Oral Agents in Type 2 Diabetes Mellitus

Transcription

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2 Oral Agents in Type 2 Diabetes Mellitus Seyed Adel Jahed, M.D., Endocrinologist Gabric Diabetes Education Association 11 th November 2017 Tehran, Iran

3 Disclosures Seyed Adel Jahed has received honoraria for lectures or as consultant taking part in advisory board meetings from: Sanofi Novo Nordisk Pars Merck Abidi Eli Lilly AstraZeneca

4 Agenda Introduction Metformin Sulfonylureas Thiazolidinediones DPP-4 Inhibitors SGLT-2 Inhibitors Conclusion

5 Agenda Metformin Sulfonylureas Thiazolidinediones DPP-4 Inhibitors SGLT-2 Inhibitors Conclusion Introduction

6 What Do We Have for Treatment of T 2 DM?

7 Therapeutic Options in Diabetes Lifestyle interventions Oral agents and non-insulin injectable drugs Insulin

8 Sixty years of HTN and T 2 DM medications in USA

9 Treatment of Diabetes No medication 14 % OADs only 57% Insulin only 14% Insulin + OADs 15% National Diabetes Information Clearinghouse. National Diabetes Statistics, Available at:

10 2017 ADA Standards of Medical Care in Diabetes: Approaches to glycemic treatment American Diabetes Association Standards of Medical Care in Diabetes. Approaches to glycemic treatment. Diabetes Care 2017; 40 (Suppl. 1): S64-S74

11 Agenda Introduction Sulfonylureas Thiazolidinediones DPP-4 Inhibitors SGLT-2 Inhibitors Conclusion Metformin

12 Herbal Medicine 1772 Genus X Goats Rue Galega 1. Officinal Goats Rue Sir John Hill Goat s Rue Aerial parts are used to treat 2. Grey Goats Rue plague, snake bites and worms and symptoms such as thirst and frequent urination 3. Sea-Side Goats Rue 3. Sea-Side Goats Rue

13 = = Botanical Heritage of Metformin Galegine Burger & White (1922) NH NH2 C NH CH2 = CH - C CH 3 CH 3 Too Toxic Galega Officinalis NH C N Metformin Elliott P. Joslin, 1927: Galegine is the forerunner of better preparations which can be given by mouth and which to some degree will replace insulin

14 J Sterne Hopital Laennac, Paris

15 Target organs and action mechanism of anti-diabetic drugs Zhou K, et al. doi: /nrendo

16 Before GLUT 4 Transporters After

17 % Decrease Basal HGP % Increase Glucose Disposal Metformin Effect on Hepatic Glucose Production and Insulin-Stimulated Glucose Disposal Controlled studies in T 2 DM: metformin 1000mg/d for 3 wks Basal hepatic glucose production Insulin-stimulated glucose disposal* % Increase % Reduction 0 Hyperinsulinaemic clamp studies. Each bar represents results of one study. Total of 22 different studies conducted Bailey & Turner, NEJM 1996; Cusi & DeFronzo, Diabetes Rev 1998

18 Metformin Kinetics Structure CH 3 NH NH N C NH C NH 2.HCI CH 3 Bioavailability 50 60%; upper GI absorption Plasma conc. Plasma t 1/2 Metabolism Elimination max 2 ug/ml (10-5 M) peak 1 2h h not metabolized urine; ~90% in 12 h secreted by renal tubules

19 Net Change from Placebo Net Change from Placebo Metformin Dose and Glycaemic Response 0 Fasting Glycaemia 0 HbA 1C * -2 ** -3 *** -4 *** (mmol/l) (%) mg *** 1000mg 1500mg 2000mg 2500mg Metformin Dose *** *** *** *** *** 500mg 1000mg 1500mg 2000mg 2500mg Metformin Dose * p<0.05; ** p<0.01; *** p<0.001 vs. placebo Garber AJ. Am J Med 1997; 102:491 7

20 Oxford UKPDS n=5102 UKPDS Post Trial Monitoring Follow up Maximum 30 years, Median 17.7 years Overweight group

21 UKPDS: Questions to be answered Does good glycemic control reduce morbidity and mortality in T 2 DM? UKPDS 33. Lancet 1998; 352: Is there an optimal therapy to improve clinical outcome? Diet Insulin Sulfonylureas Metformin Does good blood pressure control reduce morbidity and mortality and are ACEIs preferred to β-blockers? UKPDS 38. BMJ 1998; 317: Do any therapies have health care advantages in terms of cost benefit or quality of life? UKPDS 37. Diabetes Care 1999; 22:

22 Proportion of Patients with Events UKPDS: Global Clinical Outcomes in Overweight Patients 60 Any diabetes-related endpoint 21 fatal/non-fatal complications Conventional Diet Insulin or Sulfonylureas Met vs. Diet p= Metformin Met vs. SUs or Insulin p= Average Dose 2000 mg/day Vascular Protection After Chronic Exposure Time from Randomization (years) UKPDS Group. Lancet 1998; 352:

23 UKPDS: Clinical Outcomes* for Metformin Heart Attack Stroke Diabetes Deaths 39% Reduction * vs. conventional therapy 41% Reduction UKPDS 34. Lancet 1998; 352: % Reduction

24 UKPDS: Lives Saved with Metformin Deaths per 1000 patient-years Diet SUs/Insulin Metformin Treat 1000 patients for 1 year with Metformin in addition to diet there will be 5 fewer deaths. Treat 1000 patients for 1 year with Metformin in place of SUs or Insulin there will be 3 fewer deaths. UKPDS Group. Lancet 1998; 352:

25 SU/Insulin Clinic Questionnaire 1010 SU/Insulin 880 Lifestyle Clinic Questionnaire 379 Lifestyle 279 Metformin Clinic Questionnaire 136 Metformin Holman RR et al. NEJM 2008; 359:

26 Lessons from UKPDS: Legacy Effect of Earlier Metformin Therapy UKPDS Trial Intervention Diabetes-related deaths -42% -30% POST-Trial Monitoring All Cause Mortality -36% -27% CV Complications reduced and survival increased vs. other therapies Myocardial Infarction -39% -33% CV complications reduction and survival increase maintained UKPDS 34. Lancet 1998; 352: UKPDS 80. NEJM 2008; 359:

27 Treatment Recommendations From 2009, Metformin is a Foundation Therapy for T2DM Metformin NICE Asian Pacific EASD IDF 2005 UK National Clinical Guidelines for T2DM Rev 2005 IDF Clinical Guidelines Task Force. Diabet Med 2006; 23: ADA/EASD Position Statement. Diabetologia 2006; 49: Asian Pacific Type 2 Diabetes Practical Targets & Treatment. 4th Ed

28 Side Effects Gastrointestinal: metallic taste in the mouth mild anorexia nausea abdominal discomfort, soft bowel movements or diarrhea 5% of study subjects discontinue metformin because of the gastrointestinal side effects.

29 Vitamin B12 deficiency Reduces intestinal absorption of vitamin B 12 in up to 30 % of patients. Lowers serum vitamin B 12 concentrations in 5-10 %. Only rarely causes megaloblastic anemia. Peripheral neuropathy may precede the development of megaloblastic anemia.

30 Metformin contraindications, warnings, precautions Contraindications: Hypersensitivity to metformin or any component of the formulation Any potentially hypoxemic conditions: shock state acute MI renal disease with GFR< 30 ml/min decompensated heart failure respiratory failure liver failure (synthetic failure) septicemia acute or chronic metabolic acidosis with or without coma Warnings, precautions: Iodinated contrast: temporarily withdraw for 3 days after contrast medium containing iodine has been given, and start it again only after renal function has been checked. Surgical procedures: therapy should be suspended 2 days before general anaesthesia for any surgical procedures (resume only after normal oral intake resumed and normal renal function is verified). Elderly: GFR should be calculated. Do not start Metformin if 30 < GFR < 50 ml/min. Ethanol use: instruct patients to avoid excessive acute or chronic ethanol use; it may potentiate metformin's effect on lactate metabolism.

