6. Diabetes type I and II _Obesity 2023 final (1).pdf

LECTURE 6 Diabetes Mellitus and Obesity Sources: American diabetes association ADA guidelines, ACCP2023 Updates in Therapeutics® 2023 and pharmacotherapy handbook 11th : 1  Learning Objectives Describe the pathog...

LECTURE 6 Diabetes Mellitus and Obesity Sources: American diabetes association ADA guidelines, ACCP2023 Updates in Therapeutics® 2023 and pharmacotherapy handbook 11th : 1  Learning Objectives Describe the pathogenesis of Diabetes Mellitus Recognize the signs and symptoms of Diabetes Mellitus Explain the appropriate diagnosis Justify the use of pharmacotherapy and monitor the efficacy and adverse reactions. Be able to develop a therapeutic strategies for a given case GUIDELINES ADA ACE/AACE SOURCE: https://ncd.org.jo/ Pathogenesis 5  Leptin is a hormone predominantly made by adipose cells and enterocytes in the small intestine that helps to regulate energy balance by inhibiting hunger, which in turn diminishes fat storage in adipocytes  a. Age 35 or older, repeat every 3 years if normal/ 2023 ----------------------------------------------------  Diabetes Mellitus; Definition Is a group of chronic metabolic disorders that’s characterized by persistent hyperglycemia. It is associated with abnormalities in carbohydrate, fat and protein metabolism. Results from: ✓ Insufficient insulin secretion (complete lack or relative lack) ✓ Resistance to the action of insulin (sensitivity) 2  Diabetes Mellitus; Definition ◼ D.M leads to complications : 1. Acute: Hypoglycemia / DKA(Diabetic Ketoacidosis) / HHNS 2. Chronic: Microvascular complications include retinopathy, neuropathy and nephropathy. Macrovascular complications include coronary heart disease, stroke and peripheral vascular disease.. DM is the leading cause of: ✓ Blindness ✓ End-stage renal disease ✓ Lower extremity amputations Hyperosmolar hyperglycemic nonketotic syndrome (HHNS), an emergency caused by very high blood sugar, often over 600 mg/dL. Your kidneys try to get rid of the extra blood sugar by putting more sugar into the urine. This makes you urinate more and you lose too much body fluid, causing dehydration 3  Diabetes Classification Type 1 DM (5%–10% of cases) usually develops in childhood or early adulthood and results from autoimmune-mediated destruction of pancreatic β-cells, resulting in absolute deficiency of insulin. Type 2 DM (90% of cases) is characterized by a combination of some degree of insulin resistance and relative insulin deficiency. Gestational diabetes(GDM), (glucose intolerance that is first recognized during pregnancy) 4 Diagnosis & clinical presentation Type 1 Diabetes Mellitus Patients often have symptoms in the days or weeks preceding the diagnosis. The most common initial symptoms are polyuria, polydipsia, polyphagia, weight loss, fatigue, and lethargy. Individuals are often thin and are prone to develop DKA in the absence of an adequate insulin supply; Symptom onset can be triggered by infection, trauma, or psychological stress. 5 Diagnosis & clinical presentation Type 2 Diabetes Mellitus Most patients are asymptomatic or have only mild fatigue at the time of diagnosis. Many patients are incidentally found to have type 2 DM after routine laboratory testing (eg, plasma glucose or A1C) or development of complications (eg myocardial infarction, stroke). Because mild hyperglycemia may exist for years prior to the diagnosis, microvascular and macrovascular complications are often present at the time of diagnosis. 5 Most patients are overweight or obese  Impaired level Normal fasting (no caloric intake for at least 8 hours) plasma glucose The A1C Obtained : -Every 3 months if uncontrolled -Every 6 months if at goal Isra-Summer 2018 6 ADA 2022  Treatment Goals ofTreatment : The primary goal is to prevent or delay progression of longterm microvascular and macrovascular complications. Additional goals are to alleviate symptoms of hyperglycemia, minimize hypoglycemia and other adverse effects, minimize treatment burden, and maintain quality of life. 7 SUSHI  Non-pharmacologic Therapy 1. The meal plan should be moderate in carbohydrates, low in saturated fat (less than 7% of total calories), with all of the essential vitamins and minerals. 