Management Of Diabetes Mellitus

DIABETES MELLITUS TYPE II 1. Insulin Resistance Yasser Gebril Inpatient Pharmacy

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NIDDM (TYPE II DM) • • •

Serious and chronic disease. Progressive condition. Associated with a number of chronic complications. • Macrovascular complications: – Cardiovascular disease (CVD)

• Microvascular complications: – – –

Nephropathy Retinopathy Neuropathy 2

FEATURES OF TYPE I AND TYPE II DM Characteristic

Type I

Type II

Onset (age)

Usually <30

Usually >40

Type of onset

Abrupt

Gradual

Nutrition Status

Often Thin

Often Obese

Clinical Symptoms

Polydipsia, polyurea, polyphagia Often a symptomatic

Ketosis

Present

Usually absent

Endogenous insulin

Absent

Variable

Insulin therapy

Required

Sometimes

Oral hypoglycemics

Usually not effective

Often effective

Diet

Mandatory with insulin

Mandatory with or without drugs

Curtis L. Triplitt, Charles A. Reasner, and William L. Isley -Pharmacotherapy

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DIAGNOSIS OF DM • Diagnosis of diabetes is made by three criteria: – fasting plasma glucose ≥126 mg/dL, – A 2-hour value from a 75-g oral glucose tolerance test ≥200 mg/dL, – Or a casual plasma glucose level of ≥200 mg/dL with symptoms of diabetes.

• with results confirmed by any of the three criteria on a separate

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PATHOPHYSIOLOGY OF NIDDM • It is based on two main metabolic abnormalities: – Insulin resistance. – Impaired pancreatic β-cell function.

• Studies in the earliest phase of pre-diabetes have shown that insulin resistance is the predominant early abnormality, even in lean individuals who later progress to type 2 DM.

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PATHOPHYSIOLOGY OF NIDDM • Minute defects in pancreatic βcell function become evident once IGT begins and are characterized by: – Blunted early phase insulin secretion and – Late hyperinsulinemic response.

• Once diabetes is established, insulin secretion is more disrupted: – There is almost complete loss of the 6

PATHOPHYSIOLOGY OF NIDDM • The cellular and molecular mechanism of insulin resistance and β-cell dysfunction remain incompletely understood. • However, the pathologies of these two defects appear to be interlinked. • Possibly through adverse effects of hyperglycemia (glucotoxicity) and/or elevated FFA (lipotoxicity) on insulin

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PATHOPHYSIOLOGY OF NIDDM • Because the incidence of diabetes is high in families of persons with NIDDM, a strong genetic predisposition is suspected • The three major metabolic abnormalities in NIDDM are: – Defective glucose-induced insulin secretion – Increased hepatic glucose output – Inability of insulin to stimulate glucose uptake by peripheral target tissues.

• Another essential problem in NIDDM may be reduced Insulin Sensitivity of fat and muscle cells to the effects of insulin (insulin resistance)

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DEVELOPMENT OF TYPE 2 DIABETES I

II

III

IV

V

Fasting glucose

Hyperglycemia

Glucose tolerance

Abnormal glucose tolerance

Insulin sensitivity

Decreased insulin sensitivity

Insulin secretio n

Hyperinsulinemia, then β-cell failure

Normal diabetes

IGT

Type 2 9

β-Cell function (%, HOMA analysis)

THE UKPDS DEMONSTRATED THAT LOSS OF GLYCEMIC CONTROL CORRELATES WITH PROGRESSIVE LOSS OF β -CELL FUNCTION 60

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20 0 -1

0

1

2

3

4

5

6

Time from randomization (years) UK Prospective Diabetes Study Group. Diabetes 1995; 44:1249–1258.

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NORMAL INSULIN ACTION • In the fasting state 75% of total body glucose disposal takes place the brain and splanchnic tissues (liver and GIT Tissues). • Brain glucose is not altered in NIDDM. • The remaining 25% of glucose metabolism takes place in muscle, which is dependent on insulin. • In the fasting state approximately 85% of glucose production is derived from the liver. • In the fed state, carbohydrate ingestion increases the plasma 11

NORMAL INSULIN ACTION • The resultant hyperinsulinemia has two actions: 1. suppresses hepatic glucose production 2. stimulates glucose uptake by peripheral tissues.

