Endo/Repro Week 4 - Diabetes and Weight Concerns
Describe the indications, contraindications, route of administration, mechanism of action, peak level and duration, adverse effects, interactions and patient education for the following injectable preparations used to treat diabetes: premixed combinations (70%/30%, 50%/50%).
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explain the pathophysiology of neuropathy in diabetes
-Assess all type 2 diabetics for peripheral neuropathy at diagnosis and annually thereafter -->Ipswich touch test, monofilament pressure sensation, pinprick sensation, vibration perception, and ankle reflexes -Assess all diabetics with microvascular or neuropathic disease for cardiovascular autonomic neuropathy -->May manifest as resting tachycardia and orthostatic hypotension -Assess adults for symptoms of gastrointestinal neuropathy and genitourinary tract problems, including erectile dysfunction in men.
Explain the synthesis, stimuli and inhibitors of the major hormones (insulin, glucagon) involved in the regulation of plasma glucose.
-Carbohydrates are a major source of glucose -Glucose is the preferred energy source for the body → brain uses 120 glucose/day -Every cell in the body requires energy and the majority of that energy comes from glucose -The brain and the RBC need constant supplies of glucose Insulin -Pancreas produces insulin → beta cells -Decreases blood glucose by facilitating storage of glucose → released into the blood due to increased levels of glucose -->Regulates storage of glucose -->Decreases blood glucose levels -->Inhibits release of glucagon -Released throughout the day in pulsatile and rhythmic nature -Insulin release increases after a meal in response to increases in plasma levels of glucose and amino acids -Released throughout the day in pulsatile and rhythmic nature -Insulin release increases after a meal in response to increases in plasma levels of glucose and amino acids -During the absorptive state after a meal (2-4 hour time period after ingestion of a normal meal) insulin is secreted by the beta cells and glucagon is inhibited Glucagon -Pancreas produces glucagon → alpha cells -Increases blood glucose by facilitating release of glucose from storage → stimulated by hypoglycemia -->Regulates release of glucose -->Increases blood glucose levels -->Inhibits release of insulin -Target is the liver and its main physiologic effect is to increase plasma glucose to prevent or counterregulation hypoglycemia → it does this through gluconeogenesis and glycogen breakdown -In times of prolonged stress or food deprivation it activates lipase in the adipocyte which breaks down triglycerides -Antagonizes action of insulin -During the absorptive state after a meal (2-4 hour time period after ingestion of a normal meal) insulin is secreted by the beta cells and glucagon is inhibited
Explain how advanced glycation end products are implicated in diabetic erectile function.
-Excessive blood glucose levels leads to AGE production → leads to a decrease in NO production and an increase in NO synthase binding sites in penile tissue → vasoconstriction -->Testosterone also plays a role in NOS activity, so low testosterone levels (assc'd w/ DM2) contributes to lower NO levels as well
Describe criteria for diabetes diagnosis and diabetes control and interpret the following laboratory tests in the setting of screening and monitoring treatment: Fasting glucose, postprandial glucose, and hemoglobin A1C.
-Fasting glucose: dx of diabetes w/ FBG of ≥ 126 -Preprandial glucose -->ADA recommends plasma glucose range: 90-130 mg/dl -Postprandial glucose: dx of diabetes w/ 2-hr PG ≥ 200 -ADA recommendation for glycemic control: <180 mg/dl -Hemoglobin A1C -->Dx of diabetes w/ HbA1c ≥ 6.5 -->ADA recommendation for glycemic control is <7%
Describe the indications, contraindications, route of administration, mechanism of action, peak level and duration, adverse effects, interactions and patient education for the following injectable preparations used to treat diabetes: long acting (glargine, detemir).
-Insulin detemir (Levemir, Levemir FlexTouch) -Insulin glargine (Lantus, Lantus SoloStar, Basalgar KwikPen, Toujeo SoloStar) -->Toujeo is 300 units/mL --> + lixisenatide 33 mcg/mL (Soliqua 100/33) -Insulin degludec (Tresiba FlexTouch) -->Also available as 200 units/mL --> + liraglutide 3.6 mg/mL (Xultophy 100/3.6) -Peak level and duration -->Onset of action: 3-4 hours -->Peak: 3-9 hours -->Duration of action: 16-23 hours
Describe the indications, contraindications, route of administration, mechanism of action, peak level and duration, adverse effects, interactions and patient education for the following injectable preparations used to treat diabetes: intermediate acting (NPH).
