DOCSLIB.ORG

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

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Educational Approaches to the Use of Non-Insulin Anti-Diabetes Drugs 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,
Load more

Recommended publications
  • Treatment of Diabetes Mellitus
    TREATMENT OF DIABETES MELLITUS DIABETES is a condition that affects how the body makes energy from food. Food is broken down into sugar (glucose) in the body and released into the blood. When the blood sugar level rises after a meal, insulin responds to let the sugar into the cells to be used as energy. In diabetes, the body either does not make enough insulin or it stops responding to insulin as well as it should. This results in sugar staying in the blood and leads to serious health problems over time. DIAGNOSIS OF DIABETES1 • A1C Test: Lab test measuring average blood sugar over past two to three months • Fasting Blood Sugar Test: Lab test measuring blood sugar after eight hours of no food or drink • Oral Glucose Tolerance Test (OGTT): Measures blood sugar before and two hours after drinking a specific sugary liquid • Random Blood Sugar Test: Measures blood sugar at a moment in time, without any kind of preparation (like fasting) FASTING BLOOD ORAL GLUCOSE TOLERANCE RANDOM BLOOD RESULT A1C TEST SUGAR TEST TEST SUGAR TEST Diabetes ≥ 6.5% ≥126 mg/dL ≥ 200 mg/dL ≥ 200 mg/dL Prediabetes 5.7 – 6.4% 100 – 125 mg/dL 140 – 199 mg/dL N/A Normal < 5.7% ≤99 mg/dL < 140 mg/dL N/A NON-DRUG TREATMENTS2 THERAPY COST WHAT TO EXPECT Diet (Mediterranean diet) and exercise (30 minutes a day, five days a week of moderate- Weight loss $-$$ intensity exercise); 7% weight loss decreases risk of diabetes3 Psychological intervention $$-$$$ Psychotherapy may reduce diabetic distress and improve glycemic control4,5 nationalcooperativerx.com PRESCRIPTION TREATMENTS
    [Show full text]
  • The Antidiabetic Drug Lobeglitazone Has the Potential to Inhibit PTP1B T Activity ⁎ Ruth F
    Bioorganic Chemistry 100 (2020) 103927 Contents lists available at ScienceDirect Bioorganic Chemistry journal homepage: www.elsevier.com/locate/bioorg The antidiabetic drug lobeglitazone has the potential to inhibit PTP1B T activity ⁎ Ruth F. Rochaa, Tiago Rodriguesc, Angela C.O. Menegattia,b, , Gonçalo J.L. Bernardesc,d, Hernán Terenzia a Centro de Biologia Molecular Estrutural, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Campus Trindade, 88040-900 Florianópolis, SC, Brazil b Universidade Federal do Piauí, CPCE, 64900-000 Bom Jesus, PI, Brazil c Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028 Lisbon, Portugal d Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, UK ARTICLE INFO ABSTRACT Keywords: Protein tyrosine phosphatase 1B (PTP1B) is considered a potential therapeutic target for the treatment of type 2 Thiazolidinediones diabetes mellitus (T2DM), since this enzyme plays a significant role to down-regulate insulin and leptin sig- Lobeglitazone nalling and its over expression has been implicated in the development of insulin resistance, T2DM and obesity. PPAR-γ Some thiazolidinediones (TZD) derivatives have been reported as promising PTP1B inhibitors with anti hy- PTP1B perglycemic effects. Recently, lobeglitazone, a new TZD, was described as an antidiabetic drug that targetsthe Non-competitive inhibitors PPAR-γ (peroxisome γ proliferator-activated receptor) pathway, but no information on its effects on PTP1B have been reported to date. We investigated the effects of lobeglitazone on PTP1B activity in vitro. Surprisingly, lobeglitazone led to moderate inhibition on PTP1B (IC50 42.8 ± 3.8 µM) activity and to a non-competitive reversible mechanism of action.
    [Show full text]
  • Dualism of Peroxisome Proliferator-Activated Receptor Α/Γ: a Potent Clincher in Insulin Resistance
    AEGAEUM JOURNAL ISSN NO: 0776-3808 Dualism of Peroxisome Proliferator-Activated Receptor α/γ: A Potent Clincher in Insulin Resistance Mr. Ravikumar R. Thakar1 and Dr. Nilesh J. Patel1* 1Faculty of Pharmacy, Shree S. K. Patel College of Pharmaceutical Education & Research, Ganpat University, Gujarat, India. [email protected] Abstract: Diabetes mellitus is clinical syndrome which is signalised by augmenting level of sugar in blood stream, which produced through lacking of insulin level and defective insulin activity or both. As per worldwide epidemiology data suggested that the numbers of people with T2DM living in developing countries is increasing with 80% of people with T2DM. Peroxisome proliferator-activated receptors are a family of ligand-activated transcription factors; modulate the expression of many genes. PPARs have three isoforms namely PPARα, PPARβ/δ and PPARγ that play a central role in regulating glucose, lipid and cholesterol metabolism where imbalance can lead to obesity, T2DM and CV ailments. It have pathogenic role in diabetes. PPARα is regulates the metabolism of lipids, carbohydrates, and amino acids, activated by ligands such as polyunsaturated fatty acids, and drugs used as Lipid lowering agents. PPAR β/δ could envision as a therapeutic option for the correction of diabetes and a variety of inflammatory conditions. PPARγ is well categorized, an element of the PPARs, also pharmacological effective as an insulin resistance lowering agents, are used as a remedy for insulin resistance integrated with type- 2 diabetes mellitus. There are mechanistic role of PPARα, PPARβ/δ and PPARγ in diabetes mellitus and insulin resistance. From mechanistic way, it revealed that dual PPAR-α/γ agonist play important role in regulating both lipids as well as glycemic levels with essential safety issues.
