Overview of the Novel Diabetes Therapies in Patients of T2DM 大林慈濟醫院新陳代謝科 / 營養治療科 陳霆昌醫師

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1 Overview of the Novel Diabetes Therapies in Patients of T2DM 大林慈濟醫院新陳代謝科 / 營養治療科 陳霆昌醫師

2 Classification and Diagnosis of Diabetes

3 Criteria for the Diagnosis of Diabetes

4 Categories of increased risk for Diabetes (Prediabetes)

5 Correlation of A1C with average glucose Diabetes Care Vol. 37, Supplement 1, January 2014

6 Pharmacological Therapy for Hyperglycemia in Type 2 Diabetes

7 Diabetes Care 2016;39(Suppl. 1):S52 S59 PROPERTIES OF AVAILABLE GLUCOSE-LOWERING AGENTS

8 Pathogenic picture of type 2 diabetes- Ominous Octet DeFronzo RA. Diabetes. 2009;58:

9 Class: Biguanides Compound: Metformin Cellular mechanism: Activates AMP-kinase (? other) Primary physiological action: Hepatic glucose production Advantages: Extensive experience; No hypoglycemia; CVD events (UKPDS) Disadvantages: Gastrointestinal side effects (diarrhea, abdominal cramping); Vitamin B12 deficiency Contraindications: CKD, acidosis, hypoxia, dehydration, etc. Lactic acidosis risk (rare)

10 Class: Sulfonylureas Compound: 2nd Generation Glyburide/glibenclamide, Glipizide, Gliclazide, Glimepiride Cellular mechanism: Closes K ATP channels on β- cell plasma membranes Primary physiological action: Insulin secretion Advantages: Extensive experience ; Microvascular risk (UKPDS) Disadvantages: Hypoglycemia; Weight

11 Class: Meglitinides (glinides) Compound: Repaglinide, Nateglinide Cellular mechanism: Closes K ATP channels on β-cell plasma membranes Primary physiological action: Insulin secretion Advantages: Postprandial glucose excursions Dosing flexibility Disadvantages: Hypoglycemia; Weight; Frequent dosing schedule

12 Class: TZDs Compound: Pioglitazone, Rosiglitazone Cellular mechanism: Activates the nuclear transcription factor PPAR-γ Primary physiological action: Insulin sensitivity Advantages: No hypoglycemia; Durability; HDL-C Triglycerides (pioglitazone) ; CVD events (PROactive,pioglitazone) Disadvantages: Weight; Edema/heart failure; Bone fractures; LDL- C (rosiglitazone);? MI (meta-analyses, rosiglitazone)

13 Class:α-Glucosidase inhibitors Compound: Acarbose, Miglitol Cellular mechanism: Inhibits intestinal α- glucosidase Primary physiological action: Slows intestinal carbohydrate digestion/absorption Advantages:? CVD events (STOPNIDDM); Postprandial glucose excursions; No hypoglycemia; Nonsystemic Disadvantages: Generally modest A1C efficacy; Gastrointestinal side effects (flatulence, diarrhea); Frequent dosing schedule

14 Class: DPP-4 inhibitors Compound: sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin Cellular mechanism: Inhibits DPP-4 activity, increasing postprandial active incretin (GLP-1, GIP) concentrations Primary physiological action: Insulin secretion (glucose dependent) Glucagon secretion (glucose dependent) Advantages: No hypoglycemia; Well tolerated Disadvantages: Angioedema/urticaria and other immune-mediated dermatological effects? Acute pancreatitis? Heart failure hospitalizations

15 Class: SGLT2 inhibitors Compound: Canagliflozin, Dapagliflozin, Empagliflozin Cellular mechanism: Inhibits SGLT2 in the proximal nephron Primary physiological action: Blocks glucose reabsorption by the kidney, increasing glucosuria Advantages: No hypoglycemia; Weight; Blood pressure; Effective at all stages of type 2 diabetes Associated with lower CVD event rate and mortality in patients with CVD (EMPA-REG OUTCOME) Disadvantages: Genitourinary infections; Polyuria; Volume depletion /hypotension/ dizziness; LDL-C; Creatinine (transient) DKA, urinary tract infections leading to urosepsis, pyelonephritis

16 Class: GLP-1 receptor agonists Compound: Exenatide, Exenatide extended release, Liraglutide, Albiglutide, Lixisenatide, Dulaglutide Cellular mechanism: Activates GLP-1 receptors Primary physiological action: Insulin secretion, Glucagon secretion (glucose dependent) Slows gastric emptying; Satiety Advantages: No hypoglycemia; Weight; Postprandial glucose excursions; Some cardiovascular risk factors Disadvantages: Gastrointestinal side effects(nausea/vomiting/diarrhea); Heart rate;? Acute pancreatitis; C-cell hyperplasia/medullary thyroid tumors in animals; Injectable; Training requirements

17 Class: Insulin

18 第 2 型糖尿病人高血糖的處理流程圖 糖尿病學會 2015

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20 NOVEL DIABETES THERAPIES IN REVIEW -- FOCUS ON DPP-4 INHIBITORS, GLP-1 RECEPTOR AGONISTS, AND SGLT2 INHIBITORS

21 DPP-4 INHIBITORS IN THE MANAGEMENT OF TYPE 2 DIABETES MELLITUS

22 Incretins In 1900s, the concept of incretins emerged--- Certain factors 1. produced by the intestinal mucosa in response to nutrient ingestion 2. stimulate the release of substances from the endocrine pancreas 3. reduce blood glucose levels The term incretin subsequently was used to denote these glucose-lowering, intestinalderived factors. To date, only GIP and GLP-1 fulfill the definition of an incretin hormone in humans.

23 Incretins: Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) Released from the GI tract after a meal This incretin effect: approximately 60% of the insulin secreted after a meal in a healthy person. The incretin effect in a patient with T2DM is markedly reduced: < 20% of the postprandial insulin response. GLP-1 and GIP have a half-life of approximately 2 minutes--- metabolized rapidly by the serine protease enzyme dipeptidyl peptidase-4 (DPP-4). DPP-4 inhibitors are highly selective, competitive, and potent inhibitors of the DPP-4 enzyme and have been shown to increase GLP-1 concentrations by approximately 4-fold.

24 Incretin effect 增加胰島素分泌 (50% 70% of the total insulin) DM 患者 Incretin 的作用 diminished, but preserved

25 pmol/l pmol/l mmol/l Intravenous GLP-1 infusion in T2DM patients Glucose Insulin * * * * * * * * * Glucose-dependent * * * * * * mg/dl mu/l Placebo GLP-1 *P<0.05 Patients with type 2 diabetes (N=10) When glucose levels approach normal values, insulin levels decrease. Glucagon * * * * GLP-1 Infusion Minutes Adapted from Nauck MA et al. Diabetologia. 1993;36: Copyright 1993 Springer-Verlag pmol/l When glucose levels approach normal values, glucagon levels rebound.

26 DPP-4 inhibitors Dipeptidylpeptidase-4 inhibitors enhances GLP-1 levels through inhibition of DPP-4 GLP-1 t ½ =1 2 min inactive

27 Currently Available DPP-4 Inhibitors Approved by the EMA and US FDA for Use in Patients With T2DM

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29 What Reductions in A1C Should We See With DPP-4 Inhibitors? In general, a DPP-4 inhibitor is likely to provide a 0.4%-0.5% decrease in A1C. When used in combination with other antidiabetic compounds, the fall in A1C is variable eg, with sitagliptin + metformin, A1C reduction: 0.65%-1.1% from baseline 7.2%-8.7%.

30 Are There Any Body Weight, Blood Pressure, or Lipid Benefits With DPP-4 Inhibitors? Neutral effect on body weight The effects of DPP-4 inhibitors on lipid profiles and blood pressure are inconsistent

31 Is Hypoglycemia Commonly Seen With DPP-4 Inhibitors? DPP-4 inhibitors have an antihyperglycemic effect only when glucose levels are raised. Thus, the incidence of hypoglycemia with this class of drugs is very low! The effect of GLP-1 on glucagon is glucose-dependent. The counterregulatory response to hypoglycemia-- raising glucagon to counteract low blood glucose levels--are not affected.

32 Results of CV Safety Trials With DPP-4 Inhibitors Three large CV safety trials have recently reported on 3 different DPP-4 inhibitors: saxagliptin (SAVOR-TIMI 53); alogliptin (EXAMINE) and sitagliptin (TECOS). These major studies suggest that DPP-4 inhibitors do not increase the risk for CV events, but neither do they provide cardioprotective benefit.

33 For patients with renal impairment

34 Summary of Properties of DPP4 Inhibitors

35 GLP-1 RECEPTOR AGONISTS IN THE MANAGEMENT OF TYPE 2 DIABETES MELLITUS

36 GLP-1 RAs: How Do They Work? Human GLP-1 has a short half-life and is broken down rapidly by DPP-4. GLP-1 receptor agonists (GLP-1 RAs) are resistant to proteolysis by DPP-4. GLP-1 RAs stimulate GLP-1 receptors at pharmacologic doses increasing insulin & decreasing glucagon release inhibit gastric emptying & decrease appetite (ie, increase satiety) beneficial effects on glycemic control and additional benefits on body weight, blood pressure, cholesterol levels, and betacell function.

37 Increasing plasma GLP-1 concentrations Additional physiological benefits are observed at pharmacological levels of GLP-1 Pharmacological GLP-1 levels Appetite Food intake = Weight loss 2 GLP-1RAs Gastric emptying Insulin Glucagon = Plasma glucose 2 Physiological GLP-1 levels DPP-4is GLP-1 effects DPP-4is, dipeptidyl peptidase-4 inhibitors; GLP-1, glucagon-like peptide-1; GLP-1RAs, glucagon-like peptide-1 receptor agonists Adapted from Holst et al 1 1. Holst JJ et al. Trends Mol Med 2008;14: ; 2. Flint A et al. Adv Ther 2011;28:

38 Exenatide Exendin-Based GLP-1 The first GLP-1 RA (exenatide twice daily) Approved in Europe in 是從美洲毒蜥蜴 Gila monster 的唾液中分離出來的物質 (Exendin-4) 53% identical to native human GLP-1

39 Liraglutide :Human GLP-1 類似物 7 9 Liraglutide His Ala Glu Gly Thr Phe Thr Ser 97% 胺基酸序列與人類 GLP-1 同源 通過醯基化與白蛋白結合七聚體自我聚合 Asp Val C-16 脂肪酸 ( 棕櫚醯 ) Glu Ser Lys Ala Ala Gln Gly Glu Leu Tyr Ser Glu Phe 36 Ile Ala Trp Leu Val Arg Gly Arg Gly 被 DPP-4 降解 7 天然人類 GLP-1 9 His Ala Glu Gly Thr Phe Thr Ser Asp Val Lys Glu Ala Ala Gln Gly Glu Leu Tyr Ser Phe 36 Ile Ala Trp Leu Val Lys Gly Arg Gly 半衰期 = 分鐘 Ser 從皮下組織緩慢吸收 不易被 DPP-4 降解 血漿半衰期長達 13 小時 DPP-4: 二肽基酶 -4 Knudsen et al. J Med Chem 2000;43:1664 9; Degn et al. Diabetes 2004;53:

40 What Reductions in HbA1c Should We See With GLP-1 RAs? GLP-1 RAs produce superior glycemic control compared with orally available diabetes medications (eg, DPP-4 inhibitors and--in most studies--sulfonylureas. In head-to-head clinical trials, liraglutide and dulaglutide caused the greatest and equivalent reductions in HbA1c levels.

41 Benefits Beyond Glycemic Control With GLP-1 RAs GLP-1 RAs cause a decrease in body weight of approximately 3 kg GLP-1 RAs have positive effects on blood pressure and lipid parameters.

42 Safety and Adverse Effects of GLP-1 RAs GLP-1 RAs have a low risk for hypoglycemia GLP-1 RAs most frequently cause AEs of nausea, vomiting, and diarrhea These GI side effects tend to be transient and generally mild to moderate in severity Pancreatitis is a rare event and has been reported with the use of GLP-1 Ras they should be discontinued if pancreatitis is suspected and used cautiously in patients with a history of pancreatitis

43 Results of CV Safety Trial With GLP-1 RA Results from the first cardiovascular outcomes trial with a GLP-1 RA, lixisenatide Neutral. Not increase cardiovascular risk or provide cardiovascular benefit. Victoza(Liraglutide) Significantly Reduced the Risk of Major Adverse Cardiovascular Events in the LEADER Trial (Mar 04, 2016) The detailed results are planned to be presented at the 76 th Scientific Sessions of the American Diabetes Association in June 2016.

44 SGLT2 INHIBITORS IN THE MANAGEMENT OF TYPE 2 DIABETES MELLITUS

45 SGLT2 Inhibitors: How Do They Work? SGLT2 inhibitors have an insulin-independent mechanism of action. SGLT2 inhibitors increase urine glucose excretion and produce osmotic diuresis. Therapeutic SGLT2 inhibition has shown reductions in blood glucose, A1C, body weight, and blood pressure.