-Intermediate insulin (Humulin N, Humulin N KwikPen, Novolin N, Novolin N ReliOn) -Available without a prescription -Cloudy solution -Can mix with rapid- and short-acting insulins; always draw up clear before cloudy -Peak level and duration -->Onset of action: 2 hours -->Peak: 4-12 hours -->Duration of action: 12-20 hours
Describe the natural history of type 2 diabetes in terms of insulin resistance, decreased insulin secretion, and changes in fasting and postprandial glucose levels.
-Point at where insulin secretion levels fall off that glucose levels begin to increase; insulin resistance does not change much but insulin secretion decreases
Describe the USPSTF screening recommendations for Type 2 Diabetes Mellitus.
-Screening patients before signs and symptoms develop leads to earlier diagnosis and treatment, but may not reduce rates of end-organ damage. -Randomized trials show that screening for type 2 diabetes does not reduce mortality after 10 years, although some data suggest mortality benefits after 23-30 years -USPSTF recommends screening for abnormal blood glucose and type 2 diabetes in adults 40-70 years of age who are overweight or obese, and repeating testing every three years if results are normal. Individuals at higher risk should be considered for earlier and more frequent screening. -USPSTF recommends screening pregnant women for GDM at 24 weeks gestation.
Explain the major actions of insulin and glucagon on the liver, muscle and adipocytes.
-The two primary sites of short-term storage of glucose are the liver and muscle where glucose can get stored as glycogen through "glycogenesis". -It is important to note that the muscle is a main consumer of energy and much of the glucose that goes to the muscle is immediately turned into energy through glycolysis before any is stored. -Adipose tissue is the "warehouse of energy storage". CHOs are transported to the adipose tissue and stored as triglycerides through lipogenesis as long-term storage. -In skeletal muscle, glucose may enter short-term storage through glycogenesis (the conversion of glucose to glycogen when the glucose in the blood exceeds the demand). The effect here, as with utilization of glucose by tissue cells is the lowering of blood sugar. -The great majority of glucose disposal in the body happens in the skeletal muscle. Muscle cells store 1-3% of their weight as glycogen. -After a meal, the liver receives nutrient rich blood (glucose, amino acids, fatty acids) and insulin. The liver consumes 60% of the glucose from the portal circulation. Entry of glucose into the liver is not affected by insulin as the glucose transport (GLUT-2) in the liver is not influenced by insulin. -In the liver, one of 3 things happen to the nutrients: -->Metabolizes them (glycolysis). -->Stores them (glycogenesis). Liver cells store 5-8% of their weight as glycogen. -->Routes them on to other tissues
Describe the role of nitric oxide in vascular complications of diabetes.
-When there is an excess of glucose in the blood, this causes oxidative stress → so, radical oxidative species are produced. This leads to decrease in nitric oxide (and prostacyclin synthase) production from the endothelium. -When the NO levels decrease, this causes decreased vasodilation, smaller lumen of the capillaries + endothelial thickening
Explain how advanced glycation end products are implicated in diabetic neuropathy
-With excess glucose in the blood in circulation, they combine with circulating proteins to create early glycation products that are produced quickly, within a couple of days.....over more time/over weeks these glucose/protein cross-linked structural proteins then develop into Advanced Glycation End Products (AGEs). -->AGEs cause cross-linking within the nerve fibers, which damages the nerve fiber -->AGE binds to and activates RAGE receptor (found in endothelium, fibroblasts, mesangial cells, and macrophages) ----AGE is then internalized, which increases endothelial permeability to inflammatory cells and increases coagulant activity
Identify the criteria for diagnosis of Type 2 Diabetes Mellitus.
Diagnosis can be made w/: -Fasting plasma glucose level of ≥126 mg per dL (7.0mmol/L) -A1C level of 6.5% or greater -Random plasma glucose level of ≥200 mg/dL (11.1mmol/L) -75-g two-hour oral glucose tolerance test w/ a plasma glucose level of ≥200 mg per dL -Results should be confirmed w/ repeat testing on a subsequent day; however, a single random plasma glucose of 200 mg per dL or greater with typical signs and symptoms of hyperglycemia likely indicates diabetes
Describe the mechanisms by which glucagon increases energy sources including glycogenolysis, gluconeogenesis and ketogenesis.
