Optimal diabetes control Optimal diabetes control in adults.in adults.

Dr H OosthuizenDr H Oosthuizen

Management principalsManagement principals

1.1. Preserve Beta cell function.Preserve Beta cell function.

2.2. Early aggressive treatment.Early aggressive treatment.

3.3. Reduce glucose toxicity.Reduce glucose toxicity.

4.4. Treat to target.Treat to target.

5.5. Information and education.Information and education.

Three corner stones of Three corner stones of therapy.therapy.

• DietDiet

• ExerciseExercise

• Medication Medication

Additional metabolic Additional metabolic targets.targets.

• BP: 130/80 mmHg (with no proteinuria).BP: 130/80 mmHg (with no proteinuria).• BP: 125/75 mmHg (with proteiuria).BP: 125/75 mmHg (with proteiuria).• Total cholesterol Total cholesterol < 5mmol/L< 5mmol/L• LDL cholesterol < 3mmol/L LDL cholesterol < 3mmol/L (diabetes only)(diabetes only)

< 2.6mmol/L< 2.6mmol/L(additional risk(additional risk factors)factors)

• HDL cholesterol > 1mmol/LHDL cholesterol > 1mmol/L• Trigliserides < 1.7mmol/LTrigliserides < 1.7mmol/L• BMI = 20-24 kg/mBMI = 20-24 kg/m22

• Waist circumfence = 102 cm (f), 88cm (m).Waist circumfence = 102 cm (f), 88cm (m).

Medication for Type 2 Medication for Type 2 diabetic patient.diabetic patient.

6 classes of drugs:6 classes of drugs:

1.1. SulphonylureaSulphonylurea

2.2. BiguanideBiguanide

3.3. AcarboseAcarbose

4.4. MeglitinidesMeglitinides

5.5. ThiazolidinedionesThiazolidinediones

6.6. Insulin Insulin

PHARMACOLOGICAL PHARMACOLOGICAL MANAGEMENT.MANAGEMENT.

SITES OF ACTION OF CURRENT ORAL SITES OF ACTION OF CURRENT ORAL ANTIDIABETIC AGENTSANTIDIABETIC AGENTS

• Liver:Liver: glucose production - glucose production - biguanidesbiguanides

- - thiazolidinedionesthiazolidinediones

• Pancreas: Pancreas: insulin secretion - insulin secretion - sulphonylureassulphonylureas

- - meglitinidesmeglitinides

insulin replacement - insulin replacement - insulininsulin

PHARMACOLOGICAL PHARMACOLOGICAL MANAGEMENT.MANAGEMENT.

SITES OF ACTION OF CURRENT ORAL SITES OF ACTION OF CURRENT ORAL ANTIDIABETIC AGENTSANTIDIABETIC AGENTS

• Adipose tissue: Adipose tissue: peripheral glucose uptake and peripheral glucose uptake and and muscleand muscle utilization - utilization - thiazolidinedionesthiazolidinediones

- - biguanidesbiguanides

• Intestine: Intestine: glucose absorption - glucose absorption - alpha-glucosidasealpha-glucosidase

inhibitorsinhibitors

/ TZD

Biguanides :Biguanides : metformin(glucophage)metformin(glucophage)

Mechanism of actionMechanism of action• Inhibits hepatic glucose prodution Inhibits hepatic glucose prodution

(gluconeogenesis).(gluconeogenesis).• Increases the Increases the sensitivitysensitivity of peripheral tissue to of peripheral tissue to

insulin.insulin.• Increases Increases peripheral glucoseperipheral glucose uptake. uptake.• Decreases Decreases glucose absorptionglucose absorption from the from the

intestine.intestine.• Does Does notnot stimulate stimulate insulin secretion.insulin secretion.