2. Weight loss is recommended for all insulin- resistant/overweight or obese patients with type 2 DM. (type 1 should maintain normal bodywt.) 3. Aerobic exercise can improve insulin sensitivity and glycemic control and may reduce cardiovascular risk, contribute to weight control, and improve well-being. - Physical activity goals include at least 150 min/week of moderate exercise spread over at least 3 days/week with no more than 2 days between activity. 8  FACILITATING BEHAVIOR CHANGE AND WELL-BEING TO IMPROVE HEALTH OUTCOMES Physical Activity 5.26 Children and adolescents with type 1 or type 2 diabetes or prediabetes should engage in 60min/day or more of moderate- or vigorous-intensity aerobic activity, with vigorous muscle-strengthening and bone-strengthening activities at least 3 days/week. C 5.27 Most adults with type 1 C and type 2 B diabetes should engage in 150 min or more of moderate to vigorous-intensity aerobic activity per week, spread over at least 3 days/week, with no more than 2 consecutive days without activity. | 27 FACILITATING BEHAVIOR CHANGE AND WELL-BEING TO IMPROVE HEALTH OUTCOMES Smoking Cessation: Tobacco & E-cigarettes 5.32 Advise all patients not to use cigarettes and other tobacco products or e-cigarettes. A 5.33 After identification of tobacco or e-cigarette use, include smoking cessation counseling and other forms of treatment as a routine component of diabetes care. A 5.34Address smoking cessation as part of diabetes education programs for those in need. B | 28 FACILITATING BEHAVIOR CHANGE AND WELL-BEING TO IMPROVE HEALTH OUTCOMES Psychosocial Issues 5.35 Psychosocial care should be integrated with a collaborative, patient-centered approach and provided to all people with diabetes, with the goals of optimizing health outcomes and health-related quality of life. A | 29 FACILITATING BEHAVIOR CHANGE AND WELL-BEING TO IMPROVE HEALTH OUTCOMES Psychosocial Issues (continued) 5.37 Providers should consider assessment for symptoms of diabetes distress, depression, anxiety, disordered eating, and cognitive capacities using appropriate standardized and validated tools at the initial visit, at periodic intervals, and when there is a change in disease, treatment, or life circumstance. Including caregivers and family members in this assessment is recommended. B 5.38 Consider screening older adults (aged ≥65 years) with diabetes for cognitive impairment and depression. B | 30 FACILITATING BEHAVIOR CHANGE AND WELL-BEING TO IMPROVE HEALTH OUTCOMES Diabetes Distress 5.39 Routinelymonitor people with diabetes for diabetes distress, particularly when treatment targets are not met and/or at the onset of diabetes complications. B Preventive Immunizations/ACCP2023 1. Annual influenza vaccine 2. Pneumococcal pneumonia vaccination (PPSV23) 3. Hepatitis B vaccine | 31 FACILITATING BEHAVIOR CHANGE AND WELL-BEING TO IMPROVE HEALTH OUTCOMES Referral to a Mental Health Provider Facilitating Behavior Change and Well-being to Improve Health Outcomes: Standards of Medical Care in Diabetes - 2021. Diabetes Care 2021;44(Suppl. 1):S53-S72 | 32 Weight loss Pharmacological Therapy 9  Diabetes Mellitus Type I Treatment - All patients with type 1 DM require insulin, but the type and manner of delivery differ based on patient preference, lifestyle behaviors, clinician preference and available resources. - Therapy should attempt to match carbohydrate intake with glucose- lowering processes (usually insulin) and physical activity. - The goal is to allow the patient to live as normal a life as possible. Isra-Summer 2018 10  Insulin Kinetics Type Drug Name Onset Peak Duration Route Glulisine S.C Aspart Rapid- Acting IV Lispro 5-15 1-2 hours 4-6 hours minutes Regular Short- Acting 0.5-1 hour 2-3 hours 4-6 hours I.M , IV, S.C NPH 1-2 hours 4-8 hours 10-20 hours S.C Intermediate - Acting Neutral protamine never Hagedorn IV Detemir 6-8 hours S.C 2-4 hours never 3-4h (0.2-0.4) 5.7-23.2 hrs IV Glargine Not significant Long – Acting 1-2 hours ~24 hours (Flat) Degludec Not significant 1-2 hours 24-42 hours (Flat) Technosphere insulin (Afrezza) Is a dry powder inhaled regular insulin. It is rapidly absorbed with maximum blood concentrations in 12 to 15 minutes. The most common adverse effects are cough and upper respiratory infections. It is contraindicated in patients with asthma and COPD due to bronchospasm risk. 11 Insulin – Pharmacotherapy Insulin Adverse Effect: - Hypoglycemia. - Weight gain. - Lipohypertrophy. - Antibodies development to injected insulin. Storage: - Unopened injectable insulin should be refrigerated prior to use. - Opened insulin has specific duration of use in room temperature as listed before. 