diabetes mellitus and insuline analogs
DESCRIPTION
This presentation was delivered by 3rd year MBBS students of Frontier Medical College during 4th Clinico-Pharmacological Conference held in the Pharmacology Dept of College. The Presentation aims at providing key features in detail about diabetes and its Pharmacological treatment. The Presentation was well applauded by the Faculty and students of Medical College. (Abbottabad, Pakistan).TRANSCRIPT
1605 Abubakkar Raheel
1553 Nazia Hassan1652 Abrar Afridi
1638 Kehkashan AlamDiabetes Mellitus4th Clinico-Pharmacological ConferenceFrontier Medical College 3rd year MBBS
4th Clinico-Pharmacological ConferenceFrontier Medical College
Learning Objectives
Diabetes Mellitus
Define the term Diabetes mellitus. Discuss brief History of Diabetes Identify the incidence and prevalence of diabetes mellitus. Discuss the Etiology of diabetes Discuss the Biostatical analysis of Diabetes Differentiate between Type 1 Diabetes and Type 2 Diabetes Know the drugs used for its treatment
4th Clinico-Pharmacological ConferenceFrontier Medical College
Discuss the mechanism of action of Proto-Type Drugs Understand the Adverse Affects of mentioned Drugs Learn the Treatment and Management of Diabetes Discuss a Clinical Scenario Brief Question/Answer Session
Diabetes Mellitus
Learning Objectives
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• In Simple terms, Diabetes Mellitus is a disease marked by high levels of sugar in the blood. Mellitus is Latin for “sweet as honey”.
• According to our Textbook Lippincott’s Pharmacology, “Diabetes is not a single disease rather it is a heterogeneous group of Syndromes characterized by elevation of blood glucose caused by a relative or absolute deficiency of Insulin.”
Diabetes Mellitus
Definition
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Diabetes Mellitus
History
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Diabetes Mellitus
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Diabetes Mellitus
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• There are currently over 2 million people diagnosed with diabetes in the UK and there are up to another 1 million people with diabetes who have the condition and don’t know it!
• The global incidence of diabetes is rising and the number of people affected is projected to exceed 300 million by the year 2025.
(www.diabetes.org.uk)
Diabetes Mellitus
Incidence of Diabetes
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• Estimated 245 million people globally• 20% of adult population• 5% of all deaths each year• 80% of people with diabetes live in low and middle income
countries
Diabetes Mellitus
Incidence of Diabetes
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Diabetes Mellitus
Biostatical Analysis
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Diabetes Mellitus
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Diabetes Mellitus
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• A parent, brother, or sister with diabetes • Obesity • Age greater than 45 years • Some ethnic groups• Gestational diabetes or delivering a baby weighing more
than 9 pounds • High blood pressure • High blood cholesterol level • Not getting enough exercise
Diabetes Mellitus
Risk Factor which predispose to Diabetes
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Diabetes Mellitus
Normal Metabolism of Glucose
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Diabetes Mellitus
Type 1 Diabetes
Type 1 Diabetes
• Insulin not produced due to non fuctional beta-cell Hence no maintainance of basal secretion level of Insuline and no response to variations in circulating fuels.
• No insulin to ‘unlock’ the receptors • Glucose cannot enter the cell • Glucose re-enters the blood stream • Extent of glycemic control related to
metabolic complications
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Diabetes Mellitus
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Diabetes Mellitus
Type 1 Diabetes
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Diabetes Mellitus
Blood Sugar &Spine connection• Journal of Vertebral
Subluxation research
• Vagus, T-8, T-9• Disturbed Nerve
supply• Loss of pancreatic
function & insuline production
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Diabetes Mellitus
Symptoms of type 1 Diabetes
• Polyuria • Polydipsia • Weight loss in spite of polyphagia• Fatigue • Nausea • Vomiting • Coma• Patients with type 1 diabetes usually develop symptoms
over a short period of time, and the condition is often diagnosed in an emergency setting.
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Diabetes Mellitus
Morbidity/Complications
Complications of diabetes can be divided into three categories•Metabolic complications of low blood glucose levels (hypoglycaemia) and of high blood glucose levels (hyperglycaemia) e.g. Diabetic coma.•Damage to small blood vessels (microvascular) leading in turn to damage of:
retina (retinopathy)kidney (nephropathy)nerves (neuropathy)
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Diabetes Mellitus
Morbidity/Complications
• Damage to the larger arteries (macrovascular) leading to damage of:brain (leading to stroke)heart (leading to coronary heart disease) legs and feet (leading to peripheral vascular disease)
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Diabetes Mellitus
• Associated with aging, obesity, Peripheral Insuline resistance rather than by auto-immune processes or viruses.
