Drug therapy in diabetes

Drug therapy in Drug therapy in DiabetesDiabetes

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Diagnosis of DiabetesDiagnosis of Diabetes

Fasting Random OGTT(2h)

Normal <6 <7.8Impair 6.1 – 7 7.8- 11.1Diabetes >7 >11.1 +

symptoms

>11.1


Aims of managementAims of management

To achieve near normal glycaemiaTo achieve near normal glycaemia- Short term- to prevent symptoms of Short term- to prevent symptoms of

hyper & hypohyper & hypo- Long term- to prevent complicationsLong term- to prevent complications Good quality of life, near normal life Good quality of life, near normal life

expectancyexpectancy


Targets for non-pregnant Targets for non-pregnant patientspatients

HbA1c - NICE HbA1c - NICE 6.5-7.5% 6.5-7.5%

- ADA- ADA <7%<7%

- IDF- IDF <6.5%<6.5% BPBP - <130/80- <130/80 Cholesterol- LDL <2.6 (mM)Cholesterol- LDL <2.6 (mM)

HDL >1.1 HDL >1.1

TG <1.7 TG <1.7


Types of InsulinTypes of Insulin Short acting - Short acting - Soluble / Neutral insulinSoluble / Neutral insulin Insulin aspartInsulin aspart Insulin lisproInsulin lispro Intermediate acting - IsophaneIntermediate acting - Isophane Long acting - Insulin Zinc suspensionLong acting - Insulin Zinc suspension

new insulin analogue - Glargine new insulin analogue - Glargine Detemir Detemir

Biphasic- mixture of short and intermediateBiphasic- mixture of short and intermediate Biphasic lisproBiphasic lispro Biphasic IsophaneBiphasic Isophane


Types of InsulinTypes of InsulinInsulin Lispro

AspartNeutral/regular

Isophane ultratard Glargine

Onset 10-20′ 30′ 1h 4h 2-4h

Peak 1h 1-3h 4-6h 6-18h peak less

Duration 3-5h 4-8h 8-14h 24h 20-24h


Soluble insulin / Soluble insulin / neutral /clearneutral /clear

Names - Human actrapid/ Humulin S Species- Bovine, porcine, human Following s/c injection

Onset of action – 30 min Peak- 1-3 hours Duration- 4-8 hours

Only insulin suitable for intravenous route –plasma half life < 5 min, required continuous infusion

Used in diabetes Ketoacidosis


Sites of injections - Sites of injections - SubcutaneousSubcutaneous

ThighsThighs Upper buttocksUpper buttocks AbdomenAbdomen ArmsArms

Important to rotate the siteImportant to rotate the site

Rate of absorption may be significantly Rate of absorption may be significantly different – faster from arm and different – faster from arm and abdomen than from thigh and buttockabdomen than from thigh and buttock


Routes of AdministrationRoutes of Administration

Subcutaneous for long term regular useSubcutaneous for long term regular use Intravenous infusion in acute conditions- Intravenous infusion in acute conditions-

diabetes Ketoacidosis, Perioperative diabetes Ketoacidosis, Perioperative period, Hyperosmolar Nonketotic state period, Hyperosmolar Nonketotic state ONLY NEUTRAL/ CLEAR INSULIN CAN BE ONLY NEUTRAL/ CLEAR INSULIN CAN BE USEDUSED

Continuous subcutaneous insulin infusion Continuous subcutaneous insulin infusion via pump – neutralvia pump – neutral

Intraperitoneal – Peritoneal dialysis Intraperitoneal – Peritoneal dialysis patientspatients

Inhaled insulin- experimentalInhaled insulin- experimental


Untoward effect of Untoward effect of insulininsulin

HypoglycaemiaHypoglycaemia Weight gain- anabolic hormoneWeight gain- anabolic hormone Lipohypertrophy- injection to same siteLipohypertrophy- injection to same site Insulin oedemaInsulin oedema Transient deterioration in retinopathyTransient deterioration in retinopathy Insulin neuritis – actively regenerating Insulin neuritis – actively regenerating

neurone, uncommonneurone, uncommon Postural hypotensionPostural hypotension


ExampleExample

injections

Short actingShort acting Short actingIntermediate/long acting

breakfast lunch dinner

breakfast lunch dinner bedtime

bedtimeinjections

Biphasic insulin Biphasic insulinwww.freelivedoctor.com

Recurrent HypoRecurrent Hypo ? Required dose adjustment? Required dose adjustment ? Right insulin/ injection technique? Right insulin/ injection technique ? Meal/ fasting related? Meal/ fasting related ? Injections sites? Injections sites ? Exercise? Exercise Unexplained - ?autonomic Unexplained - ?autonomic

neuropathyneuropathy


Sick day rulesSick day rules

never stop insulinnever stop insulin monitor more frequentlymonitor more frequently maintain your hydrationmaintain your hydration Check for ketonesCheck for ketones Know when & how to call for helpKnow when & how to call for help