Metformin Metformin Contra-indicationsContra-indications• Impaired renal function.Impaired renal function.• Impaired hepatic function.Impaired hepatic function.• Alcoholism.Alcoholism.• Conditions which promote tissue hypoxia:Conditions which promote tissue hypoxia:

coronary heart disease, cardiac failure, peripheral vascular disease, coronary heart disease, cardiac failure, peripheral vascular disease, obstructive airways diseaseobstructive airways disease

• Pregnancy.Pregnancy.• Major surgery.Major surgery.• Type 1 DiabetesType 1 Diabetes• Ketoacidosis Ketoacidosis

MetforminMetformin

Side effectsSide effects• Diarrhea Diarrhea • Abdominal discomfortAbdominal discomfort• Nausea Nausea • Metallic tasteMetallic taste• Anorexia Anorexia • Lactic acidosisLactic acidosis• Impaired intestinal Vit BImpaired intestinal Vit B1212 & Folate absorption & Folate absorption• Megaloblastic anemia (BMegaloblastic anemia (B12 12 malabsorption)malabsorption)

MetforminMetformin

ADVANTAGESADVANTAGES• Reduces Reduces insulin resistanceinsulin resistance..• High initial High initial responseresponse rate. rate.• Long record of relative Long record of relative safety.safety.• No No weightweight gain or modest weight loss. gain or modest weight loss.

ThiazolidinedionesThiazolidinediones pioglitazone (actos), rosiglitazone (avandia)pioglitazone (actos), rosiglitazone (avandia)troglitazone (rezulin)troglitazone (rezulin)

TZD/pioglitazone: Mechanism of actionTZD/pioglitazone: Mechanism of action• Primary effects on Primary effects on adipocytesadipocytes are secodarily are secodarily

transmitted to muscle and liver via other transmitted to muscle and liver via other mediators mediators (TNF, leptin and FFA).(TNF, leptin and FFA).

• TZD induce TZD induce lipoprotein lipaselipoprotein lipase: trigliseride : trigliseride uptake into fat and circulating FFA.uptake into fat and circulating FFA.

• Reduced Reduced insulin resistanceinsulin resistance at liver and at liver and muscle.muscle.

• Enhances Enhances GLUT4 gene expressionGLUT4 gene expression, thus , thus improved insulin action at target tissue.improved insulin action at target tissue.

TZD/pioglitazone: TZD/pioglitazone: Mechanism of actionMechanism of action

• Pioglitazone increases glucose uptake in Pioglitazone increases glucose uptake in skeletal muscle and adipose tissue –skeletal muscle and adipose tissue –increasing increasing glycolysis glycolysis + synthesis of + synthesis of glycogen glycogen in skeletal muscle.in skeletal muscle.

• Increase Increase oxidationoxidation and lipogenesis in adipose and lipogenesis in adipose tissue – increase peripheral glucose tissue – increase peripheral glucose sensitivity and utilization.sensitivity and utilization.

• Reduces Reduces gluconeogenesisgluconeogenesis.(by liver).(by liver)• Reduce Reduce insulin resistanceinsulin resistance..

ThiazolidinedionesThiazolidinediones

Contra-indications/precautionsContra-indications/precautions• Impaired hepatic function or active liver Impaired hepatic function or active liver

disease.disease.• Cardiac failure.Cardiac failure.• Type 1 diabetes.Type 1 diabetes.• Diabetic ketoacidosis.Diabetic ketoacidosis.• Pregnancy.Pregnancy.• Lactation.Lactation.

ThiazolidinedionesThiazolidinediones

Side effectsSide effects• Upper Respiratory Tract infection.Upper Respiratory Tract infection.• Weight gain.Weight gain.• Anemia - Hb and Hematocrit.Anemia - Hb and Hematocrit.• Haemodulation and Oedema.Haemodulation and Oedema.• Plasma volume expansion and cardiac Plasma volume expansion and cardiac

hypertrophy.hypertrophy.• Ovulation and possible pregnancy.Ovulation and possible pregnancy.• Unknown long term safety profile.Unknown long term safety profile.

