New Antidiabetic Medications

Transcription

1 New Antidiabetic Medications A/Prof Harvey Newnham Director of General Medicine Clinical Program Director Emergency and Acute Medicine, Alfred Health, Melbourne 5 th May 2013

2 Diagnosed Diabetes USA Adults y.o. <3% to >7% last 20 years Polonsky K, NEJM 2012;367:1332

3 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

4 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

5 Patient related factors Inzucci S et al, Diab. Care, Vol 35, June 2012

6 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

7 Treatment of T2DM Insulin resistance Diet, weight loss Exercise Thiazolidenediones (Metformin) Incretin Dysfunction GLP-1 Agonists/analogues DPP-IV inhibitors (Injectable amylin analogues: Pramlintide) Hepatic glucose production Metformin Insulin Islet dysfunction Insulin secretagogues Sulfonylureas, Insulin Renal glucose excretion Sodium glucose co-transporter 2 inhibitors Appetite/CHO absorption α-glucosidase inhibitors Anti-obesity agents Xenical, Phentermine/topiramate Locaserin Bariatric surgery

8 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)

9 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 inhibitors Canagliflozin (Invokana)

10 Combinations Metformin + Glibenclamide: Glucovance Sitagliptin + Metformin: Janumet Rosiglitazone + Metformin: Avandamet Vildagliptin + Metformin: Galvumet

11 Insulins Short acting Ultrashort acting analogues: Insulin aspart: NovoRapid Insulin glulisine: Apidra Insulin lispro: Humalog Regular (neutral): Actrapid, Humulin R Intermediate acting Isophane: Humulin NPH, Protaphane Combinations Isophane + neutral: Humulin 30/70, Mixtard 30/70, Mixtard 50/50 Lispro + Lispro protamine: Humalog Mix25, Humalog Mix50 Aspart + Aspart protamine: Novomix 30 Long acting Insulin Detemir: Levemir Insulin Glargine: Lantus

12 Biguanides Metformin Activates AMP-kinase Decreases hepatic glucose output First line agent for T2DM UKPDS showed cardioprotective effects May improve stable heart failure outcomes No weight gain or hypoglycaemia 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

13 Insulin secretagogues Sulfonylureas gliclazide, glimepiride, glipizide, glibenclamide/glyburide Close K ATP channels on β-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

14 PPAR-γ agonists (Insulin sensitisers) Thiazolidinediones (Glitazones) Pioglitazone, [Rosiglitazone] 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 restenosis) Slow onset of action don t help with inpatient control

15 α-glucosidase Inhibitors Acarbose (Precose/Glucobay), Miglitol (Glyset), Voglibose Culinary mushroom (Maitake [Grifola frondosa]) natural inhibitor 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)

16 Incretins Oral glucose has greater effect on insulin release than IV 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 From Kathleen Dungan UpToDate 2013

17 Incretin Mimetic Agents - Injectable GLP-1 Receptor Agonists Exenatide (53% homology with GLP-1), exenatide ER, liraglutide (97% homology) Action 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 (Exenatide: twice daily, once weekly, Liraglutide daily) Most effective in patients who are eating

18 Incretin Mimetic Agents - Oral Dipeptidyl peptidase-4 (DPP-4) inhibitors Sitagliptin, linagliptin, saxagliptin, vildagliptin, alogliptin 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?

19 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

20 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), dapagliflozin, Promotes weight loss, lowers systolic blood pressure Low risk of hypoglycaemia Concerns Limited safety and efficacy data (3 rd line agent only) Side effects of UTI, vaginal yeast infections 11% (due to glycosuria), perhaps postural dizziness

21 Other drugs Non-sulfonylurea insulin secretagogues Metiglinides repaglinide 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

22 Inzucci S et al, Diab. Care, Vol 35, June 2012

23 Treatment escalation algorithm for T2DM Healthy eating & exercise Metformin Add sulfonylurea Add basal Insulin Add Incretin mimetic DPP-4 inhibitor or GLP-1 agonist Consider adding Incretin mimetic Acarbose TZD Intensify insulin therapy Basal-bolus or mixed regimen Continue metformin Consider ceasing other agents Consider bariatric surgery for high risk patients Adapted from Therapeutic Guidelines

24 Use of Antidiabetic Drugs in Special Cases Cardiac Renal Hepatic Patients at risk of hypoglycaemia

25 Coronary ischaemia Metformin probably beneficial for CVD outcomes Any drug: Avoid hypoglycaemia exacerbates ischaemia and may cause arrhythmias Relevance re adverse effects of sulfonylureas on CHD unproven Piolglitazone may reduce CVD events (don t use if CCF) GLP-1 receptor agonists and DPP-4 inhibitors may improve CVD risk factors AGIs may reduce CVD events

26 Cardiac failure Avoid thiazolidinediones Avoid metformin in severe heart failure

27 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.

28 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

29 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

30 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 angioedema with ACE inhibitors Exenatide decreases OCP concentration and enhances warfarin effect

31 Holstein, A et al Expert Opin. Drug Metab. Toxicol. (2012) 8(12):

32 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 (β-cell preservation) Role of pharmacogenetics

33 Other potential targets! Ranolazine Na channels in β-cells Inhibits fatty acid oxidation Selective PPARγ modulators SGLT-1 inhibitors Fructose 1,6 bisphosphatase inhibitors Glucokinase activators 11β hydroxysteroid dehydrogenase inhibitors Protein tyrosine phosphatase 1B inhibitors Acetyl-CoA carboxylase-1 and -2 inhibitors Glucagon receptor antagonists

34 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 2013

35 The End