12  Insulin – Pharmacotherapy ❖ Basal / Bolus Insulin Regimens ( mimic natural insulin) 1. Basalto prevent ketosis and control fasting BG Detemir / Glargine / Degludec / (NPH) 2. Bolus to control post-prandial glucose excursions Glulisine / Aspart / Lispro / Inhaled (Regular) ❖The way mimic the normal release of insulin from the pancreas, there are three methods: 1. “Split-mixed” insulin 2.Basal-bolus regimens using multiple daily injections (MDI) 3.Continuous subcutaneous insulin infusion (CSII) pump therapy - Amylinomimtics: Pramlintide Pramlintide is an analogue of amylin, a small peptide hormone that is released into the bloodstream by the β cells of the 13 pancreas along with insulin after a meal.Like insulin, amylin is completely absent in individuals with Type I diabetes  Insulin sensitivity factor 1. Always a need to correct for hyperglycemic excursions, despite optimal basal/bolus therapy 2. “1800 rule”: 1800/TDI = # mg/dL of glucose lowering per 1 unit of rapid-acting insulin. (a) For example, if TDI is 60 units, 1800/60 = 30, suggesting 1 unit of rapid-acting insulin will reduce BGconcentrations by 30 mg/dL. (b) Also called insulin sensitivity (c) Some advocate the “1500 rule” when using regular human insulin (i.e., 1500/TDI). 19  What are the sites for insulin injection? Patient should make rotation between the injection sites to avoid lipodystrophy. We will advice to inject in the abdomen in the morning and in other site in the evening. Why abdomen in the morning? - Absorption from this site is least affected by exercise and the most predictable. 20  Insulin side effect – Hypoglycemia Hypoglycemia, or low blood sugar, can be defined clinically as a blood glucose level of less than 50 mg/dL (2.78 mmol/L). Individuals with DM can experience symptoms of hypoglycemia at varying blood glucose levels. -Patients who have regular blood glucose levels as high as 300 to 400 mg/dL may experience symptoms of hypoglycemia BG= 100 mg/dL. -Most people whose blood glucose levels are controlled adequately may experience symptoms when levels fall below 70 mg/dL. Isra-Summer 2018 2  Treatment of hypoglycemia ❖ Treatment of hypoglycemia is as follows: ✓Glucose (10–15 g) given orally for conscious patients is preferred. ✓ Dextrose IV may be required for unconscious patients. ✓Glucagon, 1 g intramuscularly, is preferred in unconscious patients when IV access cannot be established If the blood glucose level 2 mg/dl  6 Insulin sensitizer – (4) Dipeptidyl peptidase IV inhibitors (DPP-4 Inhibitors) ❖Mechanism ofaction: Inhibit the breakdown of GLP-1 secreted during meals, which in turn increases pancreatic insulin secretion ❖Agents: Sitagliptin (Januvia) Saxagliptin, Linagliptin, Allogliptin and Vildagliptin Benefit Risk \ side effect 1. Focus on post-prandial glucose 1. Expensive 2. Once daily administration 2. Require renal dose adjustment 3. Weight neutral 18 31  7 Sodium – glucose co-transporter 2 inhibitors (SGLT-2) Inhibitors ❑Mechanism of action: -Inhibiting SGLT2 in the proximal nephron, thereby reducing glucose reabsorption and increasing urinary glucose excretion by up to 80 g/day. (used in D.M type I and II with any severity stage). ❑ Agents: Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin Benefit Risk \ side effect 1. Weight loss (1-5 kg) 1. Genital yeast infection 2. Modest BPreduction 2. Increasing UTIs 3. Reduction in serum uric acid and 3. Upper limb fractures albuminuria 4. Increase in LDL-C. 4. Fasting and post- prandial BGs 5. Are less effective at GFR< 45-60 ml/min/1.73m2 *Concomitant diuretic use may cause orthostatic hypotension and electrolyte 32 abnormalities; loop diuretics may need to be discontinued GLP-1 role  8 Glucagon-Like Peptide 1 Agonists (GLP-1) Noninsulin InjectableAgents ❑ Agents: lixisenatide, Exenatide, Liraglutide, Albiglutide and Dulaglutide Isra-Summer 2018 33 Tirzepatide is the only agent currently approved for