ThiazolidinedionesThiazolidinediones

ADVANTAGESADVANTAGES• Corrects a primary pathophysiologic Corrects a primary pathophysiologic

impairment: insulin resistance.impairment: insulin resistance.• Once daily dosing.Once daily dosing.• Lowers serum triglycerides.Lowers serum triglycerides.• Increases HDL cholesterol.Increases HDL cholesterol.• Can be used in renal insufficiency. Can be used in renal insufficiency.

Insulin secretagoguesInsulin secretagogues

• RepaglinideRepaglinide

• NateglinideNateglinide

• SulphonylureasSulphonylureas

Sulphonylureas Sulphonylureas

• Chlorpropamide (diabinese)Chlorpropamide (diabinese)• Gliclazide (diamicron, glucomed)Gliclazide (diamicron, glucomed)• Glipmepiride (amaryl)Glipmepiride (amaryl)• Glipizide (minidiab)Glipizide (minidiab)• Glybenclamide (daonil, glyben, glycomin)Glybenclamide (daonil, glyben, glycomin)• Tolbutamide (rastinon)Tolbutamide (rastinon)

SulphonylureasSulphonylureas

Contra-indicationsContra-indications• Impaired renal and hepatic function. Impaired renal and hepatic function.

• Pregnancy Pregnancy

• Type 1 diabetesType 1 diabetes

• Thyroid and adrenal dysfunction.Thyroid and adrenal dysfunction.

SulphonylureasSulphonylureas

DISADVANTAGESDISADVANTAGES• Hypoglycaemia – may be prolonged or Hypoglycaemia – may be prolonged or

severe.severe.• Weight gain.Weight gain.• Drug interactions, especially 1Drug interactions, especially 1stst generation. generation.• Hyponatraemia with Chlorpropamide.Hyponatraemia with Chlorpropamide.• Cannot use if allergic to SU compounds.Cannot use if allergic to SU compounds.• Direct Exocytosis of Beta cells: ? Beta cell Direct Exocytosis of Beta cells: ? Beta cell

life span?life span?

Type 2 HyperglycaemiaType 2 Hyperglycaemia

• 33rdrd generation sulphonylureas. generation sulphonylureas.

AmarylAmaryl

• Once daily.Once daily.

• Insulin release action.Insulin release action.

• Stimulation of glucose transport.Stimulation of glucose transport.

• Stimulation of non-oxidative glucose Stimulation of non-oxidative glucose metabolism in fat and muscle cellsmetabolism in fat and muscle cells

Meglitinide analoguesMeglitinide analogues

• Repaglinide Repaglinide

• Nateglinide Nateglinide

Nateglinide/RepaglinideNateglinide/Repaglinide

• Meglitinide group of drugsMeglitinide group of drugs

• Stimulate insulin secretion from beta Stimulate insulin secretion from beta cells (glucose dependent) cells (glucose dependent)

• Minimal excretion via kidneys Minimal excretion via kidneys

Repaglinide/NateglinideRepaglinide/Nateglinidemechanism of actionmechanism of action

• Pharmacologically distinct binding site on Pharmacologically distinct binding site on potassium channel. potassium channel.

• No direct exocytosis of insulin from beta cell.No direct exocytosis of insulin from beta cell.

• Beta cell sparing?Beta cell sparing?

• Overcome metabolic stress on cells.Overcome metabolic stress on cells.

Repaglinide/NateglinideRepaglinide/Nateglinide

ADVANTAGESADVANTAGES• Improve primary pathophysiologic impairment: insulin Improve primary pathophysiologic impairment: insulin

secretion.secretion.• Physiologic route of insulin delivery.Physiologic route of insulin delivery.• Permits flexibility in lifestyle: Dose coupled to meals –Permits flexibility in lifestyle: Dose coupled to meals –

no need for snacking-promote weight loss.no need for snacking-promote weight loss.• High initial response rate.High initial response rate.• No lag period before response.No lag period before response.• Can be used in various degrees of renal impairment.Can be used in various degrees of renal impairment.• Low incidence of severe hypoglycaemic episodes.Low incidence of severe hypoglycaemic episodes.

Alpha-Glucosidase Alpha-Glucosidase InhibitorsInhibitors

Acarbose (glucobay)Acarbose (glucobay)

Alpha-Glucosidase InhibitorsAlpha-Glucosidase InhibitorsMechanism of actionMechanism of action

• Acts by competitive inhibition of alpha-Acts by competitive inhibition of alpha-glucosidase enzymes.glucosidase enzymes.

• Reduces the rate of monosaccharide Reduces the rate of monosaccharide generation and absorption.generation and absorption.

• Delays glucose absorption in the intestine.Delays glucose absorption in the intestine.• Modulates peaks in post-prandial glucose.Modulates peaks in post-prandial glucose.• Taken with meals.Taken with meals.

Alpha-Glucosidase InhibitorsAlpha-Glucosidase InhibitorsAcarboseAcarbose

Indications Indications • Obese and non-obese Type 2 patients Obese and non-obese Type 2 patients

inadequately controlled by diet and exercise inadequately controlled by diet and exercise therapy.therapy.

• May be used in combination with Repaglinide, May be used in combination with Repaglinide, SU’s, Metformin or Insulin.SU’s, Metformin or Insulin.

Alpha-Glucosidase InhibitorsAlpha-Glucosidase InhibitorsAcarboseAcarbose

Side effectsSide effects• Dose related absorption.Dose related absorption.• FlatulenceFlatulence• Abdominal bloating/upset.Abdominal bloating/upset.• Skin reactions.Skin reactions.

Alpha-Glucosidase InhibitorsAlpha-Glucosidase InhibitorsAcarboseAcarbose

ADVANTAGESADVANTAGES• Good safety profile.Good safety profile.• No weight gain.No weight gain.• Dose coupled to meals.Dose coupled to meals.• Unique mechanism.Unique mechanism.

Rationale for COMBINATION Rationale for COMBINATION THERAPYTHERAPY

• Improving Improving metabolic metabolic effect by combining effect by combining drugs with drugs with different different mechanisms of action.mechanisms of action.

• Reducing Reducing side effectsside effects by sub-maximal by sub-maximal dosage.dosage.

• Starting combination therapy according to Starting combination therapy according to metabolic guidelinesmetabolic guidelines..

• Prescribing drugs according to Prescribing drugs according to individual individual patient need.patient need.

Management of patients Management of patients prsenting with very high Blood prsenting with very high Blood Glucose levels.Glucose levels.

• Level higher than~Level higher than~20mmol/L20mmol/L-admission into -admission into hospital,hospital, depending on symptoms. depending on symptoms.

• If type of diabetes is uncertain - If type of diabetes is uncertain - C-peptideC-peptide test needed. Check for blood/urine test needed. Check for blood/urine ketones.ketones.

Initiation of insulin may be necessary: Initiation of insulin may be necessary: • Use Use supplementation/adjustment scalesupplementation/adjustment scale..• Work insulin dosage out according to Work insulin dosage out according to

Body weight.Body weight.• Adjust insulin dosage according to Adjust insulin dosage according to blood blood

glucose readings.glucose readings.

Insulin adjustment scale Insulin adjustment scale Eg. Of patients on basal-bolus regimenEg. Of patients on basal-bolus regimen

Pre-meal readingPre-meal reading

<3mmol/L<3mmol/L

3-5mmol/L3-5mmol/L

5-7mmol/L5-7mmol/L

7-10mmol/L7-10mmol/L

10-13mmol/L10-13mmol/L

13-17mmol/L13-17mmol/L

17-22mmol/L17-22mmol/L

Change insulinChange insulin

Decrease 1-3 unitsDecrease 1-3 units

Decrease 0-1 unitsDecrease 0-1 units

Increase 0-1 unitsIncrease 0-1 units

Increase 1-2 unitsIncrease 1-2 units

Increase 2-3 unitsIncrease 2-3 units

Increase 3-4 unitsIncrease 3-4 units

Increase 4-6 unitsIncrease 4-6 units

When and how to start insulin When and how to start insulin treatment in type 2 diabetes.treatment in type 2 diabetes.