• Metabolic alterations are less (Non-ketotic)• Occurs mostly in people over 40• Type 2 diabetes is the most common of the two main
types and accounts for between 85 - 95% of all people with diabetes.
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Diabetes Mellitus
Pancreas retain some beta-cell function but variable insuline production is insufficient and there is a decrease in the number of receptors (insulin resistance)
Lack of sensitivity of target organs to either endogenous or exogenous insuline
Glucose does not enter the cell effectively Glucose re-enters the blood stream Blood glucose levels rise.
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Diabetes Mellitus
• Slower onset• Polydipsia • Polyuria • Polyphagia • Fatigue • Blurred vision • Slow-healing infections • Impotence in men
Symptoms of Type 2 Diabetes
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Diabetes Mellitus
• Hyperglycemia• Diabetic Ketoacidosis / DKA • Microvascular complications• Macrovascular complications
Complications of Diabetes
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Diabetes Mellitus
• Polyuria • Polydipsia • Fatigue • Nausea and vomiting • Muscular stiffness or aching • Mental stupor/ decreased consciousness may progress to
coma • Rapid breathing • Fruity breath (pear drops / nail varnish smell) • Headache • Low blood pressure • Decreased appetite • Abdominal pain
Symptoms of DKA
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Diabetes Mellitus
Microvascular Complications
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Diabetes Mellitus
Microvascular Complications
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Diabetes Mellitus
Microvascular Complications
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Diabetes Mellitus
Microvascular Complications
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Diabetes Mellitus
Macrovascular Complications
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Diabetes Mellitus
Macrovascular Complications
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Diabetes Mellitus
Macrovascular Complications
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Diabetes Mellitus
Macrovascular Complications
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Diabetes Mellitus
Treatment: Dugs Classification
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Diabetes Mellitus
Insuline and its Preparations
ByNazia Hassan
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Insuline is a polypeptide hormone, consisting of two peptide chains that are connected by disulphide bonds. It is synthesized as a precursor insuline (pro-insuline) that undergoes proteolytic cleavages to form insuline and C-peptide, both of which are secreted by the Beta-Cells of the pancreas.
Diabetes Mellitus
Insuline
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Diabetes Mellitus
Insuline is secreted from pancreatic B-Cell at a low basal rate and at a much higher stimulated rate in response to a variety of stimuli, especially glucose. Other stimulants include•Sugars (Mannose)•Certain Amino acids (Leucine, Arganine)•Hormones (Glucagon like polypeptide)•Glucose dependent insulinotropic polypeptide•Glucagon•Cholecystokinin•Vagal activity
Secretion
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Diabetes Mellitus
Insuline and Glucagon
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• Insulin is stored in beta cells of pancreas in the form of granules as crystals.
• Each crystal consist of 6 molecules of insulin binding with 2 atoms of Zn.
• Human pancreas can store 8gm of inuslin.
Diabetes Mellitus
Storage
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Diabetes Mellitus
Because insuline is a polypeptide, it is degraded in the gastrointestinal tract if taken orally. Therefore it is generally administered by subcutaneous injection. During Hyperglycemic emergency, it is injected Intravenously.
