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Antidiabetic drug-1

  1. 1. Antidiabetic Drug  2019    ANTIDIABETIC DRUG 1 Introduction​: Anti-diabetic drug​, any ​drug​ that works to lower abnormally high ​glucose​ (​sugar​) levels in the ​blood​, which are characteristic of the ​endocrine system​ disorder known as ​diabetes mellitus​. Diabetes is caused by the body’s inability to produce or respond to the pancreatic hormone ​insulin​. One of the important physiological actions of insulin is to control blood glucose levels. Glucose is an important nutrient for cellular ​metabolism​, and ​cells​ must receive neither too little nor too much. A deficiency in the pancreatic secretion of insulin, or lack of tissue sensitivity to the hormone, leads to diabetes, the primary feature of which is elevated blood glucose levels (​hyperglycemia​). There are a number of different types of antidiabetic drug including: 1) Insulin 2) Pramlintide (Amylin) 3) GLP-1 receptor agonists (such as Byetta and Victoza) 4) Oral hypoglycemics (tablets) 2 Classification: Page 1   
  2. 2. Antidiabetic Drug  2019    2.1 Overview of Antidiabetic drug: Class Mechanism of action Side effects Contraindications Biguanide​ (​metformin​) Enhances the effect of ​insulin Lactic acidosis Weight loss Gastrointestinal complaints are common (e.g. ​diar rhea​, abdominal cramps) Reduced ​vitamin B12​absorption Chronic kidney disease Liver​ failure Metformin​ must be paused before administration of iodinated contrast medium and major surgery. Sulfonylureas​ (e.g., ​glyburid e​, glimepiride) Increase ​insulin​ secr etion from ​pancreatic​β-cel ls Risk of ​hypoglycemia Weight gain Hematological changes: ​agranulo cytosis​, ​hemolysis Severe cardiovascular comorbidity Obesity Sulfonamide​ ​allergy​ (par ticularly long-acting sub stances) Meglitinides​ (​nateglinide​, ​rep aglinide​) Increase ​insulin​ secr etion from ​pancreatic​β-cel ls Risk of ​hypoglycemia Weight gain Severe renal or ​liver​ failure DPP-4 inhibitors​ (​saxagliptin​, ​sitagli ptin​) Inhibit GLP-1 degra dation → promotes glucose-de pendent ​insulin​ secre tion Gastrointestinal complaints Pancreatitis Headache​, dizziness Arthralgia Liver​ failure Moderate to severe renal failure GLP-1 agonists​ (​incretin mimetic drugs​: ​exenatide​, ​liraglutide​, albiglutide​) Direct stimulation of the GLP-1 ​receptor Nausea Increased risk of pancreatitisand possibly ​pancreati c cancer Preexisting, symptomatic gastrointest inal motility disorders Page 2   
  3. 3. Antidiabetic Drug  2019    SGLT-2 inhibitors​(​canagliflozin​, ​dapa gliflozin​, ​empagliflozin​) Increased glucosuria through the inhibition of SGLT-2 in the kidney Genital ​yeast​ infe ctions and ​urinary tract infections Polyuria and ​dehy dration Diabetic ketoacidosis Chronic kidney disease Recurrent urinary tract infections Alpha-glucosidase inhibitors​(​acarbose​) Reduce intestinal glucose absorption Gastrointestinal complaints (flatulence, ​diarrh ea​, feeling of satiety) Any preexisting intestinal conditions (e.g., inflammatory bowel disease) Severe renal failure Thiazolidinediones​(​pioglitaz one​) Reduce insulin resistance through the stimulation of PPARs (​peroxisome proliferator-activated ​receptors​) Increase ​transcriptio n​ of adipokines Weight gain Edema Cardiac failure Increased risk of bone ​fractures​ (​os teoporosis​) Congestive heart failure Liver​ failure Amylin analogs (pramlintide) Reduce glucagon rel ease Reduce gastric emptying Increase satiety Risk of ​hypoglycemia Nausea Gastroparesis 3 Common contraindications of antidiabetic agents ● Type 1 diabetes mellitus​: Patients require ​insulin therapy​ (see principles of ​insulin therapy​). ● Pregnancy​ and breastfeeding (also see ​gestational diabetes​): All antidiabetic agents are contraindicated. Antidiabetic drugs should be substituted with human ​insulin​ as early as possible (ideally prior to the ​pregnancy​). Page 3   
