New Antidiabetic Medications A/Prof Harvey Newnham Clinical Program Director Emergency and Acute Medicine, Director of General Medicine, Endocrinologist Alfred Health, Melbourne 29th May 2014 Diagnosed Diabetes USA Adults 18-79 y.o. <3% to >7% last 20 years Polonsky K, NEJM 2012;367:1332 Scenario 1 • 74yo man T2DM 5 years admitted with LLL Pneumonia – Gliclazide MR 60 mg, 2 mane – Metformin MR 2g mane • • • • Weight 86kg Admission RBG 14 mmol/L HbA1c 8% 6 weeks ago EGFR 70, LFTs normal How would you manage his glycaemia? 1. Continue gliclazide and metformin and add short acting insulin before meals according to scale 2. Stop gliclazide and metformin and start short acting insulin before meals to scale 3. Add sitagliptin 100 mg daily 4. Start insulin glargine (Lantus) 18 units a day 5. Start insulin aspart (Novorapid) 6 units before each meal 6. Commence an insulin infusion aiming for sugars 6-10 mmol/L • 74yo man T2DM 5 years admitted with LLL Pneumonia – – • • • • Gliclazide MR 60 mg, 2 mane Metformin MR 2g mane Weight 86kg Admission RBG 14 mmol/L HbA1c 8% 6 weeks ago EGFR 70, LFTs normal Scenario 2 • Clinic visit: – 71 yo woman DM 3 years, asymptomatic presentation and no complications – PH Grave’s disease Rx thyroidectomy • Now has deteriorating glycaemic control 18/12, • SBGM Before breakfast 10-18 – LOW 10kg 3/12 (BMI now 24kg/m2), nocturia x1, – Metformin – ceased because of taste disturbance – Gliclazide MR 30 mg mane for 1 month What is the most likely diagnosis? 1. 2. 3. 4. 5. 6. Ca pancreas T2DM with secondary failure of OHGs LADA T1DM Hyperthroidism recurrence Chronic sepsis • Clinic visit: – – • 71 yo woman DM 3 years, asymptomatic presentation and no complications PH Grave’s disease Rx thyroidectomy Now has deteriorating glycaemic control 18/12, • – – – SBGM Before breakfast 10-18 LOW 10kg 3/12 (BMI now 24kg/m2), nocturia x1, Metformin – ceased because of taste disturbance Gliclazide MR 30 mg mane for 1 month What would you do? 1. 2. 3. 4. 5. 6. 7. 8. Increase gliclazide dose Add gliptin Add SGLT2 inhibitor Add pioglitazone Start exenatide injections Start insulin glargine injections Start a basal bolus regimen Admit to hospital for investigation/stabilisation Synopsis Why is treatment of diabetes so complicated? What are the anti-hyperglycaemic agents and how do they work? Practical considerations - side effects, important drug interactions The future – better agents, more evidence Sceptics view Scourges of older people with diabetes are: – Myocardial infarction/stroke/PVD – Hypoglycaemia – Polypharmacy Antihyperglycaemic drugs: – Don’t reduce vascular disease and do cause hypoglycaemia – Or don’t cause hypoglycaemia and have unknown effects on vascular disease – 2 or more agents often needed to achieve tight glycaemic control Adapted from Richard Lehman, Cardioexchange 2014 UKPDS Complexity • No perfect solution • Pathophysiology incompletely understood • Glycaemic targets controversial – Microvascular vs macrovascular • Multiple approaches • Huge market • Consensus rather than evidence-based • Patient-centred i.e. individualised approach From Polonsky K, n engl j med 367;14 Patient-related factors Inzucci S et al, Diab. Care, Vol 35, June 2012 Antidiabetic medications • Interfere with pathophysiological defects – – – – – – – Hepatic glucose output: fasting and postprandially Insulin-stimulated glucose disposal (esp skeletal muscle) Renal threshold for glucose disposal in urine Insulin resistance Abnormal islet cell function (reversible: cf bariatric surgery) Incretin system dysfunction (GLP-1, GIP) Excess gluconeogenesis from increased FFA delivery to the liver • Modify physiology of appetite • Modify nutrient absorption &/or excretion Treatment of T2DM Insulin resistance •Diet, weight loss •Exercise •Thiazolidenediones •(Metformin) Islet dysfunction •Insulin secretagogues •Sulfonylureas, •Insulin Renal glucose excretion Incretin Dysfunction Sodium glucose co-transporter 2 (SGLT-2) inhibitors GLP-1 Agonists/analogues DPP-IV inhibitors (Injectable amylin analogues: Pramlintide) Hepatic glucose production •Metformin •Insulin Appetite/CHO absorption • a-glucosidase inhibitors •Anti-obesity agents •Orlistat (Xenical), •Phentermine/topiramate •Locaserin •Bariatric surgery Generic and Trade Names • Sulfonylureas – Gliclazide: Glyade, Nidem, Diamicron (MR = slow release) – Glipizide: Melizide, Minidiab – Glimepiride: Aylide, Diapride, Dimirel, Amaryl, – Glibenclamide (Glyburide): Glimel, Daonil • Biguanides: Metformin – Diaformin, Formet, Glucobete, Glucophage, Diabex, Metex XR (XR = extended release) Generic and Trade Names • Alpha glucosidase inhibitors – Acarbose: Glucobay • Thiazolidinediones – Pioglitazone, • Actos, Acpio, Pizaccord, Prioten, Vexazone • DPP-4 inhibitors – – – – Linagliptin: Trajenta Saxagliptin: Onglyza Sitagliptin: Januvia Vildagliptin: Galvus • Exenatide – Byetta • Sodium glucose co-transporter 2 (SGLT2) inhibitors – Canagliflozin Invokana – Dapagliflozin Forxiga Combinations • Metformin + Glibenclamide: – Glucovance • Sitagliptin + Metformin: – Janumet • Rosiglitazone + Metformin: – Avandamet • Vildagliptin + Metformin: – Galvumet • Linagliptin and Metformin: – Trajentamet Insulins • Short acting – Ultrashort acting analogues: • Insulin aspart: • Insulin glulisine: • Insulin lispro: – Regular (neutral): • NovoRapid Apidra Humalog Actrapid, Humulin R Intermediate acting – Isophane: Humulin NPH, Protaphane • Combinations – Isophane + neutral: – Lispro + Lispro protamine: – Aspart + Aspart protamine: • Long acting – Insulin Detemir: – Insulin Glargine: Levemir Lantus Humulin 30/70, Mixtard 30/70, Mixtard 50/50 Humalog Mix25, Humalog Mix50 Novomix 30 Biguanides • Metformin – – – – – – – Activates AMP-kinase Decreases hepatic glucose output First line agent for overweight T2DM UKPDS showed cardioprotective effects May improve stable heart failure outcomes No weight gain or hypoglycaemia (as monotherapy) Concerns • Lactic acidosis risk (small) – Esp if severe CCF, PVD, renal failure, haemodynamic instability, extreme old age or pulmonary disease • GIT side effects of anorexia, nausea, cramps problematic in hospital/fasting patients • May increase nephrotoxicity of iodinated contrast • Vitamin B12 deficiency Insulin secretagogues • Sulfonylureas – – – – gliclazide, glimepiride, glipizide, glibenclamide/glyburide Close KATP channels on b-cells Reduce microvascular complications Concerns • CVD from UGDP? • May impair ischaemic preconditioning (cease in ACS pts) • No consistent evidence of detrimental effect at clinical level although some suggestive studies » Direct angioplasty – SU independently associated with increased hospital mortality » Post–MI SU use appears to be predictor of new coronary events in the elderly (ave age 80) • Long duration of action makes titration of inpatient control difficult – hypoglycaemia risk if CHO interrupted • Weight gain • Limited durability of effect Review by Clement S et al Diabetes Care 2004;27:553 PPAR-g agonists (Insulin sensitisers) • Thiazolidinediones (Glitazones) – – – – – – Pioglitazone (Actos), Rosiglitazone (Avandia) Increases insulin sensitivity No hypoglycaemia Good durability May decrease CVD events (Pioglitazone - ProACTIVE) Concerns • • • • • • • Increases intravascular volume Exacerbate CCF Peripheral oedema Weight gain Bone fractures Bladder cancer Negligible effect on CAD in high risk patients (may help post-stent re-stenosis) • Slow onset of action – don’t help with inpatient control a-Glucosidase Inhibitors • Acarbose (Precose/Glucobay), Miglitol (Glyset), Voglibose • Slows intestinal CHO