2. b
3. a
4. c
5. c
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References
1. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose control withsulphonylureas or insulin compared with conventional treatment and risk ofcomplications in person with diabetes with type 2 diabetes (UKPDS 33). Lancet 1998;352: 837-53.
2. Ahmann AJ, Riddle MC. Current blood glucose lowering medicines for type 2 diabetes.Postgrad Med 2002; 111(5): 32-46.
3. Henry RR. Type 2 diabetes care: the role of insulin-sensitizing agents and practicalimplications for cardiovascular disease prevention. Am J Med 1998; 105(1A): 20S-26S.
4. Luna B, Feinglos MN. Blood glucose-lowering medicines in the management of type 2diabetes mellitus. Am Fam Physician2001; 63(9): 1747-56.
5. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. ClinicalPractice Guidelines for the Prevention and Management of Diabetes in Canada. Can JDiab 2003; 27(supple 2).
6. Yki-Jarvinnen H, Ryysy L, Nikkila K, et al. Comparison of bedtime insulin regimen inperson with diabetes with type 2 diabetes mellitus; a randomized control trial. AnnalsIntern Med1999; 130(5): 89-96.
7. Amylin Pharmaceuticals Inc and Eli Lilly & Co. Byetta (cited 2005July 25) (16 screens).(Available from: http://www.byetta.com)
8. Rubin Rr. Adherence to pharmacologic therapy in patients with type 2 diabetesmellitus. Am J Med 2005; 118(5A): 275-345.