  4. 4. Antidiabetic Drug  2019    ● Renal failure : Antidiabetic drugs that may be administered if ​GFR​ < 30 mL/min include DPP-4 inhibitors, ​incretin mimetic drugs​, ​meglitinides​, and ​thiazolidinediones​. ● Morbidity​ and surgery. ● Pause antidiabetic treatment in the following cases: ● Major surgery performed under general anesthesia. ● Acute conditions requiring hospitalization (infections, organ failure). ● Elective procedures associated with an increased risk of ​hypoglycemia​ (periods of fasting, irregular food intake). 4 Insulinotropic agents ● Mechanism: stimulate the secretion of ​insulin​ from ​pancreatic​ ​β-cells​. ● Glucose-independent: ​Insulin​ is secreted regardless of the blood glucose level, even if blood glucose levels are low → risk of ​hypoglycemia​. ● Sulfonylurea​, ​meglitinides​. ● Glucose-dependent: ​Insulin​ secretion is stimulated by elevated blood glucose levels (postprandially). These antidiabetic agents depend on residual ​β-cell​function. ● GLP-1 agonists, DPP-4 inhibitors.  5 Non-insulinotropic agents ● Mechanism:These agents do not depend on residual ​insulin​ production. ● Effective in patients with nonfunctional endocrine ​pancreatic​ ​β-cells​.. ● Biguanides​ (​metformin​), SGLT-2 inhibitor, ​thiazolidinediones​, alpha-glucosidase inhibitors. 5.1 Biguanides (Metformin) 5.1.1 Mechanism of action​: ● enhances the effect of ​insulin​. ● Reduction in insulin resistance via modification of glucose metabolic pathways. ● Inhibits ​mitochondrial​ glycerophosphate dehydrogenase (mGPD).. ● Decreases hepatic ​gluconeogenesis​ and intestinal glucose absorption. ● Increases peripheral ​insulin​ sensitivity. Page 4   
  5. 5. Antidiabetic Drug  2019    ● Lowers postprandial and fasting blood glucose levels. ● Reduces LDL, increases HDL. 5.1.2 Indications​:​ ​drug of choice in all patients with ​type 2 diabetes​. 5.1.3 Clinical characteristics: ● Glycemic efficacy: lowers ​HbA1c​ by 1.2–2% over 3 months. ● Weight loss or weight stabilization. ● No risk of ​hypoglycemia​. ● Beneficial effect on ​dyslipidemia​. ● Studies show ​metformin​ reduces the risk of macroangiopathic complications in diabetic patients. ● Cost-effective. 5.1.4 Important side effects: ● Metformin-associated lactic acidosis. ● Incidence: ​∼​ 8 cases/100,000 patient years. ● Clinical features: frequently nonspecific. ● Gastrointestinal prodromal symptoms: nausea, vomiting, ​diarrhea​, abdominal ​pain​. ● Severe symptoms: muscle cramps, ​hyperventilation​, apathy, disorientation, ​coma​. Page 5   
  6. 6. Antidiabetic Drug  2019    ● High-risk groups. ● Elderly individuals. ● Patients with cardiac or renal insufficiency. ● Diagnostics. ● Arterial blood gas​ (​ABG​): ​metabolic acidosis​ and ​anion gap​. ● ↑ Serum ​lactate​. ● Treatment: discontinue ​metformin​ and treat acidosis. ● Gastrointestinal complaints are common: nausea, ​diarrhea​, flatulence. ● Vitamin B12 deficiency​. ● Metallic taste in the mouth (dysgeusia). 5.1.5 Contraindications: ● Renal failure (if ​creatinine clearance​ < 30 mL/min). ● Severe ​liver​ failure. ● Intravenous iodinated contrast medium. ● Pause ​metformin​ prior to surgery. ● Chronic pancreatitis​, starvation ketosis, ketoacidosis, ​sepsis​. ● Heart failure​ (​NYHA​ III and IV), respiratory failure, ​shock​, ​sepsis​. ● Alcoholism​. 5.1.6 Important interactions​:​ ​sulfonylureas 5.2 Thiazolidinediones (glitazones, insulin sensitizers) 5.2.1 Active agents: ● Pioglitazone ● Rosiglitazone 5.2.2 Mechanism of action​:  ● Activation of the ​transcription factor​ PPARγ (​peroxisome​ proliferator-activated ​receptor​ of gamma type). ● ↑ ​Transcription​ of ​genes​involved in glucose and lipid metabolism. ● ↑ levels of adipokines such as adiponectin. Page 6   
