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Diabetes
 

Diabetes

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  • There are five major classes of oral diabetes medications: thiazolidinediones, biguanides, sulfonylureas, meglitinides, and alpha-glucosidase inhibitors. These five classes of medication operate in essentially three different ways. Thiazolidinediones and biguanides decrease glucose production in the liver and increase insulin sensitivity in peripheral body tissues. Sulfonylureas and meglitinides stimulate the pancreatic beta cells to make more insulin. Finally, alpha-glucosidase inhibitors slow the absorption of starches in the gut, reducing the amount of glucose that enters the bloodstream.
  • Thiazolidinediones (TZDs) enhance insulin sensitivity in muscle and adipose tissue by binding to cell receptors,which leads to an increase in glucose transporter expression. TZDs encourage beta cells to respond more efficiently by lowering the amount of glucose and free fatty acids in the bloodstream, both of which are known to be detrimental to insulin secretion. Finally, these drugs reduce glucose production in the liver. Clinical trials indicate that pioglitazone and rosiglitazone are slightly more effective at reducing A1C (1.5-1.6% reduction) than troglitazone (1.1% reduction). Some of the beneficial side effects of thiazolidinediones include an increase in HDL cholesterol and reduction of triglyceride concentrations. This class of drugs has also been shown to lower blood pressure and decrease vascular inflammation in vitro. There are clinical studies underway to further examine the cardiovascular benefit to TZDs. Some adverse effects of TZDs include weight gain, a potential increase in LDL cholesterol levels, and a possible increase in alanine aminotransferase levels (ALT). Because of the risk of weight gain, edema, and increased LDL cholesterol, thiazolidinediones are contraindicated in patients with advanced forms of congestive heart failure. Due to reported cases of liver failure and liver toxicity caused by the increase in ALT levels, TZDs are contraindicated in patients with abnormal liver function. TZDs are the most expensive of the oral antidiabetic agents.
  • The mechanism of action of metformin is not entirely understood, but it's predominant effect is to suppress hepatic glucose production and to enhance insulin sensitivity in peripheral tissues (primarily muscle). It is unclear if insulin sensitivity occurs by metformin binding to cell receptors,which leads to an increase in glucose transporter expression, or whether insulin sensitivity is simply a secondary effect of the suppressed glucose production. Metformin's ability to lower A1C and decrease fasting plasma glucose is similar to that of sulfonylurea drugs. However, the UKPDS showed that those who received metformin had less hypoglycemia and weight gain than those who received sulfonylureas. Metformin must be avoided in patients with renal impairments, as those patients are at higher risk of experiencing lactic acidosis. However, metformin is an effective monotherapy and may be an ideal drug for overweight patients since it does not cause weight gain and has been seen to cause modest amounts of weight loss when first administered. Diarrhea and abdominal discomfort can be alleviated by changes in diet and slow increases in metformin dosage.
  • Sulfonylureas (SUs) increase insulin secretion by binding to receptors on the surface of pancreatic beta cells, triggering a series of reactions which leads to insulin secretion. Because SUs cause circulating insulin levels to increase, there is a risk of hypoglycemia. There is also some concern that increased insulin levels are associated with cardiovascular disease, however the UKPDS did not show a relationship between increased mortality and SU administration. Finally, there is concern that SUs will exhaust beta cell function by increasing insulin secretion. However, the decline in beta cell function is more likely caused by the disease itself, and not the use of SUs. First generation sulfonylureas are just as efficacious as the second generation drugs, however the second generation may be more potent and safer than first. When diet and exercise fail, SUs are an effective monotherapy.
  • The mechanism of action of repaglinide is similar to that of the sulfonylurea drugs: binding to beta cell receptors to stimulate insulin secretion. The major difference between the two drug classes is that meglitinides are shorter-acting, and are most effective when taken after meals in the presence of glucose. Adverse effects include weight gain and hypoglycemia. An additional drawback to this drug is the dosing schedule since it must be taken with meals.
  • Alpha-glucosidase inhibitors (AGIs) work by blocking the enzyme in the small intestine that breaks down complex carbohydrates, alpha-glucosidase. By blocking this enzyme these drugs prevent starches from being absorbed into the bloodstream and in doing so lower blood glucose levels. AGIs are the only drug class used to treat type 2 diabetes that does not specifically target the pathology of the disease. Because AGIs work in the digestive tract, they are more effective at lowering postprandial glucose levels than fasting plasma glucose levels. On average, AGIs are less effective at lowering A1c levels than biguanides or sulfonylureas. What makes this class of drug attractive to patients and physicians is it's disassociation with weight gain and hypoglycemia. However, it is known to cause abdominal discomfort and diarrhea. AGIs are also rarely used as monotherapy because of their low efficacy.
