Transcript Optimal diabetes control in adults.

Optimal diabetes
control in adults.
Dr H Oosthuizen
Management principals
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Preserve Beta cell function.
Early aggressive treatment.
Reduce glucose toxicity.
Treat to target.
Information and education.
Three corner stones of
therapy.
• Diet
• Exercise
• Medication
Additional metabolic
targets.
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BP: 130/80 mmHg (with no proteinuria).
BP: 125/75 mmHg (with proteiuria).
Total cholesterol < 5mmol/L
LDL cholesterol < 3mmol/L (diabetes only)
< 2.6mmol/L(additional risk factors)
HDL cholesterol > 1mmol/L
Trigliserides < 1.7mmol/L
BMI = 20-24 kg/m2
Waist circumfence = 102 cm (f), 88cm (m).
Medication for Type 2
diabetic patient.
6 classes of drugs:
1. Sulphonylurea
2. Biguanide
3. Acarbose
4. Meglitinides
5. Thiazolidinediones
6. Insulin
PHARMACOLOGICAL
MANAGEMENT.
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SITES OF ACTION OF CURRENT ORAL
ANTIDIABETIC AGENTS
Liver: glucose production - biguanides
- thiazolidinediones
Pancreas: insulin secretion - sulphonylureas
- meglitinides
insulin replacement - insulin
PHARMACOLOGICAL
MANAGEMENT.
SITES OF ACTION OF CURRENT ORAL
ANTIDIABETIC AGENTS
• Adipose tissue: peripheral glucose uptake and
and muscle
utilization - thiazolidinediones
- biguanides
• Intestine: glucose absorption - alpha-glucosidase
inhibitors
/ TZD
Biguanides :
metformin(glucophage)
Mechanism of action
• Inhibits hepatic glucose prodution
(gluconeogenesis).
• Increases the sensitivity of peripheral tissue to
insulin.
• Increases peripheral glucose uptake.
• Decreases glucose absorption from the
intestine.
• Does not stimulate insulin secretion.
Metformin
Contra-indications
• Impaired renal function.
• Impaired hepatic function.
• Alcoholism.
• Conditions which promote tissue hypoxia:
coronary heart disease, cardiac failure, peripheral vascular
disease, obstructive airways disease
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Pregnancy.
Major surgery.
Type 1 Diabetes
Ketoacidosis
Metformin
Side effects
• Diarrhea
• Abdominal discomfort
• Nausea
• Metallic taste
• Anorexia
• Lactic acidosis
• Impaired intestinal Vit B12 & Folate absorption
• Megaloblastic anemia (B12 malabsorption)
Metformin
ADVANTAGES
• Reduces insulin resistance.
• High initial response rate.
• Long record of relative safety.
• No weight gain or modest weight loss.
Thiazolidinediones
pioglitazone (actos), rosiglitazone (avandia)
troglitazone (rezulin)
TZD/pioglitazone: Mechanism of action
• Primary effects on adipocytes are secodarily
transmitted to muscle and liver via other
mediators (TNF, leptin and FFA).
• TZD induce lipoprotein lipase: trigliseride
uptake into fat and circulating FFA.
• Reduced insulin resistance at liver and
muscle.
• Enhances GLUT4 gene expression, thus
improved insulin action at target tissue.
TZD/pioglitazone:
Mechanism of action
• Pioglitazone increases glucose uptake in
skeletal muscle and adipose tissue –
increasing glycolysis + synthesis of glycogen
in skeletal muscle.
• Increase oxidation and lipogenesis in adipose
tissue – increase peripheral glucose
sensitivity and utilization.
• Reduces gluconeogenesis.(by liver)
• Reduce insulin resistance.
Thiazolidinediones
Contra-indications/precautions
• Impaired hepatic function or active liver
disease.
• Cardiac failure.
• Type 1 diabetes.
• Diabetic ketoacidosis.
• Pregnancy.
• Lactation.
Thiazolidinediones
Side effects
• Upper Respiratory Tract infection.
• Weight gain.
• Anemia - Hb and Hematocrit.
• Haemodulation and Oedema.
• Plasma volume expansion and cardiac
hypertrophy.
• Ovulation and possible pregnancy.
• Unknown long term safety profile.
Thiazolidinediones
ADVANTAGES
• Corrects a primary pathophysiologic
impairment: insulin resistance.
• Once daily dosing.
• Lowers serum triglycerides.
• Increases HDL cholesterol.
• Can be used in renal insufficiency.
Insulin secretagogues
• Repaglinide
• Nateglinide
• Sulphonylureas
Sulphonylureas
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Chlorpropamide (diabinese)
Gliclazide (diamicron, glucomed)
Glipmepiride (amaryl)
Glipizide (minidiab)
Glybenclamide (daonil, glyben, glycomin)
Tolbutamide (rastinon)
Sulphonylureas
Contra-indications
• Impaired renal and hepatic function.
• Pregnancy
• Type 1 diabetes
• Thyroid and adrenal dysfunction.
Sulphonylureas
DISADVANTAGES
• Hypoglycaemia – may be prolonged or
severe.
• Weight gain.
• Drug interactions, especially 1st generation.
• Hyponatraemia with Chlorpropamide.
• Cannot use if allergic to SU compounds.
• Direct Exocytosis of Beta cells: ? Beta cell
life span?
Type 2 Hyperglycaemia
• 3rd generation sulphonylureas.
Amaryl
• Once daily.
• Insulin release action.
• Stimulation of glucose transport.
• Stimulation of non-oxidative glucose
metabolism in fat and muscle cells
Meglitinide analogues
• Repaglinide
• Nateglinide
Nateglinide/Repaglinide
• Meglitinide group of drugs
• Stimulate insulin secretion from beta
cells (glucose dependent)
• Minimal excretion via kidneys
Repaglinide/Nateglinide
mechanism of action
• Pharmacologically distinct binding site on
potassium channel.
• No direct exocytosis of insulin from beta cell.
• Beta cell sparing?
• Overcome metabolic stress on cells.
Repaglinide/Nateglinide
ADVANTAGES
• Improve primary pathophysiologic impairment: insulin
secretion.
• Physiologic route of insulin delivery.
• Permits flexibility in lifestyle: Dose coupled to meals –
no need for snacking-promote weight loss.
• High initial response rate.
• No lag period before response.
• Can be used in various degrees of renal impairment.
• Low incidence of severe hypoglycaemic episodes.
Alpha-Glucosidase
Inhibitors
Acarbose (glucobay)
Alpha-Glucosidase Inhibitors
Mechanism of action
• Acts by competitive inhibition of alphaglucosidase enzymes.
• Reduces the rate of monosaccharide
generation and absorption.
• Delays glucose absorption in the intestine.
• Modulates peaks in post-prandial glucose.
• Taken with meals.
Alpha-Glucosidase Inhibitors
Acarbose
Indications
• Obese and non-obese Type 2 patients
inadequately controlled by diet and exercise
therapy.
• May be used in combination with Repaglinide,
SU’s, Metformin or Insulin.
Alpha-Glucosidase Inhibitors
Acarbose
Side effects
• Dose related absorption.
• Flatulence
• Abdominal bloating/upset.
• Skin reactions.
Alpha-Glucosidase Inhibitors
Acarbose
ADVANTAGES
• Good safety profile.
• No weight gain.
• Dose coupled to meals.
• Unique mechanism.
Rationale for
COMBINATION THERAPY
• Improving metabolic effect by combining
drugs with different mechanisms of action.
• Reducing side effects by sub-maximal
dosage.
• Starting combination therapy according to
metabolic guidelines.
• Prescribing drugs according to individual
patient need.
Management of patients
prsenting with very high
Blood Glucose levels.
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Level higher than~20mmol/L-admission into
hospital, depending on symptoms.
• If type of diabetes is uncertain - C-peptide
test needed. Check for blood/urine ketones.
Initiation of insulin may be necessary:
• Use supplementation/adjustment scale.
• Work insulin dosage out according to
Body weight.
• Adjust insulin dosage according to blood
glucose readings.
Insulin adjustment scale
Eg. Of patients on basal-bolus regimen
Pre-meal reading
<3mmol/L
3-5mmol/L
5-7mmol/L
7-10mmol/L
10-13mmol/L
13-17mmol/L
17-22mmol/L
Change insulin
Decrease 1-3 units
Decrease 0-1 units
Increase 0-1 units
Increase 1-2 units
Increase 2-3 units
Increase 3-4 units
Increase 4-6 units
When and how to start insulin
treatment in type 2 diabetes.
Insulin therapy in Type 2 patients on
OAD’s can be started in two ways:
1. Supplemental therapy
2. Substitution therapy
Insulin initiationsuplemental therapy
• Continue OAA treatment.
• Add 02iu/kg NPH at breakfast or at bedtime.
• Dose increase by 2-4iu every 3-4 days, if
necessary.
• If more than 36iu insulin needed to obtain
control – stop OAA treatment and continue
insulin alone.
• Divide dose into 2 daily injections – 2/3 mane,
1/3 nocte-(30/70 premix).
Protophane dosage
60kg patient
70kg patient
80kg patient
90kg patient
>100 kg
patient
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12u
16u
20u
24u
28u
Insulin initiationSubstitution therapy
• Stop OAA treatment.
• Start 2 injections – 0.2iu/kg NPH or premixed
insulin (30/70); 2/3 TDD before breakfast, 1/3
TDD before supper.
• Increase dose 2-4iu every 3-4 days if
necessary.
• If PP BG is too high, prmixed insulin better
than NPH.
Drug interactions
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Substances that may enhance the
hypoglycaemic effects of oral medication
Monoamine oxidase inhibitors (MOAI’s)
Beta blocking agents
Angiotensin converting enzyme inhibitors
(ACE-inhibitors).
Non-steroidal anti-inflammatory agents
(NSAIDS)
Salicilates
Alcohol
Octreotide and anabolic steroids
Drug interactions
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Substances that may reduce the
hypoglycaemic effects of oral medication.
Oral contraceptives
Thiazides
Corticosteroids
Danazol
Thyroid hormones
Sympathomimetics
Drug interactions
Beta Blocking Agents
• May mask the symptoms of hypoglycaemia.
• May mask the body’s response to
hypoglycaemia.
Alcohol
• May intensify and prolong the hypoglycaemic
effect of oral hypoglycaemic medication.
Drug interactions
Agents that may delay the metabolism of
certain oral hypoglycaemic agents
• Interactions with antifungal agents e.g.
ketoconazole.
• Interactions with antibacterial agents e.g.
erythromycin.
Drug interactions
Compounds that induce or inhibit the
cytochrome-P450 (CYP3A4 or CYP2C9)
enzyme system
• May either delay or increase the metabolism
of certain oral hypoglycaemic agents e.g.
1. Ketoconazole is a CYP3A4 inhibitor
2. Rifampicin is a CYP3A4 inducer
Home glucose monitoring.
Advantages
• Frequent
measurements.
• Availability.
• Treatment
adaptable.
• Testing at
appropriate times.
Disadvantages
• Inaccuracy due to
wrong technique.
• Not all readings are
reported.
• Cost
Monitoring via HbA1c
Advantages
• Laboratory
measurement.
• Done 3-6 monthly.
• Gold standard.
Disadvantages
• Average reading
• Hypoglycaemic
episodes not picked
up.
• Expensive
• Different methods in
different labs.
• False security.
Home glucose monitoring.
• New trends in diabetes management.
• New Glucometers – Optium Plus
Accutrend sensor
Lifescan
Glucometer Elite
Freestyle
• Computer assisted systems.
Type 2 Diabetes
• Treat the patient not the glucometer.
• Control other risk factors:
1. Obesity – life style modification
drug therapy
2. Dislipidaemia
3. Hypertension – drug side effects
combination therapy
4. Smoking
Conclusion
• Elevated postprandial blood glucose = risk
factor for Cardiovascular disease and
mortality, independent of Fasting blood
glucose levels and HbA1C.
• Early and aggressive treatment of Type 2
diabetes, to improve glycaemic control,
decreases the risk of long term complications.
• Insulin treatment initiated when near
normalization of BG cannt be achieved with
OAA’s alone.
Conclusion
• Better BG control – reduces/avoids
atherosclerosis – BP management.
• Education on dislipidemia.
• Quality of Life factors affect control and
management.