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Educational Approaches to the Use of Non-Insulin Anti-Diabetes Drugs

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Educational approaches to the use of non-insulin anti-diabetes drugs 여의도성모병원 나 영 Contents • History of diabetes medication • Principles of drug treatment • Considerations for drug selection • Characteristics of Medicines • Pharmacology Management History of diabetes medications Discovery of insulin 1921 GLP-1(albiglutide) Biguanides (metformin) Metformin marketed in US 2014 1959 1994 First AGI(acarbose) GLP-1(liraglutide) 1995 2010 Discovery of GIP Discovery of GLP-1 First GLP-1(exenatide) 1973 1985 2005 1915 1940 1955 1970 1980 1990 2000 2010 2015 ▪ DPP-4 inhibitors ▫Sitagliptin -2006 ▫Saxagliptin -2009 Second-generation:SU TZD(troglitazone) Sulfonylureas(glimepride) ▫Linagliptin - 2011 1984 1996 1942 ▫Alogliptin - 2013 SGLT-2 inhibitor(canagliflozin) 2013 Meglitinide(repaglinide) 1997 John R. White, Jr. Diabetes Spectr 2014;27:82-86 약물 치료의 원칙 ▪ 당뇨병성 합병증을 예방하기 위해 철저하게 혈당을 조절해야 한다. (A) ▪ 혈당 조절 목표 : HbA1c 6.5%이하이다. (A) ▪ 당뇨병 진단 초기부터 적극적인 생활습관 개선 및 적절한 약물치료가 필요하다. (A) ▪ 경구약제 단독요법 시 초치료로 메트폴민을 우선적으로 고려하나, 환자 상태에 따라 적절한 약제를 선택한다. (A) ▪ 약제의 작용기전과 효능,부작용,비용 및 환자의 특성과 선호도를 고려 하여 적절한 단독 또는 병합요법 약제를 선택한다. (E) 대한당뇨병학회, 당뇨병진료지침.2015 약제선택 시 고려사항 환자의 연령 (남은 삶의 여명, 저혈당 위험성) 당화혈색소 정도, 공복 및 식후 고혈당 정도 비만 및 대사증후군 여부 인슐린 분비능 간기능 및 신장기능 이상 여부 경제적 측면 부작용 없이 혈당조절 대한당뇨병학회, 당뇨병진료지침.2015 Hyperglycemia in T2DM pancreatic incretin insulin effect secretion pancreatic glucagon _ secretion gut carbohydrate ? delivery & HYPERGLYCEMIA absorption _ + peripheral hepatic renal glucose glucose glucose uptake production excretion Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011 Anti-hyperglycemic drug GLP-1R agonists pancreatic incretin Glinides S U s insulin effect secretion DPP-4 pancreatic inhibitors glucagon _ secretion gut A G I s carbohydrate ? delivery & HYPERGLYCEMIA absorption Metformin T Z D s _ + SGLT-2 peripheral hepatic inhibitorrenal glucose glucose glucose uptake production excretion Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011 Non-insulin anti-diabetes drugs characteristics Biguanides Sulfonylureas Biguanides(metformin) Meglitinide ▪ Mechanism of action derivatives - ↓hepatic glucose production Alpha-glucosidase ▪ Efficacy inhibitors -↓ HbA1c 1~2% (lowers fasting glucose) Thiazolidinediones -rare hypoglycemia (TZDs) -Weight natural or loss (2~3kg) -↓ CVD event(UKPDS) Dipeptidyl ▪ Advers effect peptidase IV -GI side effect : N/V, diarrhea, abdominal pain (DPP-4) Inhibitors -Vitamin V12 deficiency : anemia, peripheral neuropathy -Lactic acidosis(rare) Glucagonlike ▪ Contraindicated peptide–1 - eGFR<30ml/min (Cr ≥1.4mg/dl women, ≥1.5mg/dl men) (GLP-1) agonists -Discontinue with IV contrast studies Selective sodium- : Hold day of procedure, restart 48hours later glucose transporter- ▪ Cost : Low 2 (SGLT-2) inhibitors Standards of Medical care in diabetes,2017 Oral and Injectable (Non-insulin) Pharmacological Agents for Type 2 Diabetes,2016 Biguanides Sulfonylureas Sulfonylureas Meglitinide ▪ Mechanism of action derivatives - ↑ Insulin secretion Alpha-glucosidase ▪ 2nd generation : Glyburide(Diabeta), Glipizid(Glucotrol), Glimepiride(Amaryl) inhibitors ▪ Efficacy Thiazolidinediones -↓ HbA1c 1~2% (lowers fasting and postprandial glucose) (TZDs) -↓ Microvascular risk(UKPDS) Dipeptidyl ▪ Advers effect peptidase IV -Common: hypoglycemia, weight gain (DPP-4) Inhibitors -Less common : rash,headache, N/V, photosensitivity Glucagonlike ▪ Contraindicated peptide–1 (GLP-1) agonists - Patient with hypoglycemia unawareness(e.g.eldery) - Poor renal function Selective sodium- glucose transporter- ▪ Cost : Low 2 (SGLT-2) inhibitors Oral and Injectable (Non-insulin) Pharmacological Agents for Type 2 Diabetes,2016 Biguanides Meglitinides Sulfonylureas ▪ Mechanism of action Meglitinide - ↑ Insulin secretion :약효가 빠르고 작용시간이 짧다. derivatives ▪ Repaglinide(Novonom) and Nateglinide(Fastic) Alpha-glucosidase inhibitors ▪ Efficacy -↓ HbA1c repaglinide 1% , nateglinide 0.5% Thiazolidinediones (TZDs) -↓ postprandial glucose (short acting: peak30~60min,short half-life 60~90min) -Dosing flexibility Dipeptidyl ▪ Advers effect peptidase IV -Hypoglycemia and weight gain( less than SUs ) (DPP-4) Inhibitors -Increase serum uric acid Glucagonlike -Frequent dosing schedule peptide–1 ▪ Contraindicated (GLP-1) agonists : Patient with hypoglycemia unwareness Selective sodium- : Poor renal function(nateglinide), moderate to severe liver disease glucose transporter- ▪ Cost : Moderate 2 (SGLT-2) inhibitors Oral and Injectable (Non-insulin) Pharmacological Agents for Type 2 Diabetes,2016 Biguanides Alpha-glucosidase inhibitors Sulfonylureas Meglitinide ▪ Mechanism of action derivatives - Slows intestinal carbohydrate digestion/absorption Alpha-glucosidase inhibitors ▪ Acarbose, Boglibos(Basen), Miglitol(Glyset) Thiazolidinediones ▪ Efficacy (TZDs) -↓ HbA1c 0.5~1% , rare hypoglycemia Dipeptidyl -↓ Postprandial glucose peptidase IV ▪ Advers effect (DPP-4) Inhibitors -Common: gas, bloating, abdominal pain Glucagonlike -Freguent dosing schedule peptide–1 (GLP-1) agonists ▪ Precautions Selective sodium- - Short-bowel syndrom, increase liver transaminases(acabose) glucose transporter- ▪ Cost : Low to moderate 2 (SGLT-2) inhibitors Oral and Injectable (Non-insulin) Pharmacological Agents for Type 2 Diabetes,2016 Biguanides Thiazolidinediones (TZDs) Sulfonylureas Meglitinide ▪ Mechanism of action derivatives - ↑ Insulin sensitivity of muscle, fat, and liver tissues Alpha-glucosidase inhibitors ▪ Pioglitazone (Actos),Rosiglitazone(Avandia), Lobeglitazone(Dubia) Thiazolidinediones : Increased risk of MI (rosiglitazone) (TZDs) ▪ Efficacy -↓ HbA1c 1~1.5%, rare hypoglycemia Dipeptidyl -Durable effect (low fasting and postprandial glucose) peptidase IV (DPP-4) Inhibitors -↓Triglycerides, potential decrease in MI (pioglitazone) ▪ Advers effect Glucagonlike -Weight gain (2~3kg) peptide–1 (GLP-1) agonists -Edema/heart failure/Bone fractures -↑LDL-C (rosiglitazone) ,bladder ca (pioglitazone) Selective sodium- ▪ Cost : LOW glucose transporter- 2 (SGLT-2) inhibitors Oral and Injectable (Non-insulin) Pharmacological Agents for Type 2 Diabetes,2016 Biguanides Sulfonylureas DPP-4 Inhibitors: Physiologic Action Meglitinide derivatives Alpha-glucosidase inhibitors Thiazolidinediones (TZDs) Dipeptidyl peptidase IV (DPP-4) Inhibitors Selective sodium- glucose transporter- 2 (SGLT-2) inhibitors Glucagonlike peptide–1 (GLP-1) agonists Biguanides Sulfonylureas DPP-4 Inhibitors Meglitinide ▪ derivatives Mechanism