Oral Agents for Diabetes Chapter 41 PDF

Oral Agents for Diabetes Chapter 41 Presented by Susan Hartfield PA-C, PharmD Overview Review the regulation of blood glucose Discuss hormone actions (insulin, glucagon) Discuss the metabolic progression to hyperglycemia and diabetes Review the screening and diagnosi...

Oral Agents for Diabetes Chapter 41 Presented by Susan Hartfield PA-C, PharmD Overview Review the regulation of blood glucose Discuss hormone actions (insulin, glucagon) Discuss the metabolic progression to hyperglycemia and diabetes Review the screening and diagnosis of diabetes Discuss treatment of hypoglycemia Overview Review the mechanism of action, common adverse effects, contraindications, monitoring parameters and clinical pearls regarding the following classes of drugs Biguinides Sulfonylurea’s Meglitinides Thiazolidinediones (TZD’s) Alpha glucosidase inhibitors Dipeptidyl peptidase inhibitiors (DPP-4 Inh) Sodium-glucose co-transporter 2 (SGLT 2) inhibitors  Objectives Recognize, understand, and demonstrate knowledge of pancreatic and gut hormones and antidiabetic drugs including: Generic names Pharmacokinetics and pharmacodynamics Mechanism of action Indications/contraindications Adverse effects Drug interactions Regulation of Blood Glucose ▪ Pancreatic hormones ▪ Islet of Langerhans Alpha cells - secrete glucagon which increases plasma glucose Beta cells - secrete insulin and amylin Delta cells - secrete somatostatin (GHIH) ▪ Small Intestinal L cell Secrete peptide hormones called incretins https://myendoconsult.com/learn/islet-cells-of-the-pancreas ▪ Glucagon-like peptide 1 (GLP-1): stimulates the beta cells to secrete more insulin > Inhibits alpha cells from releasing glucagon, slows gastric emptying, promotes satiety > Role is to attenuate large increase in plasma glucose that occurs with a meal ▪ Dipeptidylpeptidase 4 (DPP-4) - breaks down GLP-1  Hormone Action Insulin Promotes the uptake, usage and storage of glucose (lowering glucose plasma concentration) Promotes formation of glycogen, TG and protein Promotes the uptake of glucose by skeletal muscle and adipose tissue by activating a glucose transporter called GLUT-4 Glucose provides energy for skeletal muscle contraction. Inhibits protein catabolism. In adipose tissue, glucose is converted to fatty acid and stored as triglyceride. Hormone Action Glucagon Produced by the alpha cells of the pancreas Made in response to low glucose concentration Activates glycogenolysis and gluconeogenesis and increases hepatic glucose production Amylin Secreted by the pancreatic beta cells along with insulin Reduces the rate of rise of blood glucose Slows gastric emptying Suppresses glucagon secretion Reduces appetite Diabetes Mellitus ▪ Type I Caused by autoimmune destruction of beta cells triggered by a viral infection or other environmental factor Most common in children and adolescents 5-10% of all cases of DM Insulin deficiency. Need life-long insulin treatment Can have excessive production of ketones ▪ Type 2 Caused by insulin resistance/low insulin secretion Most common type of DM ~90% of all cases of DM Diabetes Mellitus Secondary MODY - maturity onset diabetes of the young Cystic fibrosis Pancreatectomy Drug or chemical induced (such as prednisone) Gestational New onset diabetes diagnosed in the 2nd or 3rd trimester Screening for Diabetes Screening in Children Diagnosis of Pre-Diabetes/Diabetes  The Progression of Insulin Resistance Modern life Lifestyle choices - diet (glucose, fructose), sedentary, weight gain.  episodic insulin. Initial stage of NAFLD. Labs are still “normal” Hyperinsulinemia Same lifestyle habits/diet/low exercise. Fasting insulin progressively higher, fasting glucose is progressively lower Hypoglycemic episodes Stress