treatment of T2D. GLP-1/glucose-dependent insulinotropic polypeptide agonist 1. Mechanism of action: Similar to GLP-1 agonists above - Dosing i. Initial: 2.5 mg subcutaneously once weekly ii. Increase at monthly intervals to 5, 10, or 15 mg once weekly d. Adverse effects: Similar to GLP-1 agonists e. Contraindications : Similar to GLP-1 agonists  Benefit Risk \ side effect 1. Moderate A1c reduction 1. Hypoglycemia 2. Weight loss (increased with sulfonylurea) 3. Variety of dosing strategies 2. Injection site discomfort (Twice daily to once daily ) *Post marketing reports of pancreatitis and acute renal failure. Precautions Contraindication 1. Existing gastroperesis 1. Patients with a personal 2. History of pancreatitis or family history of medullary thyroid carcinoma 3. Exenatide : Moderate renal 2. Exenatide : (CrCl < 30 impairment (CrCl < 50 ml\min) ml\min) Isra-Summer 2018 34 10 Dopamine Agonists - Bromocriptine - It reduced HbA1C by 0.3% to 0.6% in clinical trials. - The role of bromocriptine is unclear; it may be an alternative in combination with other agents. b. Colesevelam is the only studied and approved drug in this class. 36  General Approach -Patients with higher initial A1C values=10% require two agents or insulin. -Obese patients without contraindications are often started on metformin, titrated to 2000 mg/day. If the individualized A1C target is not reached after 3 months of dual-drug therapy, a third drug may be added. 37 Treatment of Complications  ‫وفاته‬ ‫عالء ولي الدين (‪ 28‬سبتمبر ‪ 11 - 1963‬فبراير ‪ ،)] 1[ 2003‬ممثل مصري‪.‬‬ ‫فارق الحياة عن عمر يناهز التاسعة والثالثون والذي وافق آنذاك أول أيام عيد‬ ‫األضحى من جراء مضاعفات السكري الذي كان يعاني منه‪.‬جدير بالذكر أن آخر‬ ‫عرض في السينما لعالء ولي الدين كان ابن عز لكن آخر فيلم قام بتصويره ولم‬ ‫يكتمل تصويره نتيجة لوفاته هو فيلم عربي تعريفه لحازم الحديدي‪.‬‬ ‫‪SOURCE: Wikipedia‬‬  Treatment of Complications (1)Retinopathy: - Is the leading cause of blindness among adults. - Dilated eye examination is required to fully evaluate diabetic eye disease. 1.early retinopathy : Maintain good glycemic control and optimizing blood pressure 2.Advanced retinopathy Treatment: bevacizumab, ranibizumab and laser photocoagulation. Isra-Summer 2018 40 (2) Neuropathy: a. Peripheral neuropathy -the most common complication in DM II patients. Present as: - Pain, tingling, numbness in the extremities. (feet more than hands). - Improvement of Glucose level may alleviate some of the symptoms. ❑Treatment option for painful neuropathy: - Pregabalin (first) -Duloxetine - Low dose tricyclic antidepressants - Gabapentin - Venlafaxine - Tramadol - NSAIDs - Topical capsaicin. 41 (2) Neuropathy: b. Autonomic neuropathy: 1. Gastroparesis (delayed gastric emptying): a. Improved with glycemic control b. Discontinuation of medications that slow gastric motility c. Use of metoclopramide for only few weeks at a time or d. low-dose erythromycin may be helpful. 2. Diabetic diarrhea is commonly nocturnal - Responds to a (10-14) day course of an antibiotic such as doxycycline or metronidazole. - Octreotide may be useful in unresponsive cases. 42 (3) Nephropathy: (Diabetic Kidney Disease) - DM may worsen renal function and progress to end- stage renal failure. - The presence of albumin in urine is an early evidence of kidney damage (microalbuminuria = 30 – 300 mcg). - Nephropathy progression can be prevented by ACE inhibitors or ARBs are considered the 1. glycemic control initial treatment of choice if urine albumin/creatinine concentrations 2. Blood pressure control. are greater than 30 mg/g. 3. ACE inhibitors and ARBs have shown efficacy in preventing the progression of renal disease in patients with diabetes. 4. Diuretics are frequently necessary due to volume- expanded states and are recommended second-line In 2016,the FDAsuggested that eGFRbe usedasa measure of kidney therapy. function rather than creatinine alone. (4) Peripheral Vascular Disease and Foot ulcer: - Foot ulcer is an open sore that develops and penetrates into subcutaneous tissues. - Peripheral vascular disease cause ischemia to the lower limbs, so blood, oxygen and nutrient not reached so the immune system not functioning properly. ❑ Treatment: focus on management of the ischemia 1. Smoking cessation 2. Correction of dyslipidemia 3. Good glycemic control 4. Antiplatelet therapy 5. Cilostazol (Pletal) may reduce symptoms in selected patients. 