Administration
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Diabetes Mellitus
• Liver and kidney remove insulin from circulation• Liver clears 60% while kidney removes about 40% of the
insulin• This ratio is inverted for exogenous subcutaneous insulin• Half life of insulin is 3-5min in the blood
Degradation
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Diabetes Mellitus
• Insulin is measured in units u/ml • 1mg is equal to 28u• Basal insulin value is 5-15microU/ml• Peak concentration can rise to 60-90microU/ml during
meals
Circulating insuline
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Diabetes Mellitus
The symptoms of hypoglycemia are the most serious and common adverse reactions to an excessive dose of Insuline.Other adverse affects include •Weight gain•Lipodystrophy•Allergic reactions •local Injection site reactions
Adverse reactions to Insuline
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Diabetes Mellitus
• S.t therapy involves twice injections daily• Int.t therapy involves three or more times injection daily• Frequency of hypogylcemic episodes, coma and seizures
are higher in Int.t than st.t therapy due to insulin excessiveness
• Patient with Int.t therapy has significant reduction in nephropathy, neuropathy and retinopathy
Standard and Intensive Therapy
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Diabetes Mellitus
Insuline Preparations
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Diabetes Mellitus
Treatment: Drugs ClassificationInsuline Preparations (Combinations)
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Diabetes Mellitus
Treatment: Drugs ClassificationInsuline Preparations (Combinations)
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Diabetes Mellitus
• This group includes lispro, aspart and glulisine • They have rapid onset of action and short acting duration
• Peak levels can be seen within 30-90min after injection • Short acting insulin includes regular insulin
Rapid acting Insuline
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Diabetes Mellitus
• It includes Neutral protamine hagedron or Isophane
• They act intermediately because of delayed absorption due to formation of less soluble complexes
• Can be used in all type of diabetes except ketoacidoses and emergency diabetes
Intermediate acting Insuline
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Diabetes Mellitus
• This group include glargine and detemir
• Its has slower onset of action and no peak level
• These can be used in combination with rapid acting insulins
Long acting Insuline
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Diabetes Mellitus
Plasma Insuline Levels/Hours
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Diabetes Mellitus
Synthetic Amylin Analogs &Insulin Secretagogues
ByKehkashan ALam
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Diabetes Mellitus
• Pramlintide is indicated as an adjunct to mealtime insulin therapy in patients with Type 1 & Type 2 Diabetes by acting as amylinomimetic.
• Pramlintide delays gastric emtying & delays postprandial Glucagon secretion.
Synthetic Amylin Analogs: Pramlintides
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Diabetes Mellitus
Pharmacokinetics
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Diabetes Mellitus
• Inhibits Glucagon release from pancrease
• Delays Gastric Emptying
• Also causes Anorexia by acting on CNS
Mechanism of action
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Diabetes Mellitus
• Along with insulin in Type 1 & Type 2 Diabetes Mellitus to control Blood Glucose level after meal
• May help in weight loss
Clinical Uses
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Diabetes Mellitus
• Hypoglycemia• Nausea• Vomiting• Anorexia
Adverse Effects
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Diabetes Mellitus
• Gastroparesis( delayed stomach emtying)• Cresol Hypersensitivity • History of Hypoglycemic unawareness
Contraindications
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Diabetes Mellitus
1) Sulfonylureas 2) Glinides1st Generation Repaglinide
• Tolbutamide Nateglinide• Tolazamide• Acetohexamide• Chlorpropamide
2nd Generation• Glibenclamide• Glyburide• Glipizide• Glimepiride
Insulin Secretagogues
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Diabetes Mellitus
• Given Orally before meals• Bind to serum proteins• Metabolized by liver• Excreted by liver or kidney• Duration of Action ranges from 12-24 hours
Sulfonylureas: Pharmacokinetics
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Diabetes Mellitus
Tolbutamide 4-5 hoursChlorpropamide 32 hoursTolzamide 7 hoursGlipizide 2-4 hoursGlimepiride 5 hours
Note: Chlorpropamide in contraindicated in elder patients because it may prolong Hypoglycemia.
Half Life
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Diabetes Mellitus
Mechanism of action
• Blockage of ATP sensitive Potassium channels
• Depolarization
• Calcium ion Influx
• Stimulation of Insulin Release from Beta cells of Pancreas
• Resulting in decrease Glucose level in body
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Diabetes Mellitus
•Hyperinsulinemia•Prolonged Hypoglycemia•Increase in Body Weight•Nausea, Vomiting, Diarrhea•Allergic Reactions like Skin Rashes•Rarely Bone Marrow depression can occur
Adverse affects
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• Severe Hepatic & Renal Failure • Pregnancy• Lactation• Porphyria• Ketoacidosis
Diabetes Mellitus
Contraindications
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• Orally administered
• Well absorbed after being taken 1-30 minutes before meal
• Metabolized to inactive products by cytochrome p450 3A4 in the liver
• Excreted through bile
• Repaglinide should be used courtiously in individuals with renal and
hepatic impairment
Diabetes Mellitus
Glinides: Pharmacokinetics
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• Bind to sulphonylurea receptor of ATP sensitive potassium
channels
• Initiate the release of insulin
• Lowers the blood glucose level
Diabetes Mellitus
Mechanism of action
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• Hypoglycemia in patients who are also taking lipid lowering
drugs like Gemfibrozil
• Weight gain
Diabetes Mellitus
Adverse affects
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Diabetes Mellitus
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Diabetes Mellitus
Insulin Sensitizers: Oral AgentsInsulin Sensitizers: Oral Agents
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Diabetes Mellitus
Biguanides
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Diabetes Mellitus
Mechanism of action
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Diabetes Mellitus
Pharmacokinetics
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Diabetes Mellitus
• Used in insulin resistant patient. i-e, insulin resistance syndrome• It does not increase weight, useful in obese diabetic
patient.• Can be given as monotherapy OR with combination
of insulin secretogogues drugs.