hormones increase More cravings insulin resistance The Progression of Insulin Resistance Escalating Diabetes Lifestyle habits sustain  blood glucose Beta cell dysfunction, fasting insulin and response to meals is lower  TG,  FFA, leptin resistance  fat tissue and fatty liver  tissue oxidative stress  systemic inflammation Presents with polyuria, polydipsia  The Progression of Insulin Resistance Metabolic Syndrome BG, TG, HDL Oxidative damage to endothelial lining of the arteries Intracellular oxidative stress Inflammation rises  homocysteine HTN worsens Visceral abdominal obesity  Major Contributors to Insulin Resistance High glycemic diet Processed food: Need Mg, biotin, calcium and chromium for healthy insulin sensitivity. Essential Fatty Acid (EFA) deficiency: impairs cell membrane and insulin receptor sensitivity. Lack of exercise: minimizes utilization of fuel,  insulin receptor sensitivity. Age Stress: Cortisol by itself raises insulin levels Genetics Medications: Steroids, diuretics (depletes Mg) Consequences of Insulin Resistance By driving down blood sugar we exacerbate the actual root cause. Insulin levels are sustained Promoting more insulin resistance Increased body fat Obesity Higher free fatty acids Worsening non-alcoholic fatty liver disease Cancer Oxidative stress Correlation of SMBG and A1C Treatment Considerations Drug efficacy A1c Fasting plasma glucose (FPG) Postprandial glucose (PPG) Comorbidities (ASCVD, HF, CKD) Cardiovascular benefits Renal effects Adverse effects Hypoglycemia Weight change MOA Oral or injectable Cost Goals of Therapy Personalize goal(s) for each patient Hemoglobin A1c – For all patients with T2DM – Goal: 48 hours following ▪ Best practice is to document adequate renal function before restarting but this is not always done. ▪ Boxed Warning: May cause rare Lactic Acidosis Serious/life-threatening ▪ Safe to use in pregnancy Metformin Obtain eGFR prior to starting metformin and at least annually in all patients – Possibly more frequently in those at high risk for renal impairment (eg. elderly) If eGFR falls to < 45 mL/min/1.73 m2 – May consider dosage reduction (50% dose reduction or 50% of maximal dose) – Monitor renal function every 3 months Starting therapy with an eGFR from 30 to 45 is not recommended Contraindicated with eGFR 3x(ULN) Weight gain Edema/ heart failure symptoms  Alpha-Glucosidase Inhibitors ▪ Agents: acarbose (Precose®) and miglitol (Glyset®) ▪ Mechanism: delay breakdown and absorption of complex carbohydrates Alpha glucosidase is an enzyme on the brush border of the GIT Does not increase insulin levels or cause hypoglycemia when used alone Does not affect absorption of lactose, fructose or glucose ▪ Reduces post-prandial glucose ▪ Minimal to no oral absorption ▪ Acarbose Initial 25mg with one meal/day Titrate gradually to three times daily (max 300mg daily)  Alpha-Glucosidase Inhibitors ▪ Adverse Effects: GI: flatulence, bloating, abdominal discomfort, diarrhea ▪ Contraindications: Short bowel syndrome, inflammatory bowel disease SCr >2mg/dL Cirrhosis Colonic ulceration Intestinal obstruction  Alpha-Glucosidase Inhibitors ▪ Clinical Pearls Take with first bite of meal Only with meals containing complex carbohydrates Decrease A1c by 0.7-0.8% Titrate dose slowly to minimize GI effects Must have glucose (dextrose) rather than sucrose (needs alpha glucosidase for breakdown) source available to treat potential hypoglycemia if on an AGI ▪ Can use glucose tablets or gel, fructose (100% apple, orange or other fruit juice or milk They do not cause lactose intolerance  Alpha-Glucosidase Inhibitors ▪ Monitoring A1C Consider adding post meal SMBG for select patients LFTs (can cause hepatitis) SCr (avoid use with SCr >2) Incretins  Selective Dipeptidyl Peptidase-4 