  7. 7. Antidiabetic Drug  2019    ● ↑ Storage of ​triglycerides​ and subsequent reduction of products of lipid metabolism (e.g., free ​fatty acids​) that enhance insulin resistance . ● Glucose utilization is increased and hepatic glucose production reduced. 5.2.3 Indications​:  May be considered as a monotherapy in patients with severe renal failure and/or contraindications for ​insulin therapy​. 5.2.4 Clinical characteristics: ● Glycemic efficacy: lowers ​HbA1c​ by 1% in 3 months. ● Favorable effect on lipid metabolism: ↓ ​triglyceride​, ↓ LDL, ↑ HDL. ● No risk of ​hypoglycemia​.  5.2.5 Important side effects: ● Fluid retention and ​edema​. ● Weight gain. ● Increased risk of ​heart failure​. ● Increased risk of bone ​fractures​ (​osteoporosis​!). 5.2.6 Contraindications: ● Congestive heart failure​ (​NYHA​ III or IV). ● Liver​ failure. Page 7   
  8. 8. Antidiabetic Drug  2019    ● Pioglitazone​: history of ​bladder cancer​ or active ​bladder cancer​; macrohematuria of unknown origin. 5.3 Sulfonylureas 5.3.1 Active agents: ● Glyburide: the standard substance of this class with a relatively long ​half-life​. ● Glipizide: a short-acting agent. 5.3.2 Mechanism of action: ● Sulfonylureas block ​ATP​-sensitive potassium channels of the ​pancreatic​ ​β-cells​. ● Depolarization​ of ​the cell​ membrane. ● Calcium influx. ● Insulin​secretion. ● Extrapancreatic effect: decreases hepatic ​gluconeogenesis​ and increases peripheral ​insulin​ sensitivity. Page 8   
  9. 9. Antidiabetic Drug  2019    5.3.3 Indications: Particularly suitable for patients who are not overweight, do not consume alcohol, and adhere to a consistent dietary routine. 5.3.4 Clinical characteristics: ● Glycemic efficacy: lowers ​HbA1c​ by 1.2% over 3 months. ● Long-term experience. ● Low-cost. 5.3.5 Important side effects: ● Life-threatening ​hypoglycemia​. ● Increased risk in patients with renal failure. ● Weight gain. ● Hematological changes: granulocytopenia, ​hemolytic anemia​. ● Allergic skin reactions. ● Alcohol intolerance. ● Compared to ​metformin​, ​sulfonylureas​ are associated with more cardiovascular (macrovascular) complications. 5.3.6 Contraindications: ● Severe cardiovascular comorbidity. ● Obesity​. ● Sulfonamide​ ​allergy​ (particularly long-acting substances). ● Severe ​liver​ failure. ● Severe kidney failure. 5.4 Meglitinides (sulfonylurea analogue) 5.4.1 Active agents: ● Repaglinide: the leading agent in the class of ​meglitinides​, which is well tolerated by patients with ​chronic kidney disease ● Nateglinide  Page 9   
  10. 10. Antidiabetic Drug  2019    5.4.2 Mechanism of action: ● Enhances ​insulin​ secretion (similar mechanism of action to that of the ​sulfonylureas​). ● Meglitinides​ should be taken shortly before meals. 5.4.3 Indications:​ particularly suitable for patients with postprandial peaks in blood glucose levels. 5.4.4 Clinical characteristics: ● Glycemic efficacy: lowers ​HbA1c​ by 0.75% over 3 months. ● More expensive than ​sulfonylureas​. 5.4.5 Important side effects: ● Life-threatening ​hypoglycemia​ (less risky than ​sulfonylureas​). ● Increased risk in patients with renal failure. ● Weight gain. ● Hepatotoxicity (rare). Page 10   
  11. 11. Antidiabetic Drug  2019    5.4.6 Contraindications: ● Severe ​liver​ failure. ● Severe renal failure. 5.4.7 Interactions:​ ​Sulfonylureas​. 5.5 Incretinmimetics (GLP-1 receptor agonists) 5.5.1 Active agents: ● Exenatide. ● Liraglutide: rapid-release formula that is administered daily. ● Albiglutide: extended-release formula that is administered once weekly. ● Dulaglutide.  5.5.2 Mechanism of action: ● Incretin effect: 1. Food intake. 2. Activation of enteroendocrine cells in the ​gastrointestinal tract​. 3. Release of GLP-1. 4. GLP-1 degradation via the enzyme DPP-4. 5. End of the GLP-1 effect. ● Incretin mimetic drugs​ bind to the GLP-1 ​receptors​ and are resistant to degradation by DPP-4 enzyme ● Increase ​insulin​ secretion, decrease glucagonsecretion, slow gastric emptying (↑ feeling of satiety, ↓ weight) Page 11   