31 CKD-EPI Creatinine Equation vs. MDRD method

32 Agenda Introduction Metformin Thiazolidinediones DPP-4 Inhibitors SGLT-2 Inhibitors Conclusion Sulfonylureas

33 Target organs and action mechanism of anti-diabetic drugs Zhou K, et al. doi: /nrendo

34 Mechanism of Action SUR1 K ATP channels contain two high affinity binding sites, one accept sulfonyl moiety and one that accept benzamide moiety. Gliclazide selectively binds to sulfonylurea receptors (SUR-1) on the surface of the pancreatic β-cells. It was shown to provide cardiovascular protection as it does not bind to SUR-2A in the heart. Diabetologia.2001; 44(8):

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37 IF: 13.6 The objective of the present study was to evaluate the safety of the sulfonylureas most frequently used and to use trial sequential analysis (TSA) to analyze whether the available sample was powered enough to support the results. Rados DV, et al. PLOS Medicine 2016;13(4): e

38 Forest plots for all-cause mortality of sulfonylureas according to comparator (placebo/diet or active comparators) Rados DV, et al. PLOS Medicine 2016;13(4): e

39 Forest plots for cardiovascular mortality of sulfonylureas according to comparator (placebo/diet or active comparators) Rados DV, et al. PLOS Medicine 2016;13(4): e

40 Forest plots for all-cause and cardiovascular mortality of Sulfonylureas as an add-on to metformin Rados DV, et al. PLOS Medicine 2016;13(4): e

41 Which SU should be used? A question arises Individual SUs express a different selectivity for pancreatic and myocardial SURs. Gliclazide seems the most selective with respect Any differences to pancreatic receptor between (SUR-1) stimulation, not binding to SUR-2A in the heart. specific SUs regarding efficacy, safety & heart effect?

42 Gliclazide vs. other Insulinotropic Agents Chan S P., Colagiuri S. Diabetes Res Clin Pract 2015;110:

43 Gliclazide vs. other Sulfonylureas HbA1c Chan S P., Colagiuri S. Diabetes Res Clin Pract 2015;110:

44 Gliclazide vs. other Sulfonylureas Hypoglycemia Chan S P., Colagiuri S. Diabetes Res Clin Pract 2015;110:

45 Lancet Diabetes Endocrinol 2015; 3:43-51.

46 Mortality Risk Among Sulfonylureas: a systematic review and network meta-analysis All-cause mortality Cardiovascular-related mortality Lancet Diabetes Endocrinol 2015; 3:43-51.

47 SUs final message! In comparison to the other SUs, Gliclazide seems to have: less hypoglycemia at least, similar efficacy Probably, better cardiovascular outcome Gliclazide MR may increase adherence and facilitate clinical use of Gliclazide. After metformin, If you decide to use a sulfonylurea as the 2 nd drug in treating T 2 DM, Gliclazide should be logically the choice.

48 Agenda Introduction Metformin Sulfonylureas DPP-4 Inhibitors SGLT-2 Inhibitors Conclusion Thiazolidinediones

49 Target organs and action mechanism of anti-diabetic drugs Zhou K, et al. doi: /nrendo

50 TZDs: Pros & Cons Positive points: Efficacy No hypoglycemia Once daily dose Use in renal CKD Targeting insulin resistance Negative points: Edema & weight gain Heart failure Fracture Bladder CA Ischemia (Rosi) Positive effect on NAFLD

51 Clinical Use of TZDs A TZD may be considered in patients with lower initial HbA 1C values or if there are specific contraindications to other OADs. If a thiazolidinedione is to be used as initial therapy, Piogitazone is preferred. The TZDs have also been studied in combination with metformin, SUs, and insulin. It is not recommended to use TZDs with a goal of prevention, even in patients felt to be at high risk of developing diabetes.