Inhibitors (DPP-4 Inhibitors) ▪ Medications-all end in “-gliptin” Alogliptin (Nesina®) Linagliptin (Tradjenta®) Saxagliptin (Onglyza®) Sitagliptin (Januvia®) DPP-4 Inhibitors ▪ Mechanism: ↑ insulin secretion in response to elevated blood glucose Decrease postprandial hyperglycemia in Type 2 DM ↑ sense of fullness and slows gastric emptying Inhibit enzymes responsible for breaking down incretin hormones ▪ The two principal incretin hormones are glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) ▪ Causes greater than 80% inhibition on DPP-resulting in a 2-fold increase in GLP-1 levels  DPP-4 Inhibitors Mechanism ▪ Basal levels of GLP-1 and GIP are low but increase rapidly after ingestion of food; they are inactivated by the enzyme dipeptidyl-peptidase 4 (DPP-4) ▪ Both GLP-1 and GIP stimulate insulin secretion ▪ GLP-1 additionally stimulates insulin synthesis, inhibits glucagon secretion and reduces gastro-intestinal motility ▪ The effects on insulin and glucagon secretion occur only when blood levels of glucose are elevated, preserving the glucagon response to hypoglycemia.  DPP-4 Inhibitors ▪ Adverse Effects: Hypoglycemia (mild); low risk for serious hypoglycemia Severe joint pain ▪ Warnings and precautions: Increased risk HF Acute pancreatitis ▪ Clinical Pearls: Can be used as monotherapy Decrease A1c by 0.5-0.7% - targets post prandial BG Weight neutral Can be used in combo with other agents Available as a single tablet combined with metformin  DPP-4 Inhibitors ▪ Monitoring A1c Renal function (dose may need adjustment) ▪ Reports of pancreatitis ▪ May increase the risk of cancer Modulator of cellular invasion Animal studies-promoted spread of existing tumor (liver/colon) ▪ Did not increase formation  DPP-4 Inhibitors Dipeptidyl peptidase-4 inhibitors and cancer risk in patients with type 2 diabetes: a meta-analysis of randomized clinical trials Found no increase in risk of cancer Other papers show mixed results DPP-4 can act as a tumor suppressor or activator. Overall risk of cancer not increased however certain types of cancer were: bladder, kidney, liver cancer, melanoma (see next slide); Colon, lung, prostate reduced. Sodium-glucose co-transporter-2 (SGLT2) inhibitors -”Glifozins” ▪ Dapagliflozin (Farxiga®) ▪ Canagliflozin (Invokana®) ▪ Bexagliflozin (Brenzavvy®) ▪ Stoagliflozin (Inpefa®) ▪ Empagliflozin (Jardiance®) Proven to reduce major CV events and CV mortality Good choice for patients with ASCVD Reduces the progression of renal disease in type II diabetics SGLT2 Inhibitor Benefits SGLT2 Inhibitors ▪ Mechanism Blocks glucose reabsorption in the kidney Increases of urinary glucose Lowers renal threshold for glucose ▪ 180mg/dl  SGLT2 Inhibitors ▪ Adverse effects: Hypotension Volume depletion/↑SCr and ↓eGFR (d/t osmotic effect of Na/glucose) ▪ AKI requiring dialysis (dapagliflozin and canagliflozin) > More likely with dehydration, ACEI, diuretic, HF Hyperkalemia Hypoglycemia (if used with insulin or sulfonylurea) Rash, hypersensitivity reactions Increase the risk of UTI and genital mycotic infections (Fournier’s gangrene) Decrease in BMD/fractures- urinary Ca loss (canagliflozin) Increased risk of bladder cancer (dapagliflozin) May be associated with acute pancreatitis ↑Risk of amputations (6 out of 1000-canagliflozin over 1 year compared to 3/1000 other DM meds)  SGLT2 Inhibitors ▪ Clinical pearls Weight loss or weight neutral A1c (↓ ~0.7 %) Contraindicated for patients with eGFR 70 mg/dL, eat a full meal  Glucagon Hormone released by alpha cells of pancreatic islets Stimulates glycogen breakdown in the liver with release of glucose Restores plasma glucose toward normal Onset in 5-20 minutes Hyperglycemic action is short-lived Glucose production decreases to the basal rate after about 60 minutes