Clinical Uses
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Diabetes Mellitus
Adverse affects
• Lactic acidosis• Reduce B12 absorption• GIT disturbance • anoxia• nausia• vomitting• Diarrhea
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Diabetes Mellitus
Contraindications
• Renal disease• Alcohalism• Hepatic disease• Acute M.I
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Diabetes Mellitus
• These are also insulin sensitizers.• Also known as glitazones.• Rosiglitazone & pioglitazone are currently available
agents.• Does not promote insulin release from pancrease.
Thiazolidinediones
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Diabetes Mellitus
• Tissues to be targeted are adipocytes, liver & skeletal muscles.
• It binds with peroxisome proliferator activated receptor gamma, a nuclear hormone receptor.
• These receptors regulate metabolism of glucose, production of free fatty acids.
• Ultimately increasing sensitivity of insulin.
M.O.A
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Diabetes Mellitus
• Both pioglitazone and rosiglitazone are well absorbed orally.• Bound extensively to plasma protein.• Metabolized by cytochrome p450 enzymes in liver.• Excreted through urine.
Pharmacokinetics
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Diabetes Mellitus
• Hepatotoxicity• Weight gain• Osteopenia• M.I• Anemia• Headache
Adverse Effects
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Diabetes Mellitus
• This group includes acarbose and Miglitol• They don’t have any effect on insulin production
Alpha glucosidase inhibitors
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Diabetes Mellitus
• Inhibits glucosidases located on the intestinal brush boarder
• So oligosaccharrides cant be converted to glucose• In addition these also inhibit pancreatic amylase• Postprandial hyperglycemia does not occure
M.O.A
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Diabetes Mellitus
• These agents are intermediatly absorbed• They don’t have any systemic affects• Excrected by kidneys in unchanged form
Pharmacokinetics
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Diabetes Mellitus
• Diarrhea• Abdominal cramp• Inflammatory bowl syndrome• Colonic ulceration
Adverse affects
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What is an Incretin affect?
Oral glucose results in a higher secretion of insulin than occurs when equal load of glucose is given IV. This effect is referred to as Incretin effect. And is markedly reduced in diabetes type 2.
Diabetes Mellitus
Incretin Mimetics
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Diabetes Mellitus
Incretin hormone
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Diabetes Mellitus
Classification
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LIRAGLUTIDE EXENATIDE
ADMINISTRATION S/C S/C
HALF LIFE LONG SHORT
INJECTION ONCE DAILY TWICE DAILY
EXCRETION - RENAL
AVOIDANCE - RENAL IMPAIRED
ADVERSE AFFECTS N.V.D.C, PANCREATITIS, ABD PAIN
N.V.D.C, PANCREATITIS, ABD PAIN
Diabetes Mellitus
Liraglutide vs Exenatide
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• Act as GLP-1 Receptor Agonists• Improve Glucose Dependent Insuline Secretion• Slow gastric Emptying time• Decrease Food Intake• Decrease post-prandial Glucagon secretion• Promote Beta-Cell proliferation
Diabetes Mellitus
Mechanism of action
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Diabetes Mellitus
Oral Agents: DPP-IV Inhibitors
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Diabetes Mellitus
GLP-1Dipeptidyl
Peptidase- IV Inhibitors
inactivates
inhibit
enzyme
Glucagon like peptide-1
Mechanism of ActionOral Agents: DPP-IV Inhibitors
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Diabetes Mellitus
A 54-year-old woman is diagnosed with type 2 diabetes mellitus after a routine follow-up for impaired fasting glucose showed that her hemoglobin A1C is now 7.6%. She has attempted to lose weight and to exercise with no improvement in her hemoglobin A1C, and drug therapy is now recommended. She has mild systemic hypertension that is well controlled and no other medical conditions.
Which of the following is the most appropriate first-line therapy?
A. AcarboseB. ExenatideC. GlyburideD. MetforminE. Sitagliptin
Short Clinical Scenario
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Diabetes Mellitus
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Diabetes Mellitus
Thank you for your patience