    [Show full text]
  • Corporate Presentation June 2019 Disclaimer
    Corporate Presentation June 2019 Disclaimer Some of the statements contained in this presentation constitute forward-looking statements. Statements that are not historical facts are forward-looking statements. Forward-looking statements generally can be identified by the use of forward-looking terminology such as “may”, “will”, “expect”, “intend”, “estimate”, “anticipate”, “believe”, “continue” or similar terminology. These statements are based on the Company’s current strategy, plans, objectives, assumptions, estimates and projections. Investors should therefore not place undue reliance on those statements. The Company makes no representation, warranty or prediction that the results anticipated by such forward- looking statements will be achieved, and such forward-looking statements represent, in each case, only one of many possible scenarios and should not be viewed as the most likely or standard scenario. Forward-looking statements speak only as of the date that they are made and the Company does not undertake to update any forward-looking statements in light of new information or future events. Forward-looking statements involve inherent risks and uncertainties. The Company cautions that a number of important factors could cause actual results to differ materially from those contained in any forward-looking statement. 2 Well Diversified Mid-to-Late Stage Metabolic Pipeline for Large Market Opportunities Global partnerships secured for late stage clinical program in type 2 diabetes • Imeglimin: First in class oral drug candidate targeting
    [Show full text]
  • Health Reports for Mutual Recognition of Medical Prescriptions: State of Play
    The information and views set out in this report are those of the author(s) and do not necessarily reflect the official opinion of the European Union. Neither the European Union institutions and bodies nor any person acting on their behalf may be held responsible for the use which may be made of the information contained therein. Executive Agency for Health and Consumers Health Reports for Mutual Recognition of Medical Prescriptions: State of Play 24 January 2012 Final Report Health Reports for Mutual Recognition of Medical Prescriptions: State of Play Acknowledgements Matrix Insight Ltd would like to thank everyone who has contributed to this research. We are especially grateful to the following institutions for their support throughout the study: the Pharmaceutical Group of the European Union (PGEU) including their national member associations in Denmark, France, Germany, Greece, the Netherlands, Poland and the United Kingdom; the European Medical Association (EMANET); the Observatoire Social Européen (OSE); and The Netherlands Institute for Health Service Research (NIVEL). For questions about the report, please contact Dr Gabriele Birnberg ([email protected] ). Matrix Insight | 24 January 2012 2 Health Reports for Mutual Recognition of Medical Prescriptions: State of Play Executive Summary This study has been carried out in the context of Directive 2011/24/EU of the European Parliament and of the Council of 9 March 2011 on the application of patients’ rights in cross- border healthcare (CBHC). The CBHC Directive stipulates that the European Commission shall adopt measures to facilitate the recognition of prescriptions issued in another Member State (Article 11). At the time of submission of this report, the European Commission was preparing an impact assessment with regards to these measures, designed to help implement Article 11.
    [Show full text]
  • CDR Clinical Review Report for Soliqua
    CADTH COMMON DRUG REVIEW Clinical Review Report Insulin glargine and lixisenatide injection (Soliqua) (Sanofi-Aventis) Indication: adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus inadequately controlled on basal insulin (less than 60 units daily) alone or in combination with metformin. Service Line: CADTH Common Drug Review Version: Final (with redactions) Publication Date: January 2019 Report Length: 118 Pages Disclaimer: The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services. While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document.
    [Show full text]
  • Lobeglitazone
    2013 International Conference on Diabetes and Metabolism Lobeglitazone, A Novel PPAR-γ agonist with balanced efficacy and safety Kim, Sin Gon. MD, PhD. Professor, Division of Endocrinology and Metabolism Department of Internal Medicine, Korea University College of Medicine. Disclosure of Financial Relationships This symposium is sponsored by Chong Kun Dang Pharmaceutical Corp. I have received lecture and consultation fees from Chong Kun Dang. Pros & Cons of PPAR-γ agonist Pros Cons • Good glucose lