8131MED - Pharmacology of diabetes 080424.pdf

2024 Pharmacology of Type 2 diabetes mellitus S Niru Nirthanan MBBS PhD FRCP (Edin) SFHEA (UK) FAAPE (USA) FAcadMEd (UK) FBPhS School of Medicine and Dentistry | Griffith Health Group [email protected] © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024...

2024 Pharmacology of Type 2 diabetes mellitus S Niru Nirthanan MBBS PhD FRCP (Edin) SFHEA (UK) FAAPE (USA) FAcadMEd (UK) FBPhS School of Medicine and Dentistry | Griffith Health Group [email protected] © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Copyright Copyright © Griffith University Griffith University claims copyright ownership of all material in this online teaching material unless expressly stated otherwise. No part of the program nor the material contained in it may be copied (except as allowed by the copyright law of your country) or further disseminated without the express and written permission of Griffith University. To seek copyright permission, email: [email protected] COMMONWEALTH OF AUSTRALIA Copyright Regulations 1969 WARNING This material has been reproduced and communicated to you by or on behalf of Griffith University pursuant to Part VB of the Copyright Act 1968 (the Act). The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act. Do not remove this notice. © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Diabetes and comorbidities the big picture © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Diabetes and comorbidities ▪ Diabetes affects > 530 million globally Global prevalence of 10.5 percent among adults aged 20 to 79 years approx 1:10 Type 2 diabetes accounts for 90 – 95% type 1 less ~ 1.9 million Australians have diabetes; > 300 develop diabetes every day ▪ Diabetes and cardiovascular disease closely linked 68 % of people > 65 years with diabetes die from some form of heart disease; and 16 % die of stroke Adults with diabetes are 2 to 4 times more likely to die from heart disease than adults without diabetes ▪ Obesity, diabetes and cardiovascular disease are closely linked Predisposition, risk factors, epidemiology ▪ Overlap in drugs used to treat these comorbidities © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Cardiovascular diseases Interplay between a spectrum of pathologies heart, vessels, endothelium NO - Endothelial cells sympathetic dysfunction to hypertension Autonomic function Cardiovascular function Renal function Endocrine function Diabetes spectrum idiopathic hypertension secondary hypertension renal artery stenosis - secondary cause of hypertension © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Management of co-morbidities ▪ Obesity ▪ Hypertension ▪ Dyslipidaemia ▪ Ischaemic heart disease © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Management of co-morbidities ▪ Obesity Diet, exercise, lifestyle modification, drug treatment, bariatric surgery positive influence ▪ Hypertension ▪ Dyslipidaemia ▪ Ischaemic heart disease © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Bariatric surgery and diabetes 2014; 311(22):2297-2304 Conclusions: In this long-term follow-up observational study of obese patients with type 2 diabetes, bariatric surgery was associated with more frequent diabetes remission and fewer complications than usual care. These findings require confirmation in randomized trials. near normal glucose levels © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Bariatric surgery and diabetes Conclusions: Among obese patients with uncontrolled type 2 diabetes, 3 years of intensive medical therapy plus bariatric surgery resulted in glycaemic control in significantly more patients than did medical therapy alone. recognise for expertise New England Journal of Medicine 2014, 370; 21 © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 GLP-1 agonists, obesity and diabetes Conclusions: In this 72-week trial in participants with obesity, 5 mg, 10 mg, or 15 mg of tirzepatide once weekly provided substantial and sustained reductions in body weight. GLP-1 agonist - substantial weight loss Ozempic - semaglutide New England Journal of Medicine 387;3 July 21, 2022 © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Management of co-morbidities ▪ Obesity Diet, exercise, lifestyle modification, drug treatment, bariatric surgery ▪ Hypertension New stringent standards (< 140 / 80 mmHg or lower) Angiotensin Converting Enzyme inhibitor (ACE inhibitor) Angiotensin Receptor Blocker (ARB) ▪ Dyslipidaemia ▪ Ischaemic heart disease © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 tightened guidelines guidelines change Blood pressure management guidelines 2014 Hypertension. 2018;71:e13–e115 Med J Aust 2016; 205 (2): 85-89. stage 1 © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Management of co-morbidities ▪ Obesity Diet, exercise, lifestyle modification, other options ▪ Hypertension New stringent standards (< 140 / 80 mmHg or lower) Angiotensin Converting Enzyme inhibitor (ACE inhibitor) Angiotensin Receptor Blocker (ARB) ▪ Dyslipidaemia New stringent standards: LDL < 2.6 mmol/L Statins ▪ Ischaemic heart disease © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Lipids management guidelines 2013 © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Management of co-morbidities ▪ Obesity Diet, exercise, lifestyle modification, other options ▪ Hypertension New stringent standards (< 140 / 80 mmHg or lower) Angiotensin Converting Enzyme inhibitor (ACE inhibitor) Angiotensin Receptor Blocker (ARB) ▪ Dyslipidaemia New stringent standards: LDL < 2.6 mmol/L Statins ▪ Ischaemic heart disease Even more stringent standards: LDL < 1.8 mmol/L Antiplatelet agents: aspirin © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Management of type 2 diabetes ▪ ▪ ▪ ▪ ▪ Low glycaemic index Restrict refined sugars Restrict saturated fats High fibre Medical Nutrition Therapy ▪ ▪ ▪ ▪ ▪ Lower blood glucose Increase insulin sensitivity Decrease insulin resistance Improve cardiovascular health Counter obesity ▪ Diabetes Self Management Education Diet Exercise ▪ ▪ ▪ ▪ and Support Immunizations Monitor blood glucose Annual check-ups Decrease risk factors ▪ Smoking cessation ▪ Alcohol reduction education even one cigarette is too much for heart all affected by diet, lifestyle and exercise Lifestyle Pharmacological management of blood glucose © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Medical nutrition therapy Because of the direct correlation between diet and management of diabetes, medical nutrition therapy is a key complement to traditional medical interventions in diabetes treatment © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Management of diabetes page 55 - update on changes © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Management of diabetes © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Management of diabetes © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Pharmacological treatment of diabetes ▪ Patient- centered approach Efficacy Potential side effects Risk of hypoglycaemia Impact on weight Comorbidities Cost Patient preferences © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Control of blood glucose physiological concepts © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Endocrine pancreas Pancreas Endocrine Paul Langerhans German pathologist 1847 – 1888 Islet of Langerhans B/ cells Insulin Amylin - islet amyloid polypeptide Islet of Langerhans A/ cells Glucagon Islet of Langerhans D/ cells Somatostatin Islet of Langerhans PP cells Pancreatic polypeptide Islet of Langerhans E/ cells Ghrelin (hunger hormone) © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Pharmacologically relevant peptides Incretins L cells in ileum, colon Glucagon-like peptide 1 (GLP-1) two major peptides K cells in duodenum, proximal jejunum Gastric inhibitory peptide (GIP) aka - glucose-dependent insulinotropic peptide Dipeptidyl peptidase - 4 (DPP- 4) Rapidly terminates the actions of incretins, GLP-1 and GIP do not last out purpose © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Insulin ▪ Produced by the -cells in the islets of Langerhans of the pancreas in response to increase in blood glucose ▪ Acts on insulin receptors - tyrosine kinase receptor class ▪ Maintains normal blood glucose range of 3 – 8 mmol/L – glucose homeostasis © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Insulin ▪ Decreases blood glucose Uptake of glucose from blood into cells – skeletal muscle, cardiac muscle and adipose tissue Promotes glycogen synthesis – conversion of glucose into glycogen in liver and skeletal muscle Inhibits gluconeogenesis – synthesis of glucose from non-carbohydrate sources ▪ Anabolic hormone Promotes synthesis – glycogen, proteins, lipids and nucleic acids Inhibits lipolysis – breakdown of fats to free fatty acids ▪ Uptake of potassium ions from blood into cells – useful in managing hyperkalaemia starvation promotes synthesis inhibits brak down key for emergency medicine - insulin infusion © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Insulin © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Glucagon ▪ ▪ ▪ ▪ ▪ ▪ Produced by the -cells in the islets of Langerhans of the pancreas in response to low glucose levels Acts on glucagon (G-protein coupled) receptors Metabolic actions are opposite that of insulin Increases blood glucose Glycogenolysis – breakdown of glycogen to glucose Gluconeogenesis – synthesis of glucose from non-carbohydrate sources Catabolic hormone – breakdown of lipids and proteins Cardiovascular effects – increases rate and force of myocardial contraction (less potent than adrenaline) Treatment of acute cardiac failure precipitated by β-blockers catabolic © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Insulin, glucagon and blood glucose © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Snapshot of other peptides Somatostatin ▪ Secreted by -cells (also by the hypothalamus) ▪ Inhibits release of both, insulin and glucagon ▪ Inhibits release of growth hormone Octreotide (long acting analogue) used to treat acromegaly (excess growth hormone) ▪ What is the role of somatostatin in gastric acid secretion? Amylin ▪ Secreted by -cells Slows gastric emptying Enhances satiety Suppresses glucagon secretion inhibits gastric acid secretion © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Snapshot of other peptides Pancreatic polypeptide ▪ Secreted by PP-cells ▪ Promotes satiety by reducing appetite ▪ Reduces gastric emptying and gall bladder contraction ▪ Reduces pancreatic exocrine secretions Ghrelin ▪ Secreted by -cells (in developing pancreas) ▪ Actions: Increases secretion of growth hormone ‘Hunger hormone’ – enhances appetite Increases fat deposition - promotes adiposity hunger © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Snapshot of other peptides L cells K cells Incretins − GLP-1, GIP ▪ Secreted by the small intestine ▪ Actions: Early stimulus for insulin release Slows gastric emptying Suppresses glucagon secretion ▪ Short acting peptides ▪ Rapidly inactivated by dipeptidyl peptidase - 4 (DPP- 4) © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Physiology and pharmacology of incretins Decreased glucose production Slows gastric emptying Stomach slow emptying omyelin Amylin Appetite, satiety? β-cells Liver Pancreas Glucose GLP-1 GIP DPP-4 inactivate rapid α-cells Inhibits glucagon secretion β-cells Stimulates insulin secretion uptake of glucose Small intestine Incretin mimetic class of drugs Rapidly inactivated Muscle DPP-4 inhibitor class of drugs © S. Niru Nirthanan 2020 © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Adipose tissue Increased glucose uptake Incretins as anti-diabetic drug targets Manipulating incretin (GLP-1, GIP) pharmacology ▪ Incretin agonists ▪ Dipeptidyl peptidase - 4 inhibitors glucagon - release glucose from glycogen source trigger - low glucose, exercise, heart attack sympathetic response longer life span of incretins Incretin agonists or analogues lowers glucose long acting - reduce degradation © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Drugs used in the treatment of type 2 diabetes mellitus pharmacological principles © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Pharmacological treatment of diabetes Class Subclass(es) 3 focuses - red and green Molecular target Insulin analogues Insulin receptors Sulfonylureas KATP channels in -cells Meglitinides (“glinides”) Drugs which increase insulin Incretin mimetics GLP-1 agonists secretion Repaglinide, Nateglinide GLP-1 receptor in -cells Inhibitors of incretin metabolism Drugs which increase sensitivity to insulin DPP-4 inhibitors GLP-1 receptor in -cells (Gliptins) AMP activated protein kinase (AMPK) in Biguanides hepatocytes Peroxisome proliferator-activated receptors Thiazolidinediones (Glitazones) (PPAR) in adipocytes, liver, muscle Dual PPAR agonists Generic examples Ultra-rapid acting, fast acting, shortacting, long-acting, ultra-long acting 1st G: Tolbutamide 2nd G: Glipizide, Glyburide, Glimepiride Exenatide, Dulaglutide, Semaglutide Sitagliptin, Saxagliptin, Linagliptin Metformin Pioglitazone α and γ PPAR isoforms Saroglitazar (in India) SGLT-2 Inhibitors (Gliflozins) Sodium/glucose cotransporter 2 (SGLT2) in renal tubules Empagliflozin, Dapagliflozin -Glucosidase inhibitors -Glucosidase in intestinal brush border Acarbose, Miglitol Amylin analogues Pancreatic -cells Pramlintide Activators of glucokinase Glucokinase in -cells RO-28–1675 © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Management of diabetes - spectrum ▪ Prevention of metabolic syndrome / type-2 diabetes ▪ Management of metabolic syndrome ▪ Management of type-2 diabetes ▪ Prevention / management of diabetic complications ▪ Prevention / management of comorbidities © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 insulin - risk of proteloytic enzymes in stomach Management of diabetes complications ▪ Acute complications 1. Hypoglycaemia 2. Diabetic ketoacidosis 3. Hyperosmolar non-ketotic coma ▪ Chronic complications ▪ Microvascular 1. Nephropathy 2. Neuropathy 3. Retinopathy ▪ Macrovascular 1. Coronary artery disease 2. Stroke 3. Peripheral vascular disease complications small vessels - arterioles © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Management guidelines for diabetes © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Insulin cleaved use as biomarker count how many molecules of insulin produced © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Insulin Pro-insulin (inactive) a and b chain cys - disulphide © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Insulin Insulin (active) a and b chain 1 amino acid difference modify one or two amino acids and have completely different properties © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Insulin formulations different formulations and brands from small amino acid substitutions - short acting, long acting... different pharmacokinetic properties © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Anabolic effects of insulin on metabolism Energy source Lipid synthesis Energy storage © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 release of insulin - 3 channels Insulin release from  cells drug bound to this protein ATP-gated GLUT2 glucose transporter ATP-sensitive Sulfonylurea K+ channel receptor -+ by voltage - positive outside, negative inside drug acts high glucose after meal -+ Voltage-gated Ca++ channel -+ -+ -+ -+ -+ +- ATP +- -+ -+ +- +- +- +- voltage change - influx of calcium ions +- +- +- -+ +- +- +- +- +- +- enters +- +- +- +- +- then channels +- shut +- +- + - + - + Depolarization triggers insulin released then positive on inside and negative on outside beta cell builds up in cell More K+ in cell Efflux occurs naturally ADP ATP ATP muscle contraction with Ca++ or release of hormones or neurotransmitters Glucokinase more glucose - more ATP produced Glucose-6-phosphate © S. Niru Nirthanan 2019 Pancreatic β-cell © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Glucose Potassium (K+) ions Calcium (Ca++) ions Insulin Insulin release from  cells summary ATP Glucokinase © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Mechanism of insulin action type 4, mostly intracellular tyrosine kinase receptors triggers internal signalling opening the gate translocated to cell surface more efficient binding of insulin, more efficient translocation Insulin signal pathway Skeletal muscle Adipose tissue © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Mechanism of insulin action Ras signalling complex – Ras is a protein that regulates cell cycle and growth Insulin receptor substrate (IRS 1 - 4) proteins undergo tyrosine phosphorylation Phosphorylated IRS interacts with the SH2 domain of phosphatidylinositol 3-kinase (PI3K) enzyme and activates this enzyme cascade effect on protein and lipid metabolism © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Insulin ▪ Decreases blood glucose Uptake of glucose from blood into cells – skeletal muscle, cardiac muscle and adipose tissue Promotes glycogen synthesis – conversion of glucose into glycogen in liver and skeletal muscle Inhibits gluconeogenesis – synthesis of glucose from non-carbohydrate sources ▪ Anabolic hormone Promote synthesis – glycogen, proteins, lipids and nucleic acids Inhibits lipolysis – breakdown of fats to free fatty acids ▪ Uptake of potassium ions from blood into cells – useful in managing hyperkalaemia © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Insulin ▪ Stimulus for release of insulin Blood glucose – level as well as rate of increase Amino acids, fatty acids Parasympathetic stimulation Incretins (GLP-1, GIP) © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Insulin © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Insulin – future directions ▪ Insulin icodec – novel insulin analogue; once weekly SC injections; prolonged action due to free fatty acid chain binding to plasma albumin ▪ Oral insulin formulations – ionic liquid solutions ▪ Inhaled insulins – Afrezza; dry powder formulation of recombinant human insulin ▪ Small molecular insulin receptor activators pump improvements oral insulin... ▪ Smart insulins – glucose responsiveness linked to speed of elimination; glucose dependent absorption of insulin from SC injection sites; maintains insulin levels proportional to glucose concentrations for prolonged periods Pettus et al. Recommendations for initiating use of Afrezza inhaled insulin in individuals with type 1 diabetes. Diabetes Technology & Therapeutics (2018) 20.6 : 448-451. Nauck MA, Wefers J, Meier JJ. Treatment of type 2 diabetes: challenges, hopes, and anticipated successes. The Lancet Diabetes & Endocrinology (2021) 9(8) : 525-544. © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Nanotechnology in diabetology Nature Reviews Drug Discovery 2015, Volume 14, 45–57 © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Nanotechnology in diabetology ▪ Nanoparticles being developed as contrast agents to assist with the early diagnosis of type 1 diabetes ▪ Nanotechnology being used to generate implantable continuous glucose monitoring sensors (CGMS) that enable more accurate real-time tracking of blood glucose levels ▪ Glucose responsive nanoparticles being developed to better mimic the physiological needs of the body for insulin ▪ Nanotechnology being used to engineer more effective vaccines for type 1 diabetes © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Galega officinalis Goat’s rue / French lilac / Italian fitch metformin © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Drugs which increase insulin sensitivity ▪ Biguanides Metformin – first line treatment of type-2 diabetes ▪ Acts on AMP-kinase enzyme which regulates cellular energy mechanisms ▪ Diverse and desirable pharmacological actions Increase glucose uptake and utilisation by skeletal muscle Reduce hepatic glucose production (gluconeogenesis) Reduce LDL and VLDL / cardiovascular risk ▪ Does not stimulate appetite therefore assists in weight loss ▪ Does not cause hypoglycaemia safe drug taking ▪ Avoid use in renal, liver or cardiac failure as it may cause a rare fatal toxic effect – lactic acidosis ▪ Interferes with absorption of Vitamin B12 rare but fatal some vegetarian and vegan or even long-term metformin need to supplement B12 © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Drugs which increase insulin sensitivity ▪ Glitazones (Thiazolidinediones) Pioglitazone ▪ Not commonly prescribed anymore, although still available ▪ Activates peroxiome proliferator activated receptors (PPAR) in adipose tissue, GAMMA - ADIPOSE ALPHA - Fibrate drugs liver and skeletal muscle Improves sensitivity to insulin by promoting transcription of several genes important for insulin signaling ▪ Mechanism of action - not fully understood Decrease hepatic glucose production Increase glucose uptake into skeletal muscle Desirable outcomes with lipid profile (increased HDL) ▪ Causes weight gain Increases lipogenesis Fluid retention - increases renal sodium reabsorption © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 reabsorb - water retained Drugs which increase circulating insulin ▪ Sulfonylureas Tolbutamide (1G) Glibenclamide (glyburide), gliclazide, glimepiride (2G) ▪ Binds to sulfonylurea receptors which inhibit KATP channels in -cells ▪ Mechanism of action Stimulates insulin release (secretagogue) Requires functional  cells for action need viable cells, less effective as diabetes processes even less so for type 1 ▪ Long half-life (except tolbutamide); tendency to accumulate ▪ Hypoglycaemia – take with food; avoid in elderly ▪ Can cause weight gain ▪ Avoid in pregnancy and breast feeding © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Sulfonylurea mechanism of action GLUT2 glucose transporter ATP-sensitive Sulfonylurea K+ channel receptor Voltage-gated Ca++ channel binds here - - - - - - - - - - - - + + + + + + + Depolarization - - - - - - + + + + + ATP + + + + + + influx of calcium - release insulin ATP ADP ATP Glucokinase Glucose-6-phosphate © S. Niru Nirthanan 2019 Pancreatic β-cell © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Glucose Potassium (K+) ions Calcium (Ca++) ions Insulin Sulfonylurea drug Drugs which increase circulating insulin ▪ Meglitinides (Glitinides) very similar to sulphonylurea Repaglinide; nateglinide ▪ Glibenclamide (sulfonylurea) molecule without the sulfonyl moiety ▪ Act by inhibition of KATP channels in -cells ▪ Mechanism of action Stimulates insulin release Requires functional  cells for action ▪ Short half-life - hypoglycaemia is less common ▪ Ironically, resemble tolbutamide (1G sulfonylurea), but much more expensive! © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Drugs which increase circulating insulin ▪ Meglitinides (Glitinides) Repaglinide; nateglinide ▪ Glibenclamide (sulfonylurea) molecule without the sulfonyl moiety ▪ Act by inhibition of KATP channels in -cells ▪ Mechanism of action Stimulates insulin release Sulfonyl group Glibenclamide Requires functional  cells for action ▪ Short half-life - hypoglycaemia is less common ▪ Ironically, resemble tolbutamide (1G sulfonylurea), but much more expensive! Meglitinide © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Postprandial hypoglycaemic agents ▪ -Glucosidase inhibitors Acarbose, miglitol ▪ Inhibits -glucosidase enzyme in the small intestinal brush border which digests complex carbohydrates Delays or prevents dietary carbohydrate absorption Postprandial rise in blood glucose is reduced ▪ Drug action is within the intestines and is largely unabsorbed into the blood ▪ Undigested carbohydrates are fermented in the colon – abdominal discomfort, flatulence, diarrhoea