Glycogenolysis → the breaking down of glycogen -Formation of glucose from glycogen; reversible process Gluconeogenesis -Amino acids are bunched together then converted to glucose; reversible process Ketogenesis -Glucagon takes fatty acids and turn them into "ketone bodies"; irreversible process -This occurs when the body is in starvation mode → when the body is not receiving enough nutrients -Ketone bodies are energy used only by the heart and brain → most critically needed to help us survive
Describe the glucose storage mechanisms facilitated by insulin including glycolysis, glycogenesis and lipogenesis.
Glycolysis → occurs in beta cells on langerhans cells -Irreversible process -Converts glucose into ATP, which is the most basic unit of energy that we use in the body; ATP is energy that can be used anywhere in the body Glycogenesis -The formation of glycogen; reversible process -Glycogen → heavily branched polymer or molecule that has a whole bunch of glucose molecules stacked on top of it -->Energy to be stored in the short-term, in the liver or muscle tissue Lipogenesis -Production of lipids or fatty acids; irreversible process -Where glucose is stored as a lipid → taking the energy of glucose and storing it long term as adipose tissue
Describe the indications, contraindications, route of administration, mechanism of action, peak level and duration, adverse effects, interactions and patient education for the following injectable preparations used to treat diabetes: rapid onset (regular insulin).
Indications -Type 1 diabetes -Pregnancy -Type 2 diabetes -->A1C > 9% -->Glycemic goals not achieved -->Glucose toxicity -->Oral meds: Adverse effects/intolerance -->Prolonged stress (illness, surgery) -->Hyperosmolar Hyperglycemic State (HHS) MOA -Stimulates carbohydrate metabolism -Facilitates glucose transfer -Stimulates lipogenesis -Stimulates protein synthesis Peak level and duration -Onset of action: 5-30 minutes -Peak: 0.5-1.5 hours -Duration of action: < 5 hours
Describe the indications, contraindications, route of administration, mechanism of action, peak level and duration, adverse effects, interactions and patient education for the following injectable preparations used to treat diabetes: ultra short acting (lispro, aspart, glulisine, rapid onset (regular insulin).
Injectable! -Regular insulin (HumuLIN R, NovoLIN R) -Available without a prescription -Can be used IV -Peak level and duration -->Onset of action: 30 minutes -->Peak: 2.5-5 hours -->Duration of action: 4-12 hours
Describe the indications, contraindications, route of administration, mechanism of action, peak level and duration, adverse effects, interactions and patient education for the following injectable preparations used to treat diabetes: GLP-1 receptor agonists (incretins) - liraglutide.
Injectable! Contraindications -Boxed warning: thyroid C-cell tumors -Pancreatitis -Not recommended for patients with severe gastrointestinal disease (e.g., gastroparesis) -Insufficient data available in human pregnancy or breast-feeding -Retinopathy (injectable semaglutide) Adverse effects -Increased risk of hypoglycemia when combined with SFU or insulin -Nausea -Diarrhea -Injection site reaction -Decreased appetite -Vomiting -Constipation Interactions -Use with caution in patients receiving oral medications that require rapid gastrointestinal absorption -Oral contraceptives, antibiotics, and other medications that are dependent on threshold concentrations for efficacy should be taken at least 1 hour before exenatide injection -Warfarin absorption may be delayed; post-marketing reports of increased INR and bleeding - monitor more closely Patient education -Store unopened pens in refrigerator -Prime pen only once before first dose (subsequent priming not necessary and may waste doses) -Inject in upper thigh, abdomen, or upper arm -Count to 5 while pushing and holding injection button during injection -Use a new needle with each use, remove needle between use -Pens should only be used for 30 days -Not a substitute for insulin
Describe the pathophysiology of type 2 diabetes in terms of insulin resistance and insulin deficiency.