  • As type 2 diabetes progresses it becomes more difficult to control with a single drug. When monotherapy fails to manage blood glucose levels, the logical next step is combination therapy. The goal of combination therapy is to combine the effects of two or more drugs to reach the desired A1C level. Ideally, one would combine two drugs with two different mechanisms of action, such as a drug that stimulates insulin secretion and a drug that improves insulin sensitivity. This slide illustrates approved combination therapies. Some of the most popular combinations are: 1. sulfonylurea with biguanide (metformin) 2. metformin and thiazolidinedione 3. sulfonylurea and thiazolidinedione If glycemic control is not accomplished with oral medications alone, adding insulin to the drug regimen or using insulin alone can be an effective next step.

Diabetes Diabetes Presentation Transcript

  • Diabetes Mellitus: A Review
  • Objectives
    • Review the criteria for the diagnosis of Diabetes and Pre-Diabetes
    • Review treatment goals in diabetes mellitus
    • Review therapeutic options to achieve treatment goals
  • Diabetes Mellitus
    • Group of metabolic diseases characterized by:
      • Hyperglycemia resulting from defects in insulin secretion, insulin action or both
      • Long term damage, dysfunction and organ failure associated with long term hyperglycemia especially in the following organs: eyes, nerves, kidneys, heart and blood vessels
  • Classification
    • Type 1 diabetes
      • results from β-cell destruction, usually leading to absolute insulin deficiency
    • Type 2 diabetes
      • results from a progressive insulin secretory defect on the background of insulin resistance
    • Other specific types of diabetes due to other causes
      • e.g., genetic defects in β-cell function, genetic defects in insulin action, diseases of the exocrine pancreas (such as cystic fibrosis), and drug- or chemical-induced (such as in the treatment of AIDS or after organ transplantation)
    • Gestational diabetes mellitus (GDM)
      • diabetes diagnosed during pregnancy
  • Criteria for Diagnosis of Diabetes
    • HbA1C ≥ 6.5%
    • The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay
    • FPG ≥ 126 mg/dl (7.0 mmol/l)
    • Fasting is defined as no caloric intake for at least 8 hours
  • Criteria for Diagnosis of Diabetes
    • 2-hour Plasma Glucose ≥ 200 mg/dl (11.1 mmol/l) during OGTT
    • The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water
    • Random Plasma Glucose ≥ 200 mg/dl
    • In patients with classic symptoms of hyperglycemia or in hyperglycemic crises.
  • Categories for Increased Risk of Diabetes
    • Impaired Fasting Glucose
      • FPG = 100 mg/dl (5.6 mmol/l) to 125 mg/dl (6.9 mmol/l)
    • Impaired Glucose Tolerance
      • 2-h plasma glucose = 140 mg/dl (7.8 mmol/l) to 199 mg/dl (11.0 mmol/l)
    • HbA1c = 5.7–6.4%
  • Criteria for Testing Asymptomatic Individuals
    • Testing should be considered in all adults who are overweight ( BMI ≥ 25 kg/m2 *) and have additional risk factors :
      • physical inactivity
      • first-degree relative with diabetes
      • members of a high-risk ethnic population (e.g., African American, Latino, Native American, Asian American, and Pacific Islander)
      • women who delivered a baby weighing >9 lb or were diagnosed with GDM
      • hypertension ( 140/90 mmHg or on therapy for hypertension)
      • HDL cholesterol level <35 mg/dl (0.90 mmol/l) and/or a triglyceride level >250 mg/dl (2.82 mmol/l)
      • women with polycystic ovarian syndrome (PCOS)
      • IGT or IFG on previous testing, A1C 5.7%,
      • other clinical conditions associated with insulin resistance (e.g., severe obesity and acanthosis nigricans)
      • history of CVD
  • Criteria for Testing Asymptomatic Individuals
    • In the absence of the above criteria, testing for pre-diabetes and diabetes should begin at age 45 years
    • If results are normal, testing should be repeated at least at 3-year intervals , with consideration of more frequent testing depending on initial results and risk status.
