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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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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

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Blood glucose-lowering medicines

UKPDS: long-term glucose control


9

Curriculum Module III-2 Slide 3 of 41

Conventional

HbA1c (%)

Intensive
7

6 0

9 6 Years of treatment

12

15

UKPDS Study Group 1998


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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
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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
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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

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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?

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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
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Blood glucose-lowering medicines

Expected effect of blood glucose-lowering medicines


Class of medicine

Curriculum Module III-2 Slide 9 of 41

Alpha-glucosidase inhibitor Biguanide Insulin sensitisers

Expected decrease in HbA1C in monotherapy 0.5-0.8%


1.0-1.5% 1.0-1.5%

Most insulin secretagogues


Nateglinide

1.0-1.5%
0.5%
Canadian Diabetes Association 2003
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Blood glucose-lowering medicines

Strategies to help people remember

Curriculum Module III-2 Slide 10 of 41

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
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Blood glucose-lowering medicines

Targets for blood glucose

Curriculum Module III-2 Slide 11 of 41

HbA1C
Target for people who can achieve it (without too much
hypoglycemia)1

Pre-meal
4-6 mmol/L

2 hours post-meal
5-8 mmol/L

< 6%

Target for most people with diabetes IDF Global guideline for Type 2 diabetes3

<7%

4-7mmol/L1 90-130mg/dl*2

5-10mmol/L1 <180mg/dl2 <8.0mmol/L <145mg/dl

<6.5%

<6.0mmol/L <110mg/dl

1CDA

2003, 2ADA 2004,

IDF 2005

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Blood glucose-lowering medicines

Suggested starting medicine

Curriculum Module III-2 Slide 12 of 41

HbA1c

BMI
>25

Suggested medicine
Biguanide alone or in combination 1 or 2 agents from different classes 2 medicines from different classes or insulin

<9%
>9%

<25

CDA 2003

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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


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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
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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
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Blood glucose-lowering medicines

Biguanides

Curriculum Module III-2 Slide 16 of 41

First-line treatment in overweight or obese people Do not cause weight gain Have some effect on resistance at the periphery

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Blood glucose-lowering medicines

Biguanides

Curriculum Module III-2 Slide 17 of 41

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

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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
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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
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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
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Blood glucose-lowering medicines

Sulphonylureas
Things to remember

Curriculum Module III-2 Slide 21 of 41

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
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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
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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

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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)
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Blood glucose-lowering medicines

Alpha glucosidase inhibitors

Curriculum Module III-2 Slide 25 of 41

Contraindications Intestinal diseases, such as Crohns Autonomic neuropathy affecting the gastro-intestinal tract
Must be taken just before a meal
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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

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Blood glucose-lowering medicines

Older people with diabetes

Curriculum Module III-2 Slide 28 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 29 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
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Blood glucose-lowering medicines

Older people with diabetes


Remember the possibility of

Curriculum Module III-2 Slide 30 of 41

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.
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Blood glucose-lowering medicines

Ineffectiveness of blood glucoselowering medicines

Curriculum Module III-2 Slide 31 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


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ACTIVITY

Blood glucose-lowering medicines


Curriculum Module IV-1 Slide 32 of 41

Class of medicine Sulphonylureas

Likely to cause weight gain

Likely to cause hypoglycaemia

Target postmeal glucose

Biguanide
Glitazones Meglitinides Alpha-glucosidase inhibitors Incretin mimetic agent

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ACTIVITY

Blood glucose-lowering medicines


Curriculum Module IV-1 Slide 33 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?

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Blood glucose-lowering medicines

Summary

Curriculum Module III-2 Slide 34 of 41

Lifestyle changes first


Start medicine as soon as needed Add a different kind No delay starting insulin

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Blood glucose-lowering medicines

Review question

Curriculum Module III-2 Slide 35 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

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Blood glucose-lowering medicines

Review question

Curriculum Module III-2 Slide 36 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
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Blood glucose-lowering medicines

Review question
3. Which statement is FALSE?

Curriculum Module III-2 Slide 37 of 41

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
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Blood glucose-lowering medicines

Review question

Curriculum Module III-2 Slide 38 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 5.36.7mmol/L but he has been experiencing hypoglycaemia most days at 3 or 4 pm. 4. What is the likely cause of JLs low blood sugars? a. Breakfast metformin b. Supper metformin c. Breakfast glyburide d. Supper glyburide
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Blood glucose-lowering medicines

Review question

Curriculum Module III-2 Slide 39 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

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Blood glucose-lowering medicines

Answers

Curriculum Module III-2 Slide 40 of 41

1. b
2. b 3. a 4. c 5. c

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Blood glucose-lowering medicines

References
1.

Curriculum Module III-2 Slide 41 of 41

2. 3. 4.

5.

6.

7. 8.

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.

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