of action - ↑ Insulin secretion,↓glucagon secretion Alpha-glucosidase ▪ inhibitors Sitagliptin(Januvia), Saxagliptin(Onglyza), Liragliptin(Trazenta), Alogiptin(Nesina) Vildagliptin(Galvus), Zemigliptin(Zemiglo) Thiazolidinediones (TZDs) ▪ Efficacy -↓ HbA1c 0.5~0.8% (lowers postprandial glucose) Dipeptidyl -rare hypoglycemia, Well tolerated peptidase IV (DPP-4) Inhibitors ▪ Advers effect Selective sodium- -Angioedema/urticaria/immune-mediated dermatological effect glucose transporter- -? Acute pancreatitis 2 (SGLT-2) inhibitors - ↑ Heart failure hospitalization (saxagliptin, ? Alogliptin) Glucagonlike ▪ Cost : High peptide–1 (GLP-1) agonists Standards of Medical care in diabetes,2017 Biguanides Efficacy of DPP4 inhibitors Sulfonylureas Meglitinide as add-on to Metformin derivatives Alpha-glucosidase inhibitors Thiazolidinediones (TZDs) Dipeptidyl peptidase IV (DPP-4) Inhibitors Selective sodium- glucose transporter- 2 (SGLT-2) inhibitors Glucagonlike peptide–1 (GLP-1) agonists John Gerich, Diabetes Research and Clinical Practice 90 (2010) 131–140 Biguanides Sulfonylureas Comparison between DPP4I Meglitinide derivatives Januvia Galvus Onglyza Trajenta Zemiglo Nesina Alpha-glucosidase 성분명 Sitagliptin Vildagliptin Saxagliptin Linagliptin Zemigliptin Alogliptin inhibitors 국내 2008 2008 2011 2012 2012.12 2014 허가 Thiazolidinediones 배설 신장 신장 신장 담즙과 위장관 간과 신장 신장 (TZDs) 경로 반감기 8-14hrs 2-3hrs 2.5(3.1)hrs 120hrs 17-21hrs 12.5~21.1hrs Dipeptidyl (hr) peptidase IV 판매 MSD 노바티스 BMS 베링거인겔하임 LG 다케다 (DPP-4) Inhibitors 대웅제약 한독 아스트라 릴리/유한양행 Selective sodium- 가격 100mg/924원 453 x 2 5mg / 850원 5mg / 831원 50mg 25mg/759원 (1일) =906원 2.5mg/588원 / 815원 glucose transporter- 2 (SGLT-2) inhibitors 이상 두통 간기능 이상 상부호흡기감염 저혈당 신장애 간기능이상 반응 감염 췌장염 비뇨기 감염 심부전 상기도감염 췌장염 알러지 두통 급성췌장염 췌장염 Glucagonlike 저혈당 어지러움 저혈당 peptide–1 임부 권장안됨 사용안됨 B등급 B등급 사용안됨 B등급 (GLP-1) agonists Biguanides Sulfonylureas GLP-1 agonists Meglitinide derivatives ↑Neuroprotection Alpha-glucosidase ↓Appetite inhibitors Brain Thiazolidinediones (TZDs) Heart Stomach ↓Gastric emptying Dipeptidyl peptidase IV ↑Cardioprotection (DPP-4) Inhibitors ↑Cardiac output GLP-1 Glucagonlike ↑Insulin biosynthesis ↑b cell proliferation peptide–1 Liver GI tract ↓b cell apoptosis (GLP-1) agonists ↑ Insulin sensitivity Muscle Selective sodium- ↑Insulin secretion glucose transporter- ↓Glucose production ↓Glucagon secretion 2 (SGLT-2) inhibitors Drucker DJ. Cell Metab. 2006;3:153-165. Biguanides Sulfonylureas GLP-1 agonists Meglitinide ▪ Mechanism of action derivatives - ↑ Insulin secretion,↓glucagon secretion, slows gastric emptying, ↑satiety Alpha-glucosidase ▪ Exenatide,Liraglutide,Albiglutide,Lixisenatide,Dulaglutide inhibitors ▪ Efficacy Thiazolidinediones -↓ HbA1c 1~1.5%, Rare hypoglycemia (TZDs) -↓ Weight (1~3kg) -↓ Postprandial glucose Dipeptidyl peptidase IV -↓ Some cardiovascular risk factor, lower CVD event and mortality(Liraglutide, LEADER) (DPP-4) Inhibitors ▪ Advers effect Glucagonlike - GI side effect : N/V, diarrhea peptide–1 - ↑Heart rate (GLP-1) agonists -?Acute pancreatitis -C-cell hyperplasia/medullary thyroid tumors in animals Selective sodium- -Injectable,