  • Criteria for Testing in Asymptomatic Children
    • Overweight (BMI 85th percentile for age and sex, weight for height, 85th percentile, or weight 120% of ideal for height)
      • Family history of type 2 diabetes in first- or second-degree relative
      • Race/ethnicity (Native American, African American, Latino, Asian American, Pacific Islander)
      • Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, polycystic ovary syndrome, or small for gestational age birthweight)
      • Maternal history of diabetes or GDM during the child’s gestation
  • Criteria for Testing in Asymptomatic Children
    • Age of initiation
      • 10 years or at onset of puberty, if puberty occurs at a younger age
    • Frequency
      • Every 3 years
  • Screening for and Diagnosis of GDM
    • Carry out risk assessment on the first prenatal visit
    • Criteria for very high risk of developing DM:
      • Severe obesity
      • Prior history of GDM or LGA infants
      • Presence of glycosuria
      • Diagnosis of PCOS
      • Strong family history of type 2 diabetes
  • Screening for and Diagnosis of GDM
    • Criteria for low risk of developing GDM:
      • Age < 25 years old
      • Weight normal before pregnancy
      • Member of an ethnic group with a low prevalence of diabetes
      • No known diabetes in first-degree relatives
      • No history of abnormal glucose tolerance
      • No history of poor obstetrical outcome
      • *does not require GDM screening
  • GDM Screening at 24-28 weeks
    • Two-step Approach:
      • Perform initial screening by measuring plasma or serum glucose 1 h after a 50-g load; 140 mg/dl identifies 80% of women with GDM, while the sensitivity is further increased to 90% by a threshold of 130 mg/dl.
      • Perform a diagnostic 100-g OGTT on a separate day in women who exceed the chosen threshold on 50-g screening.
  • GDM Screening at 24-28 weeks
    • One-step approach (may be preferred in clinics with high prevalence of GDM):
      • Perform a diagnostic 100-g OGTT in all women to be tested at 24–28 weeks.
      • To make a diagnosis of GDM, at least two of the following plasma glucose values must be found:
        • Fasting: 95 mg/dl
        • 1-hour: 180 mg/dl
        • 2-hour: 155 mg/dl
        • 3-hour :140 mg/dl
  • Prevention and Delay of Type 2 DM (Pre-Diabetic Patients)
    • Weight loss of 5-10% of TBW
    • Increase in physical activity of 150 mins/week of moderate exercise
    • For very high-risk individuals, Metformin may be added
    • Monitoring for development of DM should be done yearly
  • Initial Evaluation
  • History
    • Age, Characteristic of onset
    • Eating patterns, physical activity habits, nutritional status and weight history
    • Growth and development in children and adolescents
    • Diabetes education history
    • Review of previous treatment regimens and response to therapy
    • Current treatment of diabetes
      • including medications, meal plan, physical activity patterns, and results of glucose monitoring and patient’s use of data
  • History
    • DKA frequency, severity, and cause
    • Hypoglycemic episodes
      • Hypoglycemia awareness, frequency and cause
    • History of diabetes-related complications
      • Microvascular: retinopathy, nephropathy, neuropathy (sensory, including history of foot lesions; autonomic, sexual dysfunction and gastroparesis)
      • Macrovascular: CHD, CVD, PAD
    • Other: psychosocial problems, dental disease
  • Physical Examination
    • Height, weight, BMI
    • Blood pressure determination, including orthostatic measurements when indicated
    • Fundoscopic examination
    • Thyroid palpation
    • Skin examination (for acanthosis nigricans and insulin injection sites)
  • Physical Examination
    • Comprehensive foot examination
      • Inspection
      • Palpation of dorsalis pedis and posterior tibial pulses
      • Presence/absence of patellar and Achilles reflexes
      • Determination of proprioception, vibration, and monofilament sensation
  • Laboratory Evaluation
    • HbA1C, if results not available within past 2–3 months
    • If not performed/available within past year:
      • Fasting lipid profile, including total, LDL and HDL cholesterol and triglycerides