Oral Medications Oral Medications to Treat Type 2 to Treat Type 2

DiabetesDiabetes


Major Classes of Major Classes of MedicationsMedications

sensitize the sensitize the body to insulin body to insulin +/- control +/- control hepatic glucose hepatic glucose productionproduction

stimulate the stimulate the pancreas to pancreas to make more make more insulininsulin

slow the slow the absorption of absorption of starches starches

ThiazolidinedionesThiazolidinediones

BiguanidesBiguanides

SulfonylureasSulfonylureas

MeglitinidesMeglitinides

Alpha-glucosidaseAlpha-glucosidase

inhibitorsinhibitors


ThiazolidinedionesThiazolidinediones ↓↓ insulin resistance by making muscle and adipose cells insulin resistance by making muscle and adipose cells

more sensitive to insulin. They also suppress hepatic more sensitive to insulin. They also suppress hepatic glucose production.glucose production.

EfficacyEfficacy ↓↓ fasting plasma glucose ~1.9-2.2 mmol/Lfasting plasma glucose ~1.9-2.2 mmol/L Reduce A1C ~0.5-1.0%Reduce A1C ~0.5-1.0% 6 weeks for maximum effect6 weeks for maximum effect

Other EffectsOther Effects Weight gain, oedema Weight gain, oedema Hypoglycemia (if taken with insulin or agents that Hypoglycemia (if taken with insulin or agents that

stimulate insulin release)stimulate insulin release) Contraindicated in patients with abnormal LFT or CHFContraindicated in patients with abnormal LFT or CHF Improves HDL cholesterol and plasma triglycerides; Improves HDL cholesterol and plasma triglycerides;

usually LDL neutralusually LDL neutral Medications in this Class: pioglitazone (Actos), Medications in this Class: pioglitazone (Actos),

rosiglitazone (Avandia), [troglitazone (Rezulin) - taken off rosiglitazone (Avandia), [troglitazone (Rezulin) - taken off market due to liver toxicity]market due to liver toxicity]www.freelivedoctor.com

BiguanidesBiguanides Biguanides Biguanides ↓↓ hepatic glucose production and hepatic glucose production and

increase insulin-mediated peripheral glucose increase insulin-mediated peripheral glucose uptake.uptake.

EfficacyEfficacy Decrease fasting plasma glucose 60-70 mg/dl (3.3-3.9 Decrease fasting plasma glucose 60-70 mg/dl (3.3-3.9

mmol/L)mmol/L) Reduce A1C 1.0-2.0%Reduce A1C 1.0-2.0%

Other EffectsOther Effects Diarrhea and abdominal discomfortDiarrhea and abdominal discomfort Lactic acidosis if improperly prescribedLactic acidosis if improperly prescribed Cause small decrease in LDL cholesterol level and Cause small decrease in LDL cholesterol level and

triglyceridestriglycerides No specific effect on blood pressureNo specific effect on blood pressure No weight gain, with possible modest weight lossNo weight gain, with possible modest weight loss Contraindicated in patients with impaired renal function Contraindicated in patients with impaired renal function Medications in this Class: metformin (Glucophage), Medications in this Class: metformin (Glucophage),

metformin hydrochloride extended release (Glucophage XR)metformin hydrochloride extended release (Glucophage XR)www.freelivedoctor.com

SulfonylureasSulfonylureas Sulfonylureas increase endogenous insulin Sulfonylureas increase endogenous insulin

secretionsecretion EfficacyEfficacy

Decrease fasting plasma glucose 3.3-3.9 mmol/LDecrease fasting plasma glucose 3.3-3.9 mmol/L Reduce A1C by 1.0-2.0%Reduce A1C by 1.0-2.0%

Other EffectsOther Effects HypoglycemiaHypoglycemia Weight gain Weight gain No specific effect on plasma lipids or blood pressureNo specific effect on plasma lipids or blood pressure Generally the least expensive class of medicationGenerally the least expensive class of medication

Medications in this Class:Medications in this Class: First generation : chlorpropamide , tolazamide, First generation : chlorpropamide , tolazamide,

acetohexamide , tolbutamideacetohexamide , tolbutamide Second generation : glyburide , glimepiride , glipizide Second generation : glyburide , glimepiride , glipizide www.freelivedoctor.com

MeglitinidesMeglitinides stimulate insulin secretion (rapidly and for a stimulate insulin secretion (rapidly and for a

short duration) in the presence of glucose.short duration) in the presence of glucose. EfficacyEfficacy