digestion/absorption • No hypoglycaemia, reduced postprandial glucose • May reduce CVD events (STOP-NIDDM) • Concerns – Modest efficacy – Flatulence, diarrhoea – Frequent dosing required (tds) Incretins • Oral glucose has greater effect on insulin release than IV glucose • Glucagon-Like Peptide-1 (GLP-1) – – – – – From L-cells of small intestine Decreased in T2DM and abnormally regulated in T1DM Stimulates glucose-dependent insulin release from pancreas Metabolised by dipeptidyl peptidase-4 (DPP-4) enzyme Restores both first phase and second phase insulin response to glucose – Slows gastric emptying – Inhibits inappropriate post-meal glucagon release – Reduces food intake (increased satiety) From Kathleen Dungan UpToDate 2013 Incretin Mimetic Agents - Injectable GLP-1 Receptor Agonists • Exenatide (53% homology with GLP-1), exenatide ER, liraglutide (97% homology) • PBS Exenatide (Byetta) 5mcg b.d s/c injection1h before main meals. • Non PBS – – • Action – – – – • • • • • Exenatide (Bydureon), 2mg s/c weekly Liraglutide (Victoza) 0.6mg s/cdaily Increase glucose-dependent insulin secretion Decrease glucagon Slow gastric emptying Increase satiety No hypoglycaemia Weight reduction Preserves B-cell mass May be helpful in cardiomyopathy Concerns – – – – Nausea, vomiting, diarrhoea – 10-40% Pancreatitis? Injectable Most effective in patients who are eating Incretin Mimetic Agents - Oral • Dipeptidyl peptidase-4 (DPP-4) inhibitors – Sitagliptin Januvia, linagliptin Trajenta, saxagliptin Onglyza, alogliptin Nesina, – Action • Increases postprandial incretins GLP-1 and GIP. • Increase glucose dependent insulin secretion • Decrease glucagon secretion – No hypoglycaemia – Well tolerated, no weight gain – Concerns • • • • • Only effective in patients who are eating Care in renal dysfunction Modest efficacy Urticaria/angioedema Pancreatitis? Amylin Mimetics • Pramlintide – Activates amylin receptor (Amylin is peptide from B-cells) • Decreases glucagon, • Slows gastric emptying, • Increases satiety – Reduces postprandial glucose – Weight reduction – Concerns • • • • • Used in T1DM Modest efficacy Nausea, vomiting Frequent dosing Injectable Sodium glucose co-transporter 2 (SGLT2) inhibitors • SGLT2 Receptor in proximal tubule mediates reabsorption of 90% of filtered glucose – Effect independent of B-cell function and insulin sensitivity • Canagliflozin Invokana 100 or 300mg tab daily, authority, independent of food, dapagliflozin, Forxiga 10mg daily • Promotes weight loss, lowers systolic blood pressure • Low risk of hypoglycaemia • Concerns – Limited safety and efficacy data (3rd line agent only) – Side effects of UTI, vaginal yeast infections 11% (due to glycosuria), perhaps postural dizziness Other drugs • Non-sulfonylurea insulin secretagogues – Metiglinides – repaglinide (No longer available in Australia) • Short action, could be useful. • Hypoglycaemia, weight gain, frequent dosing • Reduces myocardial ischaemic preconditioning • Bile acid sequestering resins – – – – – • Colesevelam May decrease HGO and increase incretins No hypoglycaemia, reduces LDLc Modest effectiveness, constipation, increases TG Increases absorption of other agents Bromocriptine – – – – Modulates hypothalamic regulation of metabolism Increases insulin sensitivity No hypoglycaemia, may reduce CVD Concerns • Modest efficacy, dizziness, syncope, nausea, fatigue, rhinitis Inzucci S et al, Diab. Care, Vol 35, June 2012 Treatment escalation algorithm for T2DM Healthy eating & exercise Metformin Add sulfonylurea Add basal Insulin Add Incretin mimetic DPP-4 inhibitor or GLP-1 agonist or (SGLT2 inhibitor)? Consider adding Incretin mimetic Acarbose TZD Intensify insulin therapy Basal-bolus or mixed regimen Continue metformin Consider ceasing other agents Consider bariatric surgery for appropriate high risk patients Adapted from Therapeutic Guidelines 2014 Use of Antidiabetic Drugs in Special Cases • • • • Cardiac Renal Hepatic Patients at risk of hypoglycaemia Coronary ischaemia • Metformin probably beneficial for CVD outcomes – Not with acute event • Any drug: Avoid hypoglycaemia – exacerbates ischaemia and may cause arrhythmias • Relevance re adverse effects of sulfonylureas on CHD unproven • Pioglitazone may reduce CVD events (don’t use if CCF) • GLP-1 receptor agonists and DPP-4 inhibitors may improve CVD risk factors • Acarbose may reduce CVD events Cardiac failure • Avoid thiazolidinediones • Avoid metformin in severe heart failure Chronic kidney disease • • • • 20-30% of patients with diabetes have eGFR<60 mL/min Increased risk of hypoglycaemia Consider dose reductions and care with fluid balance Metformin has lactic acidosis risk – eGFR <30 mL/min – avoid – eGFR <45 mL/min – low dose only • Sulfonylureas have significant renal clearance: – dose adjust – avoid glibenclamide (glyburide) – Repaglinide can be used in CKD • DPP-4 inhibitors: – sitagliptin, vildagliptin, saxagliptin renally cleared and need dose reduction. – linagliptin hepatic metabolism • GLP-1 agonists – Exenatide contraindicated if eGFR<30mL/min. – Liraglutide – drug levels unaffected by renal disease. Liver disease • Hepatic steatosis common in diabetes • Pioglitazone – may improve steatosis – Avoid if ALT >2.5 x ULN • Sulfonylureas may have hepatic side effects • Incretin mimetics used in mild liver disease but avoid if history of pancreatitis • Use insulin if advanced liver disease Troublesome hypoglycaemia • Potential cause of brain dysfunction • Higher risk in elderly – Dysrhythmias, falls, delirium – Aspiration in sleep – Loss of confidence • Association with mortality (ACCORD) • Use agents with low risk of hypoglycaemia – Avoid sulfonylureas Important drug interactions • CYP2C9 polymorphisms influence sulfonylurea, glitinides and TZD metabolism • Repaglinide and TZD concentration increased by gemfibrozil • Sulfonylureas – Enhance warfarin effect and vice versa – Hypoglycaemic effect enhanced by quinolone antibiotics • Metformin – – Carbonic anhydrase inhibitors enhance risk of lactic acidosis – Iodinated contrast agents and nephrotoxicity • DPP-4 inhibitors – Increase risk of angio-edema with ACE inhibitors • Exenatide decreases OCP concentration and enhances warfarin effect Holstein, A et al Expert Opin. Drug Metab. Toxicol. (2012) 8(12):1549-1563 The future • Establish: – Cardiovascular and total mortality outcomes with different agents, combinations and treatment algorithms – Comparative glycaemic effects – Quality of life outcomes – Durability of effectiveness (b-cell preservation) – Role of pharmacogenetics Other potential targets! • Ranolazine – Sodium channels in b-cells – Inhibits fatty acid oxidation • • • • • • • • Selective PPARg modulators SGLT-1 inhibitors Fructose 1,6 bisphosphatase inhibitors Glucokinase activators 11b-hydroxysteroid dehydrogenase inhibitors Protein tyrosine phosphatase 1B inhibitors Acetyl-CoA carboxylase-1 and -2 inhibitors Glucagon receptor antagonists Alternative remedies • Cinnamon – no effect on diabetes control or complications (Cochrane review 2013) Polypharmacy Prof Danny Liew, RMH Personal communication Conclusions • Formulate treatment and glucose targets with the patient • Treat symptoms • Avoid hypoglycaemia • Minimise side effects • Treat CVD risk factors aggressively if appropriate • Minimise polypharmacy References • Inzucchi SE et al, Diabetes Care 2012:35;1364 • Inzucchi SE and McGuire DK, Circulation 2008: 117:754 • Holstein A et al, Expert Opinion Drug Metabolism and Toxicity 2012:8; 1549 • Polonsky KS, NEJM 2012:367:1332 • UpToDate 2014 The End
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