      • Liver function tests
      • Test for urine albumin excretion with spot urine albumin/creatinine ratio
      • Serum creatinine and calculated GFR
      • TSH in type 1 diabetes, dyslipidemia, or women over age 50 years
  • Referrals
    • Annual dilated eye exam
    • Family planning for women of reproductive age
    • Registered dietitian for nutritional therapy
    • Diabetes self-management education
    • Dental examination
    • Mental health professional, if needed
  • Glycemic Control
  • Glucose Monitoring
    • Self-monitoring of Blood Glucose (SMBG) for patients on insulin therapy
      • Three or more times daily
    • HbA1c
      • At least twice a year in patients meeting glycemic goals
  • Summary of Glycemic Recommendations Postprandial glucose may be targeted if A1C goals are not met despite reaching preprandial glucose goals., taken 1-2 hours after beginning the meal. HbA1c < 7.0% Preprandial Capillary Blood Glucose 70-130 mg/dl (3.9 – 7.2 mmol/L) Peak Postprandial Capillary Blood Glucose < 180 mg/dl (< 10.0 mmol/L)
  • Key Concepts in Setting Glycemic Goals
    • HbA1C is the primary target for glycemic control
    • Goals should be individualized based on:
      • duration of diabetes
      • age/life expectancy
      • comorbid conditions
      • known CVD or advanced microvascular complications
      • hypoglycemia unawareness
      • individual patient considerations
    • More or less stringent glycemic goals may be appropriate for individual patients
  • Glycemic Control for Women with GDM
    • Preprandial Capillary Glucose = 95 mg/dl (5.3 mmol/l) and either
    • 1-h postmeal = 140 mg/dl (7.8 mmol/l)
    • OR
    • 2-h postmeal = 120 mg/dl (6.7 mmol/l)
  • Glycemic Control for Pregnant Women with Pre-existing DM
    • Premeal, bedtime, and overnight glucose
      • 60–99 mg/dl (3.3–5.4 mmol/l)
    • Peak postprandial glucose
      • 100 –129 mg/dl (5.4 –7.1 mmol/l)
    • HbA1C = 6.0%
  • Goals of Treatment Summary of Recommendations for Glycemic, Blood Pressure and Lipid Control HbA1c < 7.0% Blood Pressure < 130/80 mm Hg LDL Cholesterol < 100 mg/dl (2.6 mmol/L) Triglycerides < 150 mg/dl (3.7 mmol/L) HDL Cholesterol > 40 mg/dl (1.1 mmol/L) ♂ > 50 mg/dl (1.3 mmol/L) ♀
  • Diabetes Management
  • Pharmacologic Treatment
    • Patients with diabetes and hypertension should be treated with a regimen that includes either an ACE inhibitor or an ARB .
    • Statin therapy for diabetic patients:
      • With overt CVD
      • Without CVD who are over the age of 40 and have risk factors for CVD
  • Pharmacologic Treatment
    • Aspirin therapy (75-162 mg) for
      • Patients with history of CVD
      • Patients > 40 years old or who have additional risk factors such as:
        • Family history of CVD
        • Hypertension
        • Smoking
        • Dyslipidemia
        • Albuminuria
  • Pharmacologic Treatment
    • Annual influenza vaccination. Provide at least one lifetime pneumococcal vaccination.
    • Achieve blood sugar control with oral hypoglycemic agents and/or insulin.
  • Oral Hypoglycemic Agents
  • Major Classes of Medications
    • 1. Drugs that sensitize the body to insulin and/or control hepatic glucose production
    • 2. Drugs that stimulate the pancreas to make more insulin
    • 3. Drugs that slow the
    • absorption of starches
      • Thiazolidinediones
      • Biguanides
      • Sulfonylureas
      • Meglitinides
      • Alpha-glucosidase inhibitors
  • Thiazolidinediones/Glitazones
    • Thiazolidinediones decrease insulin resistance by making muscle and adipose cells more sensitive to insulin. They also suppress hepatic glucose production.
    • Efficacy
      • Decrease fasting plasma glucose ~35-40 mg/dl (1.9-2.2 mmol/L)
      • Reduce HbA1C ~0.5-1.0%
      • 6 weeks for maximum effect
    • Other Effects
      • Weight gain, edema
      • Hypoglycemia (if taken with insulin or agents that stimulate insulin release)
      • Contraindicated in patients with abnormal liver function or CHF
      • Improves HDL cholesterol and plasma triglycerides; usually LDL neutral
    • Medications in this Class: pioglitazone, rosiglitazone
  • Biguanides
    • Biguanides decrease hepatic glucose production and increase insulin-mediated peripheral glucose uptake.