Insulin therapy in Type 2 patients on Insulin therapy in Type 2 patients on OAD’s can be started in two ways:OAD’s can be started in two ways:

1.1. Supplemental therapy Supplemental therapy

2.2. Substitution therapySubstitution therapy

Insulin initiation-Insulin initiation-suplemental therapysuplemental therapy

• Continue OAA treatment.Continue OAA treatment.• Add 02iu/kg NPH at breakfast or at bedtime.Add 02iu/kg NPH at breakfast or at bedtime.• Dose increase by 2-4iu every 3-4 days, if Dose increase by 2-4iu every 3-4 days, if

necessary.necessary.• If more than 36iu insulin needed to obtain If more than 36iu insulin needed to obtain

control – stop OAA treatment and continue control – stop OAA treatment and continue insulin alone.insulin alone.

• Divide dose into 2 daily injections – 2/3 mane, Divide dose into 2 daily injections – 2/3 mane, 1/3 nocte-(30/70 premix).1/3 nocte-(30/70 premix).

Protophane dosageProtophane dosage

60kg patient60kg patient == 12u 12u

70kg patient70kg patient == 16u 16u

80kg patient80kg patient == 20u20u

90kg patient90kg patient == 24u24u

>100 kg =>100 kg = 28u28u

patientpatient

Insulin initiation-Insulin initiation-Substitution therapySubstitution therapy

• Stop OAA treatment.Stop OAA treatment.• Start 2 injections – 0.2iu/kg NPH or premixed Start 2 injections – 0.2iu/kg NPH or premixed

insulin (30/70); 2/3 TDD before breakfast, 1/3 insulin (30/70); 2/3 TDD before breakfast, 1/3 TDD before supper.TDD before supper.

• Increase dose 2-4iu every 3-4 days if Increase dose 2-4iu every 3-4 days if necessary.necessary.

• If PP BG is too high, prmixed insulin better If PP BG is too high, prmixed insulin better than NPH.than NPH.

Drug interactionsDrug interactions

Substances that may Substances that may enhanceenhance the the hypoglycaemic effects of oral medicationhypoglycaemic effects of oral medication

• Monoamine oxidase inhibitors (MOAI’s)Monoamine oxidase inhibitors (MOAI’s)• Beta blocking agentsBeta blocking agents• Angiotensin converting enzyme inhibitors Angiotensin converting enzyme inhibitors

(ACE-inhibitors).(ACE-inhibitors).• Non-steroidal anti-inflammatory agents Non-steroidal anti-inflammatory agents

(NSAIDS)(NSAIDS)• Salicilates Salicilates • Alcohol Alcohol • Octreotide and anabolic steroidsOctreotide and anabolic steroids

Drug interactionsDrug interactions

Substances that may Substances that may reducereduce the the hypoglycaemic effects of oral medication.hypoglycaemic effects of oral medication.

• Oral contraceptivesOral contraceptives• ThiazidesThiazides• CorticosteroidsCorticosteroids• DanazolDanazol• Thyroid hormonesThyroid hormones• Sympathomimetics Sympathomimetics

Drug interactionsDrug interactions

Beta Blocking AgentsBeta Blocking Agents• May mask the symptoms of hypoglycaemia.May mask the symptoms of hypoglycaemia.• May mask the body’s response to May mask the body’s response to

hypoglycaemia.hypoglycaemia.