Insulin Resistance → prediabetic state -At level of skeletal muscle first - insulin does not have the same effect, less glucose uptake → more insulin produced -As long as insulin can be produced this is prediabetes Insulin Deficiency --> T2D -Beta cells begin to stop making insulin which leads to DMII -Still not sure about physiology of why the beta cells become defective/don't produce enough insulin
Explain the process of insulin signal transduction in the liver, muscle, adipocytes and brain.
Lipogenesis -Storing glucose in long-term storage in adipose tissue -More efficient manner of storage; irreversible -Glycogenolysis (reversible) is the breaking down of glycogen in primarily the liver to form glucose. After fasting overnight, glycogenolysis provides 50% of the overall hepatic glucose output. -Gluconeogenesis (reversible) is the formation of new glucose molecules in the body. -->It occurs after prolonged fasting (>18 hours). -->The main difference between glycogenolysis and gluconeogenesis is that glycogenolysis involves the formation of glucose molecules from a glucose source (glycogen), while gluconeogenesis forms glucose from non-glucose sources, molecules that are not made up of glucose (amino acids, lactate, pyruvate, and glycerol). -->Gluconeogenesis occurs primarily in the liver. ----Muscle tissue breaks proteins down into amino acids and these go to the liver to form glucose. -Ketogenesis (irreversible) is the conversion of fatty acids into ketone bodies in the liver. This happens in starvation mode. Ketone bodies are forms of energy used only by the heart and brain.
Describe the indications, contraindications, mechanism of action, peak level and duration, adverse effects, interactions and patient education for the following oral drugs used to treat diabetes: bile acid sequestrants (colesevelam).
MOA: bile acid sequestrant -Role in cholesterol treatment - binds bile acids → ↑ oxidation of cholesterol to bile acid → ↓ serum cholesterol -The mechanism by which colesevelam improves glycemic control is not fully known -Colesevelam has been mostly studied in combination with metformin, sulfonylureas, and insulin Administration: orally, once or twice daily Pharmacokinetics: not absorbed or metabolized; minimal renal elimination Adverse effects: Constipation, dyspepsia, nausea, dysphagia, decreased absorption of fat-soluble vitamins Contraindications -History of bowel obstruction or GI motility disorders -Triglycerides > 500 mg/dL -History of hypertriglyceridemia-induced pancreatitis Drug interactions -↓ levels of glyburide, levothyroxine (↑ TSH in patients receiving thyroid hormone replacement), and combined oral contraceptives that contain ethinyl estradiol -Post-marketing reports of: --> ↓ phenytoin levels --> ↓ INR in patients receiving warfarin -Administer drugs with a known or potential interaction with colesevelam (or drugs with a narrow therapeutic index) at least 4 hours prior to colesevelam
Describe the indications, contraindications, mechanism of action, peak level and duration, adverse effects, interactions and patient education for the following oral drugs used to treat diabetes: oral GLP-1 receptor agonists (oral semaglutide).
MOA: decrease insulin-dependent glucose secretion & inappropriate glucagon secretion, slows gastric emptying Administration considerations -Take 30 minutes before any food, beverage or other oral meds -Take with a "sip" (< 4 oz.) of plain water only -Swallow tabs whole: do not split, crush, or chew Adverse effects -Increased risk of hypoglycemia when combined with SFU or insulin -Nausea -Abdominal pain -Diarrhea -Decreased appetite -Vomiting -Constipation Precautions -Boxed warning: thyroid c-cell tumors -Pancreatitis -Not recommended for patients with severe gastrointestinal disease (e.g., gastroparesis) -Use in pregnancy may cause harm; insufficient data available in breast-feeding -->Stop Rybelsus® 2 months before a planned pregnancy Drug interactions -SFU or insulin: increased risk of hypoglycemia when combined -Levothyroxine: exposure increased 33% when co-administered -May impact absorption of other oral medications
Describe the indications, contraindications, mechanism of action, peak level and duration, adverse effects, interactions and patient education for the following oral drugs used to treat diabetes: thiazolidinediones (pioglitazone, rosiglitazone).