    • Efficacy
      • Decrease fasting plasma glucose 60-70 mg/dl (3.3-3.9 mmol/L)
      • Reduce HbA1C 1.0-2.0%
    • Other Effects
      • Diarrhea and abdominal discomfort
      • Lactic acidosis if improperly prescribed
      • Cause small decrease in LDL cholesterol level and triglycerides
      • No specific effect on blood pressure
      • No weight gain, with possible modest weight loss
      • Contraindicated in patients with impaired renal function (Serum Cr > 1.4 mg/dL for women, or 1.5 mg/dL for men)
    • Medications in this Class: metformin, metformin hydrochloride extended release
  • Sulfonylureas
    • Sulfonylureas increase endogenous insulin secretion
    • Efficacy
      • Decrease fasting plasma glucose 60-70 mg/dl (3.3-3.9 mmol/L)
      • Reduce HbA1C by 1.0-2.0%
    • Other Effects
      • Hypoglycemia
      • Weight gain
      • No specific effect on plasma lipids or blood pressure
      • Generally the least expensive class of medication
    • Medications in this Class:
      • First generation sulfonylureas : chlorpropamide, tolazamide, acetohexamide, tolbutamide
      • Second generation sulfonylureas: glyburide, glimepiride glipizide
  • Meglitinides
    • Meglitinides stimulate insulin secretion (rapidly and for a short duration) in the presence of glucose.
    • Efficacy
      • Decreases peak postprandial glucose
      • Decreases plasma glucose 60-70 mg/dl (3.3-3.9 mmol/L)
      • Reduce HbA1C 1.0-2.0%
    • Other Effects
      • Hypoglycemia (although may be less than with sulfonylureas if patient has a variable eating schedule)
      • Weight gain
      • No significant effect on plasma lipid levels
      • Safe at higher levels of serum Cr than sulfonylureas
    • Medications in this Class: repaglinide, nateglinide
  • Alpha-glucosidase Inhibitors
    • Alpha-glucosidase inhibitors block the enzymes that digest starches in the small intestine
    • Efficacy
      • Decrease peak postprandial glucose 40-50 mg/dl (2.2-2.8 mmol/L)
      • Decrease fasting plasma glucose 20-30 mg/dl (1.4-1.7 mmol/L)
      • Decrease HbA1C 0.5-1.0%
    • Other Effects
      • Flatulence or abdominal discomfort
      • No specific effect on lipids or blood pressure
      • No weight gain
      • Contraindicated in patients with inflammatory bowel disease or cirrhosis
    • Medications in this Class: acarbose
  • Dipeptidyl Peptidase 4 Inhibitors
    • Increase glucose-mediated insulin secretion
    • Suppress glucagon secretion
    • Efficacy
      • Lowers HbA1c by 0.6-0.9%
      • Weight neutral
      • Well-tolerated
    • Other effects
      • Does not cause hypoglycemia
      • Increase in upper respiratory tract infections
    • Medications in this class: sitagliptin, vidagliptin
  •  
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  • Treatment of Type 2 Diabetes Mellitus COMBINATION THERAPY – ORAL DRUGS ONLY COMBINATION THERAPY – ORAL DRUGS with INSULIN DIAGNOSIS THERAPEUTIC LIFESTYLE CHANGE MONOTHERAPY
  • Titration of Metformin
    • Low-dose metformin (500 mg) once or twice per day with meals (breakfast and/or dinner) or 850 mg once per day
    • After 5 to 7 days, if with no GI side effects, increase dose to 850 or two 500 mg tablets twice per day (to be taken before breakfast and/or dinner)
    • If with GI side effects, decrease to previous lower dose. Increase dose at later time.
    • Maximum dose: 1000 mg twice per day
  • Combination Therapy for Type 2 Diabetes Sulfonylureas Thiazolidinediones Alpha Glucosidase Inhibitors Meglitinide Biguanides Insulin
  • Combination Therapy: Fixed Dose Pills
    • Glucovance (Glibenclamide + Metformin)
    • Eugloplus (Glibenclamide + Metformin)
    • Norsulin (Gliclazide + Metformin)
    • Avandamet (Rosiglitazone + Metformin)
    • Janumet (Sitagliptin + Metformin)
  • Contraindications for Use of OHAs Drug Class Contraindications Sulfonylureas Known allergies to SUs, Pregnancy, Hepatic & Renal insufficiency Meglitinides Known allergies, Pregnancy Biguanides Clinical states involving hypoxia Alpha Glucosidase Inhibitors Known allergies, GI disturbances Glitazones Known or suspected liver disease,  liver enzymes
  • Treatment of Type 2 Diabetes Mellitus COMBINATION THERAPY – ORAL DRUGS ONLY COMBINATION THERAPY – ORAL DRUGS with INSULIN DIAGNOSIS THERAPEUTIC LIFESTYLE CHANGE MONOTHERAPY