6. Revascularization is successful with some patients. 7. Local debridement and appropriate footwear and foot care are important in the early treatment of foot lesions. 8. Topical treatments and other measures may be beneficial in more advanced lesions.  (5) Diabetic Ketoacidosis When your cells don't get the glucose they need for energy, your body begins to burn fat for energy, which produces ketones. The body does this when it doesn’t have enough insulin to use glucose, the body’s normal source of energy. When ketones build up in the blood, they make it more acidic. 45  Diabetic Ketoacidosis ❖ Signs/symptoms: 1. Thirst 2. abdominal pain 3. fruity breath 4. tachycardia 4. low Na / high K 5. ketones in urine ❖ Most common causes either : 1. Infection/acute illness 2. Inappropriate/inadequate insulin therapy ❖ Treatment : NOT about normalizing blood glucose 1. Find and fix underlying cause (if known) 2. Fluid Replacement (IV Na% depends on serum Na) 3. Potassium supplementation: Depends on baseline K 4. IV insulin: (0.1Unit\kg\hu) (Hold if baseline serum K< 3.3 meq/L until corrected) 46 Obesity 47  Obesity Therapy Issues ◼ How long to treat for??? ◼ Minimal comparative between agents studies; lacking ◼ Long-term safety; unknown Off-label medications used but not well studied specifically for obesity: Selective serotonin reuptake inhibitors, zonisamide, metformin, pramlintide Zonisamide is a medication used to treat the symptoms of epilepsy and Parkinson's disease Obesity - Classification Isra-Summer 2018 48 https://www.thecalculatorsite.com/health/bmicalculator.php Obesity – Treatment Isra-Summer 2018 49  Obesity – Treatment ◼ Orlistat – Inhibits gastric and pancreatic lipases so reduced fat absorption ❑ Rx (Xenical): 120 mg three times daily (up to 1 hour prior to meals) ❑ OTC (Alli): 60 mg three times daily (up to 1 hour prior to meals) ❑ LOTS GI ADRs: flatulence, oily stool, loose stool ❑ FDA 2012: Increased risk for kidney stones/liver injury 50  Obesity – Treatment ◼ Lorcaserin (approved 2012) ❑ Selective serotonin 2C agonist (reduce hunger) ❑ ADRs: Headache, dizziness, nausea, dry mouth, constipation, memory disturbances, hypoglycemia (in diabetes) ❑ Avoid use if also taking serotonergic agents (e.g. SSRIs) ❑ Stop if < 5% weight loss after 12 weeks 51  Obesity – Treatment ◼ Phentermine/extended-release topiramate (approved 2012) ❑ ADRs: dry mouth, constipation, insomnia, memory disturbances, increased heart rate ❑ Efficacy: 60+% attain 5% wt loss, 35-45% 10% loss ❑ Women of childbearing age must have negative pregnancy test before and monthly after starting ❑ Stop if < 5% weight loss after 12 weeks of higher doses Mechanism of action: Phentermine promotes appetite suppression and decreased food intake secondary to its sympathomimetic activity. Mechanism of topiramate is unknown, but it may cause appetite suppression and satiety through increased γ- 52 aminobutyrate activity.  Obesity – Treatment ◼ Bupropion/Naltrexone (approved Fall 2014) ❑ Extended-release formulation ❑ Weekly dose titration over four weeks to improve tolerability / limit ADRs ❑ Reduce dose in moderate/severe renal impairment ❑ ADR profile: nausea, constipation, HA (headache), vomiting, insomnia, dry mouth, increased BP/pulse ❑ Contraindications: seizure DO, uncontrolled HTN, eating DO, chronic opioid use, concurrent use of other products containing naltrexone or bupropion ❑ Discontinue if not at least a 5% weight loss after 12 weeks Mechanism of action: Reuptake inhibitor of dopamine and norepinephrine (bupropion) and opioid antagonist (naltrexone)  Obesity – Treatment ◼ Liraglutide (approved late 2014) ❑ GLP-1 analog - Dosage is different than use in T2DM (3 mg once daily) ❑ Similar precautions / contraindications as with DM formulation ❑ Similar GI side effects nausea/vomiting (N/V) ❑ Initiate at 0.6 mg once daily (subcutaneous) and increase weekly in 0.6 mg increments ❑ Discontinue if < 4% weight loss after 16 weeks of therapy or can’t tolerate 54  8 Glucagon-Like Peptide 1 Agonists (GLP-1) Noninsulin InjectableAgents ❑ Agents: Exenatide, Liraglutide, Albiglutide and Dulaglutide Isra-Summer 2018 33