MOA: increase insulin sensitivity at muscle at liver; decrease free fatty acids Advantages -A1C decrease 1-1.5% -No hypoglycemia -Lipid effects Disadvantages -Liver function monitoring -Cardiac effects (induce CHF) -Weight gain and edema Dosing: -Pioglitazone (Actos®): 15-30 mg QD (Max: 45 mg QD) -Rosiglitazone (Avandia®): 2-4 mg QD (Max: 4 mg BID) -->** Full effect in 8-12 weeks! Precautions -Pre-existing liver disease: periodic liver function monitoring -New York Heart Association Class III or IV heart failure (contraindicated) -Fluid retention (NSAIDs, COX-2 inhibitors) -Increased fertility -Fractures -CVD risk Adverse effects -Heart failure (edema) -Weight gain (edema & metabolic weight gain) -Anovulatory women with insulin resistance may become pregnant
Describe the indications, contraindications, mechanism of action, peak level and duration, adverse effects, interactions and patient education for the following oral drugs used to treat diabetes: DPP-4 inhibitors (sitagliptin).
MOA: increase natural half-life of GLP-1, thereby causing increased release of insulin from beta cells and decrease hepatic glucose production Not for type 1 or children Adverse effects -Upper respiratory tract infection -Nasopharyngitis -Headache
Describe the indications, contraindications, mechanism of action, peak level and duration, adverse effects, interactions and patient education for the following oral drugs used to treat diabetes: SLGT2 inhibitors (empagliflozin).
MOA: inhibit SGLT2 which decreases reabsorption of filtered glucose and thereby increases urinary glucose excretion -Blocks SGLT2 co-transporter reducing renal glucose reabsorption and thus increasing urinary glucose excretion (80-100g/day) Pros: effective, no hypoglycemia, weight loss, ↓BP, ↓CVD/death? Cons: expensive, genital mycotic and UTIs, ↑LDL, not effective w/ ↓GFR, DKA?, fractures?, amputations? Adverse effects -UTIs -Genital mycotic infections (i.e. vaginal yeast infection) -Nausea -Increased frequency of urination -Increased thirst Precautions -UTI/genital mycotic infections -Hypotension -Osmotic diuretic -Euglycemic diabetic ketoacidosis (DKA) -Necrotizing fasciitis -Fournier's gangrene -Acute kidney injury -Bone fractures (possibly) Drug interactions -Diuretics: increase urine volume, voiding frequency, volume depletion -Hypoglycemia when combined with SFU or insulin
Describe the indications, contraindications, mechanism of action, peak level and duration, adverse effects, interactions and patient education for the following oral drugs used to treat diabetes: biguanides (metformin).
MOA: reduces hepatic glucose production & improves peripheral insulin sensitivity at muscle Advantage: weight benefit, hypoglycemia rare, decrease A1c by 1.0-2.0%, positive effects on lipids Disadvantage: GI SEs, many contraindications, BBW (lactic acidosis) -Monotherapy or combination therapy with SFU or insulin -->Increasing use in combination with GLP-1 RAs and SGLT2i Pre-diabetes -Starting dose: 500 mg daily or BID or 850 mg daily with meals -Increase by 500 mg to 850 mg 1-2 weeks -Use lower doses in older patients -Optimal effective daily dose = 2000 mg/day Contraindications -Renal Disease: eGFR < 30 ml/min/1.73 m2 -Cardiac or respiratory insufficiency likely to cause central hypoxia or reduced peripheral perfusion -Heart failure (caution) -History of lactic acidosis -Acute illness, major surgery, or severe infection -Liver disease, including EtOH with abnormal LFTs -Alcohol abuse with binge drinking -Use of IV contrast agents (discontinue day of medical procedure and restart in 48 hours) -May result in ovulation and increase risk of pregnancy
Describe the mechanism of action of the following classes of non-insulin antidiabetic drugs: Meglitinides, DPP-4 Inhibitors, Incretin (GLP-1) Mimetics.