• The majority (80% to 85%) of glucose that is taken up by peripheral tissues is disposed of in muscle, with only a small amount (4% to 5%) being metabolized by adipocytes. 12

NORMAL INSULIN ACTION • Although fat tissue is responsible for only a small amount of total body glucose disposal, it plays a very important role in the maintenance of total body glucose homeostasis. • The decline in plasma FFA concentration results in increased glucose uptake in muscle, and reduces hepatic glucose production. • Thus a decrease in the plasma FFA concentration lowers plasma glucose by both decreasing its production

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7- Dissociation

TRANSLUCATION OF GLUCOSE TRANSPORTERS BY INSULIN 8Translocatio n 6Transport

Glucos e Glucos e

1Association Kernili Et al; Insulin Stimulated Translocation of Glucose Transporters in the isolated rat adipose cell.

Glucose Transpor ters 5Fusion 4Binding

3Translocatio n 2- Signal 14

INSULIN RESISTANCE • Definition: – A defective binding of insulin to a receptor and blunting of insulin signal transduction

• Conditions associated with elevated insulin levels (Hyperinsulinism), such as obesity, may be the result of downregulation in the number of insulin receptors, effectively resulting in a state of insulin resistance. • Conversely, decrease in insulin levels, (e.g. diabetes) may lead to an upregulation of the receptors, which may shift the insulin dose-response curve; that is less insulin would be required to

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INSULIN RESISTANCE • IR has been associated with a number of hormonal and metabolic states, including: – Cushing’s syndrome (excessive corticosteroids) – Acromegaly (Excessive growth hormone) and – Gestational diabetes

• Physiological or psychological stress also can contribute to insulin resistance. 16

METABOLIC SYNDROME • Patients are said to have metabolic

syndrome if they show three or more of the following: – – – –

Abdominal obesity Atherogenic dyslipidemia Raised blood pressure Insulin resistance with or without glucose intolerance

• Associated with obesity is a sedentary lifestyle, and inactivity; that may contribute to higher blood pressure, elevated blood lipid levels, and insulin resistance associated with glucose intolerance (insulin resistance syndrome).

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ROLE OF FREE FATTY ACIDS IN THE PATHO-GENESIS OF TYPE 2 DIABETES Lipotoxicity Inhibition of β -cell function Reduced insulin secretion

Elevate d plasma Large insulin resistant FFA adipocytes Reduced suppression of lipolysis

Increased glucose output

Hyperglycemia

Reduced glucose uptake

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ELEVATED CIRCULATING FFA IS A CENTRAL FACTOR IN THE DEVELOPMENT OF TYPE 2 DIABETES Insulin resistance

Decreased glucose uptake into muscle and adipose tissue and raised hepatic glucose output

High insulin demand and insulin resistance in pancreas

i ty c xi o ot c u gl

Increased lipolysis

lip ot ox ic ity

Elevated circulating FFA

Hyperglycemia

β -cell dysfunction Arner P. Diabetes Obes Met 2001;3 (Suppl.1); S11–S19.

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IMPAIRED INSULIN SECRETION • The pancreas in people with a normal functioning β cell is able to adjust its secretion of insulin to maintain normal glucose tolerance. • Thus in non-diabetic individuals, insulin is increased in proportion to the severity of the insulin resistance and glucose tolerance remains normal. • Impaired insulin secretion is a uniform finding in type 2 diabetic patients and the evolution of β-cell dysfunction has been well characterized in diverse 20

IMPAIRED INSULIN SECRETION • DeFronzo and colleagues measured the fasting plasma insulin concentration and performed oral glucose tolerance tests in 77 normal weight type 2 diabetic patients and over 100 lean subjects with normal or impaired glucose tolerance. • The relationship between the fasting plasma glucose concentration and the fasting plasma insulin concentration resembles an inverted U or horseshoe. • As the fasting plasma glucose concentration rises from 80 to 140 mg/dL, the fasting plasma insulin concentration increases progressively, peaking at a value that is 2- to 2.5-fold greater than in normal 21 weight non-diabetic controls. When the fasting plasma glucose concentration

THE RELATIONSHIP BETWEEN FASTING PLASMA INSULIN AND FASTING PLASMA GLUCOSE

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DEVELOPMENT OF TYPE 2 DIABETES I

II

III

IV

V

Fasting glucose

Hyperglycemia

Glucose tolerance

Abnormal glucose tolerance

Insulin sensitivity

Decreased insulin sensitivity

Insulin secretio n

Hyperinsulinemia, then β-cell failure

Normal diabetes

IGT

Type 2 23

SITE OF INSULIN RESISTANCE IN TYPE 2 DIABETES • Liver

– Resulting in increased Glucose output (gluconeogenesis)