Alcohol Alcohol • May intensify and prolong the hypoglycaemic May intensify and prolong the hypoglycaemic

effect of oral hypoglycaemic medication.effect of oral hypoglycaemic medication.

Drug interactionsDrug interactions

Agents that may delay the metabolism of Agents that may delay the metabolism of certain oral hypoglycaemic agentscertain oral hypoglycaemic agents

• Interactions with antifungal agents e.g. Interactions with antifungal agents e.g. ketoconazole.ketoconazole.

• Interactions with antibacterial agents e.g. Interactions with antibacterial agents e.g. erythromycin.erythromycin.

Drug interactionsDrug interactions

Compounds that induce or inhibit the Compounds that induce or inhibit the cytochrome-P450 (CYP3A4 or CYP2C9) cytochrome-P450 (CYP3A4 or CYP2C9) enzyme systemenzyme system

1.1. May either delay or increase the metabolism May either delay or increase the metabolism of certain oral hypoglycaemic agents e.g. of certain oral hypoglycaemic agents e.g.

2.2. Ketoconazole is a CYP3A4 inhibitorKetoconazole is a CYP3A4 inhibitor

3.3. Rifampicin is a CYP3A4 inducerRifampicin is a CYP3A4 inducer

Home glucose monitoring.Home glucose monitoring.

AdvantagesAdvantages• Frequent Frequent

measurements.measurements.• Availability.Availability.• Treatment Treatment

adaptable. adaptable. • Testing at Testing at

appropriate times.appropriate times.

DisadvantagesDisadvantages• Inaccuracy due to Inaccuracy due to

wrong technique.wrong technique.• Not all readings are Not all readings are

reported.reported.• Cost Cost

Monitoring via HbAMonitoring via HbA11cc

AdvantagesAdvantages• Laboratory Laboratory

measurement.measurement.• Done 3-6 monthly.Done 3-6 monthly.• Gold standard.Gold standard.

DisadvantagesDisadvantages• Average readingAverage reading• Hypoglycaemic Hypoglycaemic

episodes not picked episodes not picked up.up.

• Expensive Expensive • Different methods in Different methods in

different labs.different labs.• False security.False security.

Home glucose monitoring.Home glucose monitoring.

• New trends in diabetes management.New trends in diabetes management.

• New Glucometers – Optium Plus New Glucometers – Optium Plus

Accutrend sensorAccutrend sensor

LifescanLifescan

Glucometer EliteGlucometer Elite

FreestyleFreestyle

• Computer assisted systems.Computer assisted systems.

Type 2 DiabetesType 2 Diabetes

1.1. Treat the patient not the glucometer.Treat the patient not the glucometer.2.2. Control other risk factors:Control other risk factors:3.3. ObesityObesity – life style modification – life style modification

drug therapy drug therapy4.4. DislipidaemiaDislipidaemia5.5. Hypertension Hypertension – – drug side effects drug side effects

combination therapy combination therapy6.6. SmokingSmoking

Conclusion Conclusion

• Elevated Elevated postprandial blood glucosepostprandial blood glucose = risk = risk factor for Cardiovascular disease and factor for Cardiovascular disease and mortality, independent of Fasting blood mortality, independent of Fasting blood glucose levels and HbAglucose levels and HbA1C1C..

• Early and aggressiveEarly and aggressive treatment of Type 2 treatment of Type 2 diabetes, to improve glycaemic control, diabetes, to improve glycaemic control, decreases the risk of long term complications.decreases the risk of long term complications.

• Insulin treatment initiated when near Insulin treatment initiated when near normalizationnormalization of BG cannt be achieved with of BG cannt be achieved with OAA’s alone.OAA’s alone.

ConclusionConclusion

• Better BG control – reduces/avoids Better BG control – reduces/avoids atherosclerosis – atherosclerosis – BP managementBP management..

• Education on Education on dislipidemia.dislipidemia.• Quality of Quality of Life factorsLife factors affect control and affect control and

management. management.