retain and slow down reduce workload © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Incretin enhancing drugs ▪ Incretins are intestinal hormones that stimulate insulin release ▪ Incretin mimetics (incretin agonists; GLP-1 receptor agonists) mimic Exenatide, liraglutide, lixisenatide (daily) Exenatide (long acting), albiglutide, dulaglutide, semaglutide (weekly) Injectable (SC) long-acting analogues of GLP-1 Binds to GLP-1 receptors in -cells and mimics GLP-1 Excellent glucose control: significant reduction in HbA1C (by > 1.1 %) Multiple mechanisms of action and benefits Stimulates insulin release Inhibits glucagon release Delays gastric emptying Reduces appetite Significant weight reduction – obesity treatment Gila monster dynthetic - last longer, significant HbA1c reduction ▪ ▪ ▪ ▪ © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Incretin enhancing drugs ▪ GLP-1 receptor agonist Semaglutide (oral) ▪ First and only orally administered GLP-1 receptor agonist ▪ 94% similar to human GLP-1 ▪ Modified to prevent rapid degradation by DPP-4 replace 2 amino acids and spacer avoids degradation and can be taken orally © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 The last word………. SGLT-2 inhibitor DPP-4 inhibitor comparing oral drug was as effective or better - no refrigeration, cost-effective GLP-1 agonist (oral) GLP-1 agonist (injectable) © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 GLP-1 Agonists – expanded uses © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Incretin enhancing drugs ▪ Gliptins ▪ Dipeptidyl peptidase-4 (DPP- 4) inhibitors ▪ Sitagliptin, vildagliptin, saxagliptin, linagliptin ▪ Oral administration ▪ Inhibits DPP - 4 enzyme that degrades endogenous incretins Prolongs the action of endogenous GLP-1 and GIP act for longer time - incretins ▪ Moderate effect in lowering blood glucose © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Physiology and pharmacology of incretins Decreased glucose production Slows gastric emptying Stomach Amylin Appetite, satiety? β-cells Liver Pancreas Glucose GLP-1 GIP DPP-4 α-cells Inhibits glucagon secretion β-cells Stimulates insulin secretion Small intestine Incretin mimetic class of drugs Rapidly inactivated Muscle DPP-4 inhibitor class of drugs © S. Niru Nirthanan 2020 © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Adipose tissue Increased glucose uptake Amylin analogues ▪ Amylin is a peptide hormone secreted by -cells (together with insulin) ▪ Pramlintide ▪ Synthetic analogue of amylin ▪ Mimics amylin’s actions: Slows gastric emptying Enhances satiety Suppresses glucagon secretion ▪ Helps with weight loss ▪ May cause hypoglycaemia ▪ High cost © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Dual PPAR agonists: saroglitazar ▪ Agonists at both, PPARα and PPAR receptors ▪ Peroxiome proliferator activated receptors γ (PPARγ) Molecular target of glitazones, anti-diabetic drug Lowers blood glucose ▪ Peroxiome proliferator activated receptors  (PPARα) Molecular target of fibrates, lipid lowering drug Lowers triglycerides ▪ Diabetes and dyslipidemia are commonly associated modifiable risk factors for cardiovascular diseases not widespread use ▪ Useful for treating metabolic syndrome © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 SGLT2 inhibitors © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Glucose reabsorption in the nephron type 1 and 2 transporter glucose taken and reabsorbed Nature Reviews Cardiology 13, 75–77 (2016) © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 SGLT2 inhibitors most type 2, other type 1 Nature Reviews Cardiology 13, 75–77 (2016) © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 SGLT2 inhibitors ▪ Sodium-glucose co-transporter 2 inhibitors Gliflozins; flozins Dapagliflozin, empagliflozin, canagliflozin, ▪ SGLT2 proteins are predominantly found in the proximal renal tubules and are responsible for >90% of glucose reabsorption (and ~65% of sodium ion reabsorption) ▪ Gliflozins reduce renal glucose reabsorption by inhibiting SGLT2 ▪ Increased excretion of glucose and sodium (and water, by osmotic diuresis) in urine Glycosuria Natriuria Diuresis more water retained © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Benefits of SGLT2 inhibitors reduce arterial stiffness reduce heart failure and CV effects some reactive effects ACE inhibitors - reverse nephropathy GFR, glomerular filtration rate CV, cardiovascular events HGP, hepatic glucose production SNS, sympathetic nervous system Nature Reviews Nephrology 13, 11–26 (2017) © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 SGLT2 inhibitors ▪ Multiple benefits – ideal drug for diabetes? Significant reduction in HbA1C (by 0.5 – 1.1 %) and plasma glucose Does not cause hypoglycaemia (mechanism of action is not insulin dependent) Weight reduction not insulin Reduction in blood pressure Improvement in cardiovascular and renal end-points Prevents diabetic nephropathy ▪ Adverse effects Mycotic genital infections Necrotising fasciitis can lead to genital infection - poor hygiene aware Urinary tract infections © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 A new look at diabetes management ▪ Combination therapy with more than one drug Traditional stepwise approach Start with one (metformin), and add second drug when HBA1C target is try diet, exercise exceeded ( 8.5 - 9%) ▪ Significant cardiovascular and renal benefits have been established with SGLT2 inhibitors and GLP1 agonists in type 2 diabetes combination therapy Perkovic et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. New England Journal of Medicine 380.24 (2019): 2295-2306. ▪ Initial therapy with drugs with complementary modes of action Metformin + SGLT2 inhibitor Metformin + incretin mimetics (GLP-1 agonists) Metformin + SGLT2 inhibitor + incretin mimetics (GLP-1 agonists) van Baar et al. SGLT2 inhibitors in combination therapy: from mechanisms to clinical considerations in type 2 diabetes management. Diabetes Care 41.8 (2018): 1543-1556. © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 SGLT2 inhibitors – cardiovascular benefits 386;21 nejm.org May 26, 2022 reduced cardiovascular events v placebo © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 SGLT2 inhibitors – cardio-renal benefits © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Glucokinase activators © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Glucokinase activators ATP increase glucose processing - increase ATP production efficiency Glucokinase © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Glucokinase activators © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Drug interactions and blood glucose 2001;24:83-5 | 1 July 2001 © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Drug interactions and blood glucose some interactions Some medications that can raise blood glucose Drug Probable mechanism Clonidine Clozapine Corticosteroids Thiazide diuretics Nicotinic acid Nifedipine (but not other calcium antagonists) Oral contraceptive hormones Phenytoin Phenothiazines Sugar-containing syrups (antibiotics / cough mixtures) Adrenergic action ? Impairs insulin secretion Oppose insulin action Oppose insulin action ? Opposes insulin action Delays insulin action Oppose insulin action Blocks insulin secretion Not known Increased glucose intake Note: Clinical relevance of some effects is uncertain © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Drug interactions and blood glucose Some medications that may lower blood glucose Drug Suggested mechanism ACE inhibitors Increase insulin action Alcohol Inhibits hepatic glucose production and release Fibrates Not known Monoamine oxidase inhibitors Not known Quinine (? quinidine) Increases insulin secretion Salicylates (large dose) Not known Note: Clinical relevance of some effects is uncertain © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Drug interactions Potential interactions between sulfonylureas or meglitinides and other drugs which alter hepatic enzymes Inducers of metabolism: reduce hypoglycaemic drug concentration Inhibitors of metabolism: increase hypoglycaemic drug concentration Phenytoin Allopurinol* Phenobarbitone Chloramphenicol Rifabutin Cimetidine* Rifampicin Erythromycin 'Azole' antifungals * Only sulfonylurea concentrations are increased © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Response to hypoglycaemia ▪ Reduction in insulin secretion ▪ Secretion of counter-regulatory hormones Glucagon Adrenaline Glucocorticoids Growth hormone © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 Effects of hormones on blood glucose Hormone Main actions Stimuli Effect Main regulatory hormone ↑ Glucose uptake Insulin ↑ Glycogen synthesis ↓ Glycogenolysis Acute rise in blood glucose Incretins (GIP, GLP-1) ↓ Blood glucose Hypoglycaemia (e.g. with exercise, stress) ↑ Blood glucose ↓ Gluconeogenesis Main counter-regulatory hormones Glucagon ↑ Glycogenolysis Adrenaline ↑ Glycogenolysis ↓ Glucose uptake Glucocorticoids ↑ Gluconeogenesis ↓ Glucose uptake and utilisation Growth hormone ↓ Glucose uptake GIP, gastric inhibitory peptide; GLP-1, glucagon-like peptide-1. © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 The last word www.thelancet.com Vol 398 July 17, 2021 © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024 The last word……….really, the very last word New England Journal of Medicine (2021) 384: 13, 1248 - 1260 © S. Niru Nirthanan | School of Medicine and Dentistry | Griffith University | 2024