• Peripheral Muscles – Reduced uptake by Muscles, increased output (glyconenolysis)

• Peripheral Adipocyte – Reduced uptake by adipocytes, increased output (Lipolysis) 24

GOALS OF THERAPY • Reducing symptoms of hyperglycemia. • Reducing the onset and progression of retinopathy, nephropathy, and neuropathy complications. • Intensive therapy for associated cardiovascular risk factors. • Improving quality and quantity of life

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TREATMENT OF IR • Metformin • Thiazolidinediones

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METFORMIN • Metformin should be included in the therapy for all type 2 DM patients, if tolerated and not contraindicated, as it is the only oral anti-hyperglycemic medication proven to reduce the risk of total mortality and cardiovascular death, according to the United Kingdom Prospective Diabetes Study. 27

PHARMACOLOGY • Metformin enhances insulin sensitivity of both hepatic and peripheral (muscle) tissues. • This allows for an increased uptake of glucose into these insulin-sensitive tissues. • Reduction of carbohydrate absorption from GIT 28

PHARMACOKINETICS • Metformin has approximately 50% to 60% oral bioavailability, low lipid solubility, and a volume of distribution that approximates body water. • Metformin is not metabolized and does not bind to plasma proteins. • Metformin is eliminated by renal tubular secretion and glomerular filtration. The average half-life of metformin is 6 hours, though pharmacodynamically, metformin’s antihyperglycemic effects last >24

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EFFICACY OF METFORMIN • Metformin consistently reduces HbA1c levels by 1.5% to 2.0%, fasting plasma glucose levels by 60 to 80 mg/dL, and retains the ability to reduce fasting plasma glucose levels when they are extremely high (>300 mg/dL). • Metformin also has positive effects on several components of the insulin resistance syndrome. • Metformin decreases plasma triglycerides and LDL-C by approximately 8% to 15%, as well increasing HDL-C very modestly

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EFFICACY CONT… • Metformin reduced macro-vascular complicati-ons in obese subjects in the UKPDS. • Metformin significantly reduced allcause mort-ality and risk of stroke vs. intensive treatment with sulfonylureas or insulin. • Metformin also reduced diabetesrelated death and myocardial infarctions vs. the conventional treatment arm of the UKPDS.

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ADVERSE EFFECTS • Gastrointestinal side effects, including abdominal discomfort, stomach upset, and/or diarrhea in approximately 30% of patients. • Anorexia and stomach fullness is likely part of the reason loss of weight is noted with metformin. • These side effects are usually mild and can be minimized by slow titration. • Metallic taste • Interference with vitamin B12 absorption • Hypoglycemia during intense exercise has been documented, but are clinically uncommon.

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CONTRAINDICATIONS • Any disease state that may increase lactic acid production or decrease lactic acid removal may predispose to lactic acidosis. • Tissue hypo-perfusion, such as that due to congestive heart failure, hypoxic states, shock, or septicemia, • Severe liver disease or alcohol consumption. • renal insufficiency • Elderly patients

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THIAZOLIDINEDIONES • Pioglitazone (Glustin - Actos) • Rosiglitazone (Avandia)

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PHARMACOLOGY • Thiazolidinediones work by binding to the PPAR-γ, which are primarily located on fat cells and vascular cells. • Thiazolidinediones enhance insulin sensitivity at muscle, liver, and fat tissues indirectly. • Thiazolidinediones cause preadipocytes to differentiate into mature fat cells in PPAR-γ= peroxisome proliferator activator subcutaneous fat stores. receptor-γ

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MECHANISM OF ACTION OF THIAZOLIDINEDIONES Nuclear receptor PPARγ ( peroxisome proliferator activator receptor ) ↓ Transcription of glucose transporter gene GLUT4 ↓ Increase in insulin mediated peripheral glucose uptake and utilization ( muscle, adipose tissue ) ↓ Maximal effect reached after 3-6 weeks 36

TZD EFFECTS AT TARGET TISSUES Carbohydrate Decreases plasma glucose levels Pancreas

Gut

Blood glucose

Digesti Decreases ve excessive lipolysis enzyme and reduces free s fatty acids

Insulin Decreases excessive hepatic glucose production

Liver

Adipose tissue Muscle Improves insulin-mediated glucose uptake

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PHARMACOKINETICS • Pioglitazone and rosiglitazone are well absorbed with or without food. Both are highly (>99%) protein bound to albumin. • The half-life of pioglitazone and rosiglitazone is 3 to 7 hours and 3 to 4 hours, respectively. • Both medications have a duration of antihyperglycemic action of over 24 hours.