  12. 12. Antidiabetic Drug  2019    5.5.3 Clinical characteristics: ● Glycemic efficacy: lowers ​HbA1c​ by 0.5–1.5% over 3 months ● Subcutaneous injection ● Weight loss ● No risk of ​hypoglycemia 5.5.4 Side effects: ● Gastrointestinal complaints (particularly impaired gastric emptying!) ● Increased risk of pancreatitis and potentially ​pancreatic cancer​ : 5.5.5 Contraindications: ● Preexisting symptomatic gastrointestinal motility disorders ● Chronic pancreatitis​ or a family history of ​pancreatic​ tumors 5.6 Dipeptidyl peptidase-4 inhibitors (gliptins) 5.6.1 Active agents: ● Sitagliptin ● Saxagliptin 5.6.2 Mechanism of action: Page 12   
  13. 13. Antidiabetic Drug  2019    ● Gliptins​ indirectly increase the endogenous incretin effect by inhibiting the dipeptidyl peptidase. ● 4 enzyme that breaks down glucagon-like peptide 1. ● Increased ​insulin​ secretion, decreased glucagon secretion, delayed gastric emptying. 5.6.3 Indications​:​  ​Antihyperglycemic therapy algorithm for type 2 diabetes​. 5.6.4 Clinical characteristics: ● Glycemic efficacy: lowers ​HbA1c​ by 0.5–0.75% over 3 months.No risk of hypoglycemia unless ​insulin​ and/or insulinotropic drugs are used simultaneously. 5.6.5 Important side effects: ● Gastrointestinal complaints: ​diarrhea​, ​constipation​ (milder than in GLP-1 agonist exposure). ● Nasopharyngitis and upper respiratory tract infection. ● Arthralgia. ● Headaches, dizziness. ● Urinary infections (mild). ● Increased risk of pancreatitis. ● Acute renal failure​. Page 13   
  14. 14. Antidiabetic Drug  2019    5.6.6 Contraindications: ● Hypersensitivity. ● Liver​ failure. 5.7 SGLT-2 inhibitors (gliflozins) 5.7.1 Active agents: ● Dapagliflozin ● Empagliflozin ● Canagliflozin 5.7.2 Mechanism of action: ● Reversible inhibition of the sodium-dependent glucose co-transporter (SGLT-2) in the proximal tubule of the kidney. ● reduced glucose reabsorption in the kidney. ● glycosuria and polyuria. 5.7.3Indications:​ A treatment option used especially in young patients with treatment-compliant ​type 2 DM​ without significant renal failure. Page 14   
  15. 15. Antidiabetic Drug  2019    5.7.4 Clinical characteristics: ● Glycemic efficacy: lowers ​HbA1c​ by 0.6% over 3 months. ● Promotes weight loss. ● Reduces blood pressure. 5.7.5 Important side effects: ● Urinary tract infections​, genital infections (​vulvovaginitis​, ​balanitis​). ● Dehydration​ as a result of polyuria. ● Severe ​diabetic ketoacidosis​. 5.7.6 Contraindications: ● Chronic kidney disease​. ● Recurrent urinary tract infections​ (e.g., in patients with anatomical or functional anomalies of the urinary tract). 5.8 Alpha-glucosidase inhibitors 5.8.1 Active agents: ● Acarbose ● Miglitol 5.8.2 Mechanism of action: ● Inhibits alpha-glucosidase. ● Decreased intestinal glucose absorption. ● The drug is particularly effective in controlling postprandial blood glucose levels. ● The undigested ​carbohydrates​ reach the colon, where they are degraded by intestinal bacteria, resulting in the production of intestinal gas. Page 15   
  16. 16. Antidiabetic Drug  2019    5.8.3 Clinical characteristics: ● Glycemic efficacy: lowers ​HbA1c​ by 0.8% over 3 months. ● No risk of ​hypoglycemia​. 5.8.4 Important side effects:​ gastrointestinal complaints (flatulence, abdominal discomfort, ​diarrhea​). 5.8.5 Contraindications ● Inflammatory bowel disease. ● Conditions associated with ​malabsorption​. ● Severe renal failure. Page 16   
  17. 17. Antidiabetic Drug  2019    References: 1. https://www.amboss.com/us/knowledge/Antidiabetic_drugs 2. American Diabetes Association. Diabetes Basics. Accessed 11/5/2018 3. MIMS. 2013. [12 December 2013]. Available from: ​http://www​.mims.co.uk/ Page 17   

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