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    International Journal of Molecular Sciences Review The Opportunities and Challenges of Peroxisome Proliferator-Activated Receptors Ligands in Clinical Drug Discovery and Development Fan Hong 1,2, Pengfei Xu 1,*,† and Yonggong Zhai 1,2,* 1 Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China; [email protected] 2 Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China * Correspondence: [email protected] (P.X.); [email protected] (Y.Z.); Tel.: +86-156-005-60991 (P.X.); +86-10-5880-6656 (Y.Z.) † Current address: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA. Received: 22 June 2018; Accepted: 24 July 2018; Published: 27 July 2018 Abstract: Peroxisome proliferator-activated receptors (PPARs) are a well-known pharmacological target for the treatment of multiple diseases, including diabetes mellitus, dyslipidemia, cardiovascular diseases and even primary biliary cholangitis, gout, cancer, Alzheimer’s disease and ulcerative colitis. The three PPAR isoforms (α, β/δ and γ) have emerged as integrators of glucose and lipid metabolic signaling networks. Typically, PPARα is activated by fibrates, which are commonly used therapeutic agents in the treatment of dyslipidemia. The pharmacological activators of PPARγ include thiazolidinediones (TZDs), which are insulin sensitizers used in the treatment of type 2 diabetes mellitus (T2DM), despite some drawbacks. In this review, we summarize 84 types of PPAR synthetic ligands introduced to date for the treatment of metabolic and other diseases and provide a comprehensive analysis of the current applications and problems of these ligands in clinical drug discovery and development.
  • Utah Medicaid Pharmacy and Therapeutics Committee Drug

    Utah Medicaid Pharmacy and Therapeutics Committee Drug

    Utah Medicaid Pharmacy and Therapeutics Committee Drug Class Review DPP-4 Inhibitor Products AHFS Classification: 68:20.05 Dipeptidyl Peptidase-4 Inhibitors Alogliptin (Nesina) Alogliptin and Metformin (Kazano) Alogliptin and Pioglitazone (Oseni) Linagliptin (Tradjenta) Linagliptin and Empagliflozin (Glyxambi) Linagliptin and Metformin (Jentadueto, Jentadueto XR) Saxagliptin (Onglyza) Saxagliptin and Dapagliflozin (Qtern) Saxagliptin and Metformin (Kombiglyze XR) Sitagliptin (Januvia) Sitagliptin and Metformin (Janumet, Janumet XR) Final Report November 2017 Review prepared by: Elena Martinez Alonso, B.Pharm., MSc MTSI, Medical Writer Valerie Gonzales, Pharm.D., Clinical Pharmacist Vicki Frydrych, Pharm.D., Clinical Pharmacist Joanita Lake, B.Pharm., MSc EBHC (Oxon), Assistant Professor University of Utah College of Pharmacy Michelle Fiander, MA, MLIS, Systematic Review/Evidence Synthesis Librarian Joanne LaFleur, Pharm.D., MSPH, Associate Professor University of Utah College of Pharmacy University of Utah College of Pharmacy, Drug Regimen Review Center Copyright © 2017 by University of Utah College of Pharmacy Salt Lake City, Utah. All rights reserved 1 Contents List of Abbreviations .................................................................................................................................... 3 Executive Summary ...................................................................................................................................... 4 Introduction ..................................................................................................................................................