46 Sodium- Glucose Cotransporters Site SGLT1 Mostly intestine Some kidney SGLT2 Sugar Specificity Glucose or galactose Glucose Affinity for glucose Capacity for glucose transport Role High Km= 0.4 Mm Low Dietary glucose absorption Renal glucose reabsorption Almost exclusively kidney Low Km = 2 Mm High Renal glucose reabsorption Lee YJ, at al. Kidney Int Suppl. 2007;72:S27-S35.

47 The Kidneys Play an Important Role in Glucose Control Normal Renal Glucose Physiology 180 g of glucose is filtered each day Virtually all glucose reabsorbed in the proximal tubules & reenters the circulation SGLT2 reabsorbs about 90% of the glucose SGLT1 reabsorbs about 10% of the glucose Virtually no glucose excreted in urine Mather, A & Pollock, C. Kidney International. 2011;79:S1-S6.

48 Targeting the Kidney Chao EC, et al. Nat Rev Drug Discovery. 2010;9:

49 Renal Glucose Transport Chao, EC & Henry RR. Nature Reviews Drug Discovery. 2010;9:

50 Altered Renal Glucose Control in Diabetes That s Why Renal Glucose be targeted! Gluconeogenesis is increased > 2X in postprandial relative to the postabsorptive states in T2DM patients Renal contribution to hyperglycemia 3-fold increase relative to patients without diabetes Glucose reabsorption Increased SGLT-2 expression and activity in renal epithelial cells from patients with diabetes vs. normoglycemic individuals Marsenic O. Am J Kidney Dis. 2009;53: Bakris GL, et al. Kidney Int. 2009;75(12): Rahmoune H, et al. Diabetes. 2005;54(12):

51 Reductions in HbA1c With SGLT2 Inhibitors Mean Change From Baseline With SGLT2 and DPP-4 Inhibitors Stratified by Baseline HbA1c Levels: Patients With T2DM Had Mean egfr of 94 ml/min/1.73 m 2

52 Body Weight, Blood Pressure, or Lipid Benefits With SGLT2 Inhibitors Osmotic diuresis causes fluid loss and volume depletion and a short-term weight loss but does not contribute to weight loss over the long term, which is related to a loss of calories linked to glycosuria. SGLT2 inhibitors increase fat oxidation and decrease waist size loss of body fat BW loss: 2-3 kg --- reaches a maximum after a few months, maintained over the long-term a fall in SBP ( 3-4 mm Hg), DBP (2 mm Hg) (without HR increase) HDL -C, TG, LDL-C, little or no change in HDL- C/LDL-C ratio (Mechanisms unknown)

53 Safety and Adverse Effects With SGLT2 Inhibitors? SGLT2 inhibitors have a low rate of hypoglycemic events AEs: Genital infections (10-15% in women, 1-4% in men), Repeated UTI Polyuria and volume depletion postural dizziness, hypotension, dehydration, fainting Transient decrease in egfr of 3%-10% A signal for an increase in risk for bladder, prostate, and breast cancer in the dapagliflozin clinical trials (no evidence for carcinogenic or genotoxic activity in preclinical studies)

54 Safety and Adverse Effects With SGLT2 Inhibitors? Diabetic ketoacidosis, rare adverse event --- mechanisim may be: Lowering the insulin dose to reduce the risk for hypoglycemia in insulin-treated patients can contribute to ketoacidosis, as there is insufficient insulin to suppress lipolysis and ketogenesis SGLT2 inhibitors cause glucagon secretion, which can stimulate ketogenesis SGLT2 inhibitors may decrease renal clearance of ketone bodies, increasing plasma ketone body levels Other contributing factors could be major illness and/or reduced food and fluid intake

55 Results of CV Safety Trials With SGLT2i --- EMPA-REG OUTCOME trial A 14% reduction in the primary endpoint The primary outcome was: death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (3-point major adverse cardiac event [MACE]) A 35% reduction in heart failure hospitalization

56 Results of CV Safety Trials With SGLTi : 38% reduction in CV death, 32% reduction in all-cause mortality In a patient population with established cardiovascular disease, empagliflozin reduced the risk for death from CV and all-cause mortality, and the benefit appeared early in the first few months of the trial and continued to grow until study end

57 Sulfonylureas (and insulin) SUMMARY Metformin Thiazolidinediones SGLT2 inhibitors GLP-I analogs & DPP IV inhibitors

58 健保 藥品給付規定 修正規定 糖尿病用藥 Drugs used in diabetes

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