Diabetes Mellitus Supplemental Notes PDF

## DIABETES MELLITUS ### What is Diabetes Mellitus? - Group of metabolic disorders that share the phenotype of hyperglycemia - Syndrome characterized by: - Hyperglycemia - Insulin Resistance - Relative Impairment in insulin secretion - **NICE TO KNOW:** - Scandinavia (Finland) and...

## DIABETES MELLITUS ### What is Diabetes Mellitus? - Group of metabolic disorders that share the phenotype of hyperglycemia - Syndrome characterized by: - Hyperglycemia - Insulin Resistance - Relative Impairment in insulin secretion - **NICE TO KNOW:** - Scandinavia (Finland) and Sardinia: Highest incidence of Type 1 DM - Pacific Islands and Middle East: Highest prevalence of Type 2DM ### CLINICAL MANIFESTATION - Symptoms of hyperglycemia: polyuria, polydipsia, weight loss, fatigue, weakness, blurry vision, frequent superficial infections and slow healing of skin lesions after minor trauma. - Type 1 diabetes follows the same diagnostic criteria as T2DM but the presence of auto-antibodies is present in T1DM ### PATHOPHYSIOLOGY - A diagram showing the pathophysiology of type 2 diabetes. It shows the involvement of various organs like pancreas, liver, muscle, gut, and adipocytes. Also mentions the medications in the treatment of the disease, such as sulphonylureas (SU), thiazolidinediones (TZD), meglitinides, DPP-4 inhibitors, GLP-1 receptor agonists, alpha glucosidase inhibitors, and metformin. ### RISK FACTORS FOR DIABETES - Family history of diabetes - Obesity (BMI ≥ 25 kg/m²) - Physical inactivity - Race (Asian, Asian American, African American, Pacific Islander) - Previously identified prediabetes state - History of GDM or delivery of baby >4kg - Hypertension (BP ≥140/190) - HDL <35 mg/dL &/or triglycerides >250 mg/dL - Polycystic ovary syndrome or acanthosis nigricans - History of cardiovascular disease ### Laboratory Diagnosis - The diagnosis is made on the basis of the confirmed test. - Screening tests: - Fasting plasma glucose (preferred) - 75g 2-hour oral glucose tolerance test - HbA1c - Unless there is a clear clinical diagnosis (DM emergency, presence of unequivocal hyperglycemia), a second test is required for confirmation ### CLINICAL PEARLS - ADA 2022 recommends screening all individuals >35 years every 3 years - Screening should be earlier if overweight (BMI>25) + one additional risk factors for DM - Most common pattern of dyslipidemia is hypertriglyceridemia and reduced high-density lipoprotein (HDL) - Abnormal screening test should be repeated without delay before making definitive diagnosis. - If there are two discordant test results, repeat the test that is abnormal ### ANY OF THE FOLLOWING: | Test | Result | |------------------------------|------------------------------------| | HbA1ca | ≥6.5% | | Fasting Plasma Glucose (FPG)b | ≥126mg/dL (7.0 mmol/L) | | 2-hour plasma glucose during 75-g OGTT | ≥200mg/dL (11.1 mmol/L) | | Random Blood Sugarc | ≥200mg/dL (11.1 mmol/L) with classic symptoms of hyperglycemia | - a Perform HbA1C with an assay-standardized method - b Fasting: defined as no caloric intake for at least 8 hours - c Random: defined as without regard to time since last meal **For FPG, 2-gour PG, or A1C criteria: in the absence of unequivocal hyperglycemia, these criteria should be confirmed by repeat testing on a different day.