52 Agenda Introduction Metformin Sulfonylureas Thiazolidinediones SGLT-2 Inhibitors Conclusion DPP-4 Inhibitors

53 Target organs and action mechanism of anti-diabetic drugs Zhou K, et al. doi: /nrendo

54 Plasma glucose (mmol/l) Insulin (mu/l) Role of incretin effect in healthy insulin response 15 Plasma glucose 80 Insulin response Incretin effect Time (min) Oral glucose load (50 g) Time (min) IV glucose infusion Insulin response is greater following oral glucose than IV glucose, despite similar plasma glucose concentration IV, intravenous Nauck M et al. Diabetologia 1986;29:46 52

55 Insulin (mu/l) Insulin (mu/l) The incretin effect is diminished in T 2 DM 80 Healthy controls 80 Type 2 diabetes * * Incretin effect * * * * * * * * Time (min) Oral glucose Time (min) IV glucose *p<0.05, healthy volunteers (n=8) Nauck M et al. Diabetologia 1986;29:46 52

56 Incretines

57 Native GLP-1 is rapidly degraded by DPP-4 Adapted from Hansen et al. Endocrinology 1999;140:

58 How to overcome DDP-4 effect? Find a substance to inhibit the effect: DPP-4 Inhibitors OR Use a substance resistant to the effect: GLP-1 Receptor Agonists

59 Mechanism of action of GLP-1RAs and DPP-4 inhibitors Gut GLP-1RAs work like natural GLP-1 and are DPP-4-resistant The enzyme DPP-4 breaks down GLP-1 Food DPP-4 Food-activated GLP-1 response Beta cell GLP-1R DPP-4 inhibitors act to block the DPP-4 enzyme Glucose-dependent insulin secretion

60 What are the currently available DPP-4 Inhibitors on the market? Sitagliptin Saxagliptin Vildagliptin Linagliptin Alogliptin Dosage 100 mg qd 5 mg qd 50 mg bid 5 mg qd 25 mg qd Approximate half-life 12 hours 2 hours 3 hours >120 hours 21 hours Elimination Renal clearance (75%) Hepatic metabolism to active metabolite (half:renal excretion (12%- 29% unchanged parent and 21%- 52% as metabolite) Hepatic metabolism to active metabolite Renal :half excretion (12%- 29% unchanged parent and 21%- 52% as metabolite) Entero-hepatic Eliminated unchanged in feces via biliary excretion (85%) Renal clearance (63%) Effect on weight Neutral Neutral Neutral Neutral Neutral Adverse events Low Low Low Low Low

61 Sitagliptin: Practical Clinical Points Well tolerated Once daily use No weight gain No risk of hypoglycemia No cardiovascular concern No increase risk of facture No risk of pancreatic cancer Cautious in patient with history of pancreatitis May be added to all diabetes medications except for GLP-1 RAs & prandial insulins Simple renal dose adjustment GFR (ml/m): mg 50 mg 100 mg

62 LSM A1C Change From Baseline, % DPP-4 Efficacy Sitagliptin + Metformin Co-administration Week Placebo-Adjusted Results Mean A1C = 8.8% Open label Mean A1C = 11.2% 0.0 n=175 n=178 n=177 n=183 n=178 n= Sitagliptin 100 mg qd a 1.0 a Metformin 500 mg bid a 1.6 a Metformin 1,000 mg bid a Sitagliptin 50 mg + metformin 500 mg bid Sitagliptin 50 mg + metformin 1,000 mg bid b 3.5 Goldstein BJ, et al. Diabetes Care 2007; 30: All patients Treated Population a LSM placebo adjusted change b LSM change from baseline without adjustment for placebo. bid=twice a day; qd=once a day.

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64 Changes in HbA 1c metformin + sitagliptin vs. metformin + sulfonylurea

65 Achievements of HbA 1c <7% metformin + sitagliptin vs. metformin + sulfonylurea

66 Changes in body weight metformin + sitagliptin vs. metformin + sulfonylurea

67 Hypoglycemic events metformin + sitagliptin vs. metformin + sulfonylurea

68 Agenda Introduction Metformin Sulfonylureas Thiazolidinediones DPP-4 Inhibitors Conclusion SGLT-2 Inhibitors

69 Target organs and action mechanism of anti-diabetic drugs Zhou K, et al. doi: /nrendo

70 Renal glucose re-absorption in healthy individuals Filtered glucose load 180 g/day SGLT2 ~ 90% SGLT1 ~ 10% Gerich JE. Diabet Med. 2010;27:

71 Renal glucose re-absorption in patients with hyperglycaemia Filtered glucose load SGLT2 ~ 90% SGLT1 ~ 10% When blood glucose increases above the renal threshold (~ 180 mg/dl), the capacity of the transporters is exceeded, resulting in urinary glucose excretion Gerich JE. Diabet Med. 2010;27:

72 Urinary glucose excretion via SGLT2 inhibition Filtered glucose load > 180 g/day SGLT2 inhibitor SGLT1 SGLT2 inhibitors reduce glucose re-absorption in the proximal tubule, leading to urinary glucose excretion* and osmotic diuresis *Loss of ~ 80 g of glucose/day (~ 240 cal/day) Gerich JE. Diabet Med. 2010;27:

73 Phlorizin (1933): extracted from bark of apple trees

74 Current FDA approved SGLT 2 inhibitors Canagliflozin (Invokana, 100 & 300 mg) Dapagliflozin (Forxiga, 5 & 10 mg) Empagliflozin (Jardiance, 10 & 25 mg) All may be used as once daily tablets in the morning.

75 SGLT 2 i therapy: Clinical benefits

76 Points in using SGLT 2 inhibitors Pros Action is independent of insulin Easy to use, once daily in morning Efficacious as dual and triple therapy and combination with insulin Lack of hypoglycemia Weight reduction SBP reduction Reduction of CVD mortality Reduction of all cause mortality Slowing progression of nephropathy Cons Modest improvement in glycemia Lower efficacy with decreasing egfr Increased genital mycotic infection DKA Mild LDL elevation Mild volume depletion Bone loss (Canagloflolizin) Bladder Cancer (Dapagloflolizine) Limb Amputation (Canagloflolizin)

77 Agenda Introduction Metformin Sulfonylureas Thiazolidinediones DPP-4 Inhibitors SGLT-2 Inhibitors Conclusion

78 Metformin SU TZD DPP4I SGLT2i Weight Slight loss Gain Gain Neutral Loss Hypoglycemia Neutral mod to severe Neutral Neutral Neutral FPG lowering Mod mod Mod Mild Mild to moderate PPG lowering Mild Mod Mild Mod Mild to moderate Renal impairment/ GU Contraindicated in stage 4, 5 CKD Increased hypoglycemia risk May worsen fluid retention Dose adjust-ment (except linagliptin) Contraindicated from stage 3B CKD GI adverse effects Mod Neutral Neutral Neutral* Neutral CHF Neutral Neutral Mod Neutral Beneficial CVD Possible benefit? Neutral Neutral Beneficial Bone Neutral Neutral Mod bone loss Neutral? NAFLD benefit Mild Neutral Mod Neutral?

79 What to take home? In the era of growing number of diabetes medications and new data, we should consider the below factors to select the proper component for each individual patient: Effectiveness Safety profiles Side effects Extra-glycemic effects Cardiovascular effects Our experience in handling Availability Patient preference Cost Up to this time, considering the above factors among all anti-hyperglycemic medications, no other agent has more favorable properties than Metformin. As indicated in all diabetes guidelines, Metformin should be placed in the top of the therapeutic list. In a logic way, any other OADs should be started only after full dosage of Metformin has been used.

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