↓↓ peak postprandial glucosepeak postprandial glucose ↓↓ plasma glucose 3.3-3.9 mmol/Lplasma glucose 3.3-3.9 mmol/L ↓↓ HbA1C 1.0-2.0%HbA1C 1.0-2.0%

Other EffectsOther Effects Hypoglycemia (may be less than with sulfonylureas if Hypoglycemia (may be less than with sulfonylureas if

patient has a variable eating schedule)patient has a variable eating schedule) Weight gain Weight gain No significant effect on plasma lipid levelsNo significant effect on plasma lipid levels Safe at higher levels of serum Cr than sulfonylureasSafe at higher levels of serum Cr than sulfonylureas

Medications in this Class: repaglinide , nateglinideMedications in this Class: repaglinide , nateglinide


Alpha-glucosidase Alpha-glucosidase InhibitorsInhibitors Alpha-glucosidase inhibitors block the enzymes Alpha-glucosidase inhibitors block the enzymes

that digest starches in the small intestinethat digest starches in the small intestine EfficacyEfficacy

↓↓ peak postprandial glucose 2.2-2.8 mmol/Lpeak postprandial glucose 2.2-2.8 mmol/L ↓↓ fasting plasma glucose 1.4-1.7 mmol/Lfasting plasma glucose 1.4-1.7 mmol/L Decrease A1C 0.5-1.0%Decrease A1C 0.5-1.0%

Other EffectsOther Effects Flatulence or abdominal discomfort Flatulence or abdominal discomfort No specific effect on lipids or blood pressureNo specific effect on lipids or blood pressure No weight gainNo weight gain Contraindicated in patients with inflammatory Contraindicated in patients with inflammatory

bowel disease or cirrhosisbowel disease or cirrhosis Medications in this Class: acarbose , miglitol Medications in this Class: acarbose , miglitol


Efficacy of Efficacy of Monotherapy with Oral Monotherapy with Oral

Diabetes AgentsDiabetes AgentsDrug Fasting Plasma

Glucose Reduction (mmol/l)

A1C Reduction

(%) Thiazolidinedione 1.9-2.2 0.5-1.0

Sulfonylurea 3.3-3.9 1.0-2.0

Biguanide 3.3-3.9 1.0-2.0

Meglitinide 3.3-3.9 1.0-2.0

Alpha-glucosidase inhibitor

1.4-1.7 0.5-1.0

DeFronzo Annals of Internal Medicine 1999;131:281-303

Nathan N Engl J Med 2002; 347:1342-1349 www.freelivedoctor.com

Treatment of Type 2 Treatment of Type 2 DiabetesDiabetes

DiagnosisDiagnosis

Therapeutic Lifestyle ChangeTherapeutic Lifestyle Change

Combination Therapy - Oral Drug with InsulinCombination Therapy - Oral Drug with Insulin

Combination Therapy - Oral Drugs OnlyCombination Therapy - Oral Drugs Only

MonotherapyMonotherapy


Sulfonylurea + Biguanide Sulfonylurea + Biguanide Glyburide + Metformin - Glyburide + Metformin -

GlucovanceGlucovance Glipizide + Metformin - Glipizide + Metformin - MetaglipMetaglip

Thiazolidinedione + BiguanideThiazolidinedione + Biguanide Rosiglitazone + Metformin - Rosiglitazone + Metformin - Avandamet Avandamet

Fixed Combination Pills

Combination Therapy for Type 2 Combination Therapy for Type 2 DiabetesDiabetes


Combination Therapy for Type 2 Diabetes

Combination Therapy for Type 2 Diabetes

BiguanidesBiguanides

InsulinInsulin

SulfonylureasSulfonylureas

Alpha-glucosidase Inhibitors

Alpha-glucosidase Inhibitors

MeglitinideMeglitinide

ThiazolidinedionesThiazolidinediones


Clinic ChecklistsClinic Checklists Glycaemic control- home monitoring, Glycaemic control- home monitoring,

HbA1c, inj site, hypoHbA1c, inj site, hypo Diet, exercise, Smoking, alcohol Diet, exercise, Smoking, alcohol BPBP WeightWeight Macrovascular- CVA, IHDMacrovascular- CVA, IHD Microvascular- Retinopathy, Microvascular- Retinopathy,

microalbuminuria, neuropathymicroalbuminuria, neuropathy Foot Foot Lipid profile, renal function, TSHLipid profile, renal function, TSH


Special circumstancesSpecial circumstances Intercurrent illnessIntercurrent illness Peri-operative periodPeri-operative period PregnancyPregnancy Childhood and adolescentsChildhood and adolescents Others- travelling across time zonesOthers- travelling across time zones

ExerciseExercise

AlcoholAlcohol

DrivingDriving


New developmentsNew developments



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Drug therapy in diabetes