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EFFICACY • Pioglitazone and rosiglitazone, given for about 6 months, reduce HbA1c values∼1.5% and reduce FPG levels by approximately 60 to 70 mg/dL at maximal doses. • Glycemic-lowering onset is slow, and maximal glycemic-lowering effects may not be seen until 3 to 4 months of therapy. • The efficacy of both drugs is dependent on sufficient insulinemia. If there is insufficient endogenous insulin production (β-cell function) or exogenous insulin delivery via injections, neither will lower glucose concentrations efficiently. • Patients who are more obese, or who gain weight on either medication tend to have a39

EFFICACY • Pioglitazone consistently decreases plasma triglyceride levels by 10% to 20%, whereas rosiglitazone tends to have a neutral effect. LDL-C concentrations tend to increase with rosiglitazone 5% to 15%, but do not significantly increase with pioglitazone. • Both appear to convert small, dense LDL particles, which have been shown to be highly atherogenic, to large, fluffy LDL particles, that are less dense. Large, fluffy LDL particles may be less atherogenic. • Both drugs increase HDL similarly, up to 3 to 9 mg/dL. 40

MICRO and MACRO VASCULAR COMPLICATIONS • Thiazolidinediones reduce HbA1c levels, which have been shown to be related to the risk of microvascular complications. • Macrovascular outcome studies are in progress. Thiazolidinediones improve endothelial function, raise HDL levels, slightly lower blood pressure, and have been shown to reduce restenosis after percutaneous transluminal coronary

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ADVERSE EFFECTS. • Troglitazone, the first thiazolidinedione approved, caused hepatotoxicity and had 28 deaths from liver failure, which prompted removal from the U.S. March 2000. • No evidence of hepatotoxicity was reported in an analysis of more than 5,000 patients given rosiglitazone or pioglitazone. • Several case reports of hepatotoxicity with rosiglitazone or pioglitazone have been reported, but improvement in ALT was consistently noted when the drug

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HEPATOTOXICITY • Prior to therapy, it is recommended that an ALT be checked. ALT monitoring vigilance has been lowered, and it is now recommended that the ALT be checked periodically at the practitioner’s discretion. • Prior guidelines recommended every 2 months for the first year of therapy, then periodically. Patients with ALT levels >2.5 times the upper limit of normal should not start either medication, and if the ALT is >3 times the upper limit of normal the medication should be

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CONTRAINDICATION • Hypersensitivity to Glitazones • Type 1 diabetes • Presence of clinical liver abnormalities • Pregnancy • CHF

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SIDE EFFECT 1. Fluid retention – edema in 5% of case4s ? Mechanism 2. Aggravation of CHF ( any degree ) 3. In Europe until now combination with insulin is contraindicated 4. Weight gain, moderate, plateaus over time 5. Hepatic dysfunction with Troglitazone but not with rosiglitazone, it has significant hepatic toxicity

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PREVENTION OF NIDDM • Aggressive management of cardiovascular disease risk factors in type 2 DM is necessary to reduce the risk for adverse cardiovascular events or death. • Smoking cessation, use of anti-platelet therapy as a primary prevention strategy, aggressive management of dyslipidemia minimally to goal low density lipoprotein-cholesterol (LDL-C) (<100 mg/dL) and secondarily to raise high-density lipoprotein-cholesterol (HDL-C) to ≥40 mg/dL, and treatment of hypertension (again often requiring

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PREVENTION OF NIDDM • Prevention stratigies for prevention of NIDDM are established: – Lifestyle modification – Dietary restriction of fat – Aerobic exercises for 30 minutes 5 times a week, and – Weight loss

• To date, medications have been less effective than lifestyle changes to prevent progression to type 2 DM. 47

PATIENT EDUCATION • Patient education and ability to demonstrate self-care and adherence to therapeutic lifestyle and pharmacologic interventions are crucial to successful outcomes. • Multidisciplinary teams of health care professionals including physicians (primary care, endocrinologists, ophthalmologists, and vascular surgeons), podiatrists, dietitians, nurses, pharmacists, social workers, behavioral health specialists, and certified diabetes educators are needed to optimize

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TEAM APPROACH TO THE TREATMENT OF THE DIABETIC PATIENT Nurse Educator

Physician

Pharmaci st

Fitness Trainer

Dietician 49

Questions?

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THANK YOU 51