Meglitinides (is a form of secretagogue?) -Ex: Repaglinide, Nateglinide -MOA: enhanced insulin secretion -Rapid acting insulin secretagogues -Taken w/ meals -Pros: good for postprandial hyperglycemia and in renal insufficiency -Cons: hypoglycemia, more expensive Incretin Based Therapies -See picture DPP-4 Inhibitors -Prevents Native GLP-1 Breakdown -Prolongs Duration of Native GLP-1 Action -Ex: Sitagliptin, Saxagliptin, Linagliptin, Alogliptin -MOA: Prevents GLP-1 inactivation, prolonging duration of action of 'native' GLP-1, leading to enhanced glucose-dependent insulin secretion -Pros: effective, no hypoglycemia, no weight gain, OK in CKD, best for postprandial hyperglycemia Incretin (GLP-1) Mimetics / GLP-1 Receptor Analogs/Agonists -Resistant to DPP4 Action -GLP-1 Analog ex: Exenatide, Liraglutide, Gulaglutide, Lixisenatide, Semaglutide -MOA: increased GLP-1 'like' activity results in: -->Glucose dependent insulin secretion -->Glucagon suppression -->Reduced gastric emptying -->Reduced energy intake -Pros: effective, no hypoglycemia, weight loss, best for postprandial hyperglycemia, decreases CVD/death? -Cons: expensive, injections, nausea, pancreatic disease?
Describe the pathophysiology of type 2 diabetes in terms of abnormalities in b-cell function, hepatic glucose production, intestinal glucose absorption, and adipocyte metabolism.
Pathogenesis of Type 2 Diabetes -Take a nml individual w/genetic predisposition → increase in weight but also need insulin resistance which leads to decreased insulin secretion → T2D Core defects -Islet-cell dysfunction -Increase hepatic glucose output -Insulin resistance -Decreased release of incretins -Decrease glycosuria → decreased ability to excrete glucose
Describe how concentrations of insulin and glucagon change following a meal and during periods of fasting.
Role of incretins -Two incretins: -->GIP (glucose-dependent insulinotropic peptide) -->GLP-1 (glucagon-like peptide-1) -Both are deactivated by an enzyme - DPP-4 -Incretins are gut hormones secreted form the enteroendocrine cells that are located in the epithelium of the small intestine -Incretins are secreted within minutes after eating and their trigger is the release of glucose in the lumen of the small intestine. They travel to the pancreas where they stimulate the release of insulin from the beta cells (insulinotropic) and inhibit glucagon release from the alpha cells -There is a more rapid incretin response to meal ingestion in the AM than in the afternoon Absorptive state -Some of the glucose is taken up by cells in the body that need energy. Glucose is first converted into energy through glycolysis in the brain and RBCs. These cells do not need insulin to use glucose. Most of the other cells that need energy at the time will require insulin to act as a key for the entry of glucose into the system. -Also occurring while eating occurs is the secretion of incretins in the gut. They travel to the beta cells of the pancreas to initiate insulin release. -Once the blood glucose is absorbed through the intestine wall and glucose in the circulation increases, the beta cells of the pancreas sense the glucose and they increase their secretion of insulin into the blood. -Glucose and insulin then travel together through the bloodstream to more distant parts of the body. -->Insulin promotes energy storage. Therefore, when energy is plentiful, the extra glucose is stored. Post-absorptive state - "catabolic state" -Glucagon stimulates the body to release energy. The body uses several processes to create energy and release it into the bloodstream. -Glycogen, protein and triglycerides are degraded. The liver, adipose tissue, muscle and brain then share these substrates. -The goals during times of fasting are the following: -->Maintain adequate plasma levels of glucose to secure energy metabolism to brain, RBC and other tissues utilizing glucose as a sole fuel -->Mobilize fatty acids from adipose tissue so that ketone bodies can be synthesized and released by the liver to supply energy to other tissues. Ketone bodies are water soluble and appear in the blood and urine by the 2nd day of a fast. They can be used by most tissues including the brain as fuel.
Compare the following classes of non-insulin antidiabetic drugs in terms of mechanism of action and appropriate use, including approaches to combination therapy: sulfonylureas, biguanides, thiazolidinediones.
Sulfonylureas (is a form of secretagogue) -Ex: Glyburide, Glipizide, Glimepiride -MOA: enhanced insulin secretion, stimulate B cells (block K+ from leaving) -Pros: they work, inexpensive -Cons: hypoglycemia, weight gain, hyperinsulinemia?, enhanced β-cell destruction? Biguanides (Metformin)* 1st line -MOA: reduces hepatic glucose production -->Some direct effect on insulin sensitivity? -Pros: effective, relatively inexpensive, no weight gain, no hypoglycemia -Cons: GI side effects (bloating, diarrhea), Lactic Acidosis -Contraindications: -->CRI (chronic renal insufficiency): CR > 1.5 or GFR <30-45 -->Significant cardiopulmonary or liver disease, hypotension, binge drinking -Dosing: start low and go slow for better tolerability! -->Discontinue for hospitalizations or procedures Thiazolidinediones (TZDs) -Ex: Pioglitazone and Rosiglitazone -MOA: 'insulin sensitizer' -Pros: effective, no hypoglycemia, CVD/endothelial benefits?, reduced mortality?, fatty liver benefits -Cons: weight gain, edema, CHF, fractures, bladder cancer? -Remember: little clinical effect for ~6 week
Describe the indications, contraindications, mechanism of action, peak level and duration, adverse effects, interactions and patient education for the following oral drugs used to treat diabetes: sulfonylureas second generation (glyburide, glipizide, glimepiride).
Sulfonylureas second generation (glyburide, glipizide, glimepiride) MOA: increase the release of insulin from pancreatic beta cells Advantages: lowers A1c by 1-2%, generally well tolerated, inexpensive, proven microvascular outcomes Disadvantages: risk of hypoglycemia, weight gain, rash/pruritus (photosensitivity; possible cross sensitivity in sulfa allergic patients) -Increase dose if goal not achieved in 4-6 weeks -Do not need to max dose to get best effect Contraindications in: -Pregnancy/Breast feeding (except glyburide) -Children -Type 1 DM -Elderly, debilitated, malnourished patients (risk of fall) -Presence of adrenal or pituitary insufficiency -Severe allergic reaction to sulfa -Severe hepatic or renal insufficiency Adverse effects -Hypoglycemia prolonged, potentially lethal -Weight gain -Hypersensitivity reactions -Antabuse reaction (chlorpropamide) -Hyponatremia (chlorpropamide) Drug interactions -Fluroquinolones (hypoglycemia/hyperglycemia) -Gemfibrozil (hypoglycemia) -Highly protein bound drugs (e.g., Sulfonamide, Clarithromycin) -Allopurinol, probenecid (decrease urinary excretion of SU, therefore increase SU action)
describe the pathophysiology of retinopathy in diabetes
Why we asses -It is the leading cause of new blindness in ages 25-74 years old at 12% of all blindness in the US -Nearly 28% of people older than 40 years old with type 2 diabetes have diabetic retinopathy How to assess and monitor -Dilated and comprehensive eye exam by ophthalmologist or optometrist at the time of diagnosis -If no evidence of retinopathy on annual eye exam, then exams every 1-2 years may be considered -->Retinal photography may serve as a screening tool, but is not a substitute for a comprehensive eye exam -->If any level of diabetic retinopathy is present, subsequent dilated retinal exams should be done annually -->Any evidence of retinopathy should be followed by ophthalmology Slowing the progression -Tight glycemic and blood pressure control
Explain how advanced glycation end products are implicated in diabetic nephropathy
Why we assess -Diabetic nephropathy is the leading cause of chronic kidney disease in the United States. -It is also one of the most significant long-term complications in terms of morbidity and mortality for individual patients with diabetes. -Diabetes is responsible for 30-40% of all end-stage renal disease (ESRD) in the United States. How to assess and monitor -Declining renal function may be the first indicator of kidney damage (even prior to albuminuria) --> <90 for GFR may indicate a problem -Assess urine albumin excretion in people with type 2 diabetes starting at diagnosis and repeating annually -->Use albumin-to-creatinine ratio in a random spot-urine collection to assess urine albumin excretion. Results are reported as albumin in mg/g creatinine and are roughly equivalent to albumin excretion in mg/day. Confirm abnormal results on repeat testing. -Measure serum creatinine in all diabetics once a year (regardless of the degree of urine albumin excretion) so you can estimate GFR. Slowing the progression -ACE inhibitor/ARB lower systemic hypertension by decreasing AngII → decreased afferent arteriole tone, which increases blood to glomeruli increases GFR Pathophysiology -Excessive blood glucose leads to advanced glycation end products (AGEs), which cause cross-linking of collagen in endothelial and mesangial cells -->This leads to basement membrane thickening → increased protein loss from blood into urine -->Mesangial expansion → loss of podocyte feed and widening of slits → increased protein losses from blood to urine