** ### GUIDELINES FOR ONGOING, COMPREHENSIVE MEDICAL CARE FOR PATIENTS WITH DIABETES - Individualized glycemic goal and therapeutic plan - Self-monitoring of blood glucose (individualized frequency) - HbA1c testing (2-4 times/year) - Lifestyle management in the care of diabetes, including: - Diabetes self-management education and support - Nutrition therapy - Physical activity - Psychosocial care, including evaluation for depression, anxiety - Detection, prevention, or management of diabetes-related complications, including: - Diabetes-related eye examination (annual or biannual) - Diabetes-related foot examination (1-2 times/year by provider; daily by patient) - Diabetes-related neuropathy examination (annual) - Diabetes-related kidney disease testing (annual) - Manage or treat diabetes-relevant conditions, including: - Blood pressure (assess quarterly) - Lipids (annual) - Consider antiplatelet therapy - Influenza / pneumococcal / hepatitis B immunizations ### MNEMONIC - 4 limbs - HbA1c and BP assessed 4x times a year - aNNuaL - Neuropathy, Nephropathy, Lipids - 2 eyes and 2 feet - Biannual eye and foot exam ### Other work up/examination (to check for end organ damage) - CBC - for patients with anemia, HbA1c is not reliable - Blood Chemistry important to note renal function (kidney disease is a known complication; also, to adjust doses of anti-dm medications) - Urinalysis - to check for presence of microalbuminuria / proteinuria, glucosuria - Lipid Profile - usual pattern normal of slightly elevated LDL, elevated total cholesterol and triglyceride and low HDL - 12L ECG - to check for ischemic changes - 2D Echocardiogram - determine the baseline function of the heart - Eye Exam - check for retinopathy and cataract formation - Foot Exam check for areas of decrease sensation and non-healing wound ### Treatment - Medical nutrition therapy, exercise and weight loss. - Metformin monotherapy should be started at diagnosis of type 2 diabetes unless there are contraindications, such as: - Renal insufficiency (GFR <30 ml/min); decrease dose at (GFR < 45) - Any form of acidosis - Unstable CHF - Liver disease - Severe hypoxemia - Consider dual combination therapy when A1c ≥9%. - Consider combination injectable therapy when A1c is ≥ 10%, RBS ≥300 mg/dL or with symptoms of catabolism - A table showing the combination therapy strategy for patients with type 2 diabetes. It shows the progression from initial treatment, combination therapy, to reassessing HbA1c. ### GLYCEMIC MANAGEMENT OF TYPE 2 DIABETES - Diet, exercise, and weight loss are the best initial therapy for type 2 diabetes. - Metformin is the preferred initial pharmacologic agent for T2DM - Metformin blocks gluconeogenesis. ### In choosing your second line therapy - With established ASCVD or CKD - GLP-1RA (Liraglutide) with proven CV benefit; either/or - SGL2Ti (Empagliflozin) with proven CVD benefit - With NO established ASCVD or CKD - Compelling need to minimize hypoglycemia - DPP-4i (sitagliptin, linagliptin) - GLP-1RA (Liraglutide) - SGLT2i (Canagliflozin, Empagliflozin) - TZD (Pioglitazone) - Minimize weight gain or promote weight loss - GLP-1RA - SGLT2i - COST is a major issue - SU (Gliclazide) - TZD ### TREATMENT GOALS FOR ADULTS WITH DIABETES - **Glycemic Control:** - HbA1c <7.0% - Pre-prandial capillary plasma glucose 4.4-7.2 mmol/L (80-130 mg/dL) - Post-prandial capillary plasma glucose <10.0 mmol/L (<180 mg/dL) - **Blood pressure:** <140/90 mmHge - **HbA1c target:** <7.5 or 8% for patients with impaired awareness of hypoglycemia - **HbA1c target:** 8.0 or 8.5% for elderly individuals with multiple, chronic illnesses and impaired activities of daily living - **Every 2-3 months you monitor patients. You examine the foot in every visit. Eye exam annually. Things that you must request every ff up visit are the following: HbA1c, BP diary, LDL, Triglycerides** ### DM Meds Effect on Weight Gain and Hypoglycemia | CLASS | Hypoglycemia | Weight Change | |-----------|---------------|---------------| | Metformin | No | Modest Loss | | SGLT-21 | No | Loss | | GLP-1 RAS | No | Loss | | DPP4i | No | Neutral | | TZD | No | Gain | | SU | Yes | Gain | | Insulin | Yes | Gain | ### CLINICAL PEARLS ANTIDIABETIC AGENTS - Promotes weight gain - Sulfonylureas - TZD - Insulin - Promotes weight loss - Metformin - SGLT2 inhibitor - GLP1 receptor agonist - Weight neutral - DPP-4 inhibitor - Incretins increase insulin release and decrease glucagon secretion. - Glucagon-like peptide (GLP) is a confusing misnomer: Glucagon raises glucose and FFA levels. GLP decreases glucagon. ### INSULIN | PREPARATION | ONSET OF ACTION | PEAK | DURATION | |---------------------------|-----------------|---------|----------| | Rapid-acting Insulin | <15 mins | 30-90 mins | 2-4 hours | | **Lispro** | | | | | **Aspart** | | | | | **Glulisine** | | | | | Short-Acting Insulin | 30-60 mins | 2-3 hours | 3-6 hours | | **Human Regular** | | | | | Intermediate-acting Insulin | 2-4 hours | 4-10 hours | 10-16 hours | | **Isophane / Human NPH** | | | | | Basal Insulin Analogs | 2-4 hours | Minimal | Up to 24 hours | | **Glargine** | | | | | **Detemir** | 1-4 hours | | | | **Degludec** | 30-90 mins | | 72 hours | ### Metformin - Is considered for prevention of T2DM in prediabetics, especially if BMI>35, Age<60, prior GDM, rising HbA1c 5.7-6.0% and FBS 100-100 mg/dL - Other agents in delaying progression: alpha glucosidase inhibitors, thiazolidinediones - Metformin should be discontinued in those receiving radiographic contrast material. ### CLASS | EXAMPLE | MOA | SIDE EFFECTS | |-----------------------------------------------|---------------------------------------------|----------------------------------------------------------|------------------------------------------------| | Sulfonylureas (SU) | Gliclazide, Glibenclamide, Glimepiride, Glipizide, Repaglinide, Nateglinide | Insulin secretagogues: increases insulin secretion | Hypoglycemia, Weight gain, GI upset, Lactic acidosis | | Non-Sulfonylureas | | | | | Biguanides | Metformin | Insulin sensitizers | Weight loss, GI upset, Lactic acidosis | | Thiazolidinediones | Pioglitazone | | Edema, weight gain, CHF, anemia, fractures, bladder cancer | | Alpha-glucosidase inhibitors | Acarbose, Miglitol, Vogilbose | Inhibits intestinal absorption of sugars | Weight loss, diarrhea, flatulence | | DPP-IV Inhibitors | Sitagliptin, Saxagliptin, Linagliptin, Vildagliptin, Tenegliptin, Gemigliptin | | Headache, nasopharyngitis, hypersensitivity | | GLP-1 agonists | Exenatide SC, Liraglutide SC, Dulaglutide SC (once weekly), Semaglutide SC (once weekly), Exenatide-extended release SC (once weekly) | Incretin-related drugs: prolongs endogenous action of GLP-1 | Skin irritation after injection, Gl symptoms, C-cell hyperplasia in rats | | Na-Glucose Transporter-2-inhibitors (SGLT2i) | Dapagliflozin, Canagliflozin, Empagliflozin, Ertugliflozin | Increases urinary glucose excretion | Urinary tract infection, dehydration, risk of fractures (canagliflozin), bladder cancer (dapagliflozin), diabetic ketoacidosis | ### PHARMACOLOGIC TREATMENT OF HYPERGLYCEMIA IN ADULTS WITH TYPE 2 DIABETES - A flowchart showing the treatment approach for patients with type 2 diabetes. - **First-line Therapy:** depends on comorbidities, patient-centered treatment factors, including cost and access considerations, and management needs, and generally includes metformin and comprehensive lifestyle modification. - **ASCVD/INDICATORS OF HIGH RISK, HF, CKD:** - **NONE:** - Incorporate agents that provide adequate EFFICACY to achieve and maintain glycemic goals. - Higher glycemic efficacy therapy: GLP-1 RA; insulin; combination approaches. - Consider additional comorbidities, patient-centered treatment factors, and management needs in choice of therapy. - **+ ASCVD/INDICATORS OF HIGH RISK, +HF:** PREFERABLY use SGLT2i with primary evidence of reducing CKD progression, or SGLT2i with evidence of reducing CKD progression in CVOTS, or GLP-1 RA with proven CVD benefit if SGLT2i not tolerated or contraindicated. - **+CKD:** - For patients with CKD without albuminuria (e.g., eGFR <60 mL/min/1.73 m²), recommend the following to decrease cardiovascular risk: - **MINIMIZE HYPOGLYCEMIA:** No/low inherent risk of hypoglycemia: DPP-4i, GLP-1 RA, SGLT2i, TZD. For SU or basal insulin, consider agents with lower risk of hypoglycemia. - **MINIMIZE WEIGHT GAIN/ PROMOTE WEIGHT LOSS:** PREFERABLY use GLP-1 RA with good efficacy for weight loss, or SGLT2i. - **CONSIDER COST AND ACCESS:** Available in generic form at lower cost: Certain insulins. Consider insulin available at the lowest acquisition cost. - For patients with CKD and albuminuria (e.g., 200 mg/g creatinine), PREFERABLY use SGLT2i with primary evidence of reducing CKD progression. ### Adverse effect of OHA/Insulin: Hypoglycemia - Whipple's triad: symptoms of hypoglycemia, low plasma glucose concentration, relief of symptoms after plasma glucose level is raised. - The most serious complication of therapy for DM is hypoglycemia ### Chronic complications of diabetes - **Macrovascular:** - Coronary heart disease - Peripheral arterial disease - Cerebrovascular disease - **Microvascular:** - Nephropathy (albuminuria, ↓renal function) - Retinopathy and macular edema - Neuropathy - **Others** - Cataracts - Cardiac autonomic neuropathy - Sexual dysfunction (erectile dysfunction) - Gastroparesis - Wound infections ### Anticipatory Care - **Blood Pressure:** - Individualized Targets - Achieve SBP <130 but NOT <120 - Older People (>65): 130-139 - DBP <80 but not <70 - **Lipid Targets:** - Moderate CV risk: <100 - High CV Risk: <70 - Very High CV Risk: <55 ### SUPPLEMENT: BASIC SCIENCES CORRELATES - Sorbitol accumulation → swelling of the lens → cataract formation. - ACE inhibitors dilate the efferent arteriole and ↓intraglomerular hypertension. (ACE and ARB are proven to decrease rate of progression of nephropathy) ### CLINICAL PEARLS - Non-proliferative retinopathy is found in many individuals who have had DM for >20 years. - The most effective therapy for diabetic retinopathy is prevention. - Diabetic nephropathy is the leading cause of chronic kidney disease (CKD), ESRD, and CKD requiring renal replacement therapy. - The most common form of diabetic neuropathy is distal symmetric polyneuropathy. - Erectile dysfunction and retrograde ejaculation may be one of the earliest signs of diabetic neuropathy. - The most common pattern of dyslipidemia is hypertriglyceridemia and reduced high-density lipoprotein (HDL) cholesterol levels. - The common skin manifestations of DM are xerosis and pruritus. - **A graph showing the blood glucose level trend of dawn phenomenon and Somogyi effect; a graph showing plasma insulin level with respect to hours corresponding to different types of insulin doses. - A diagram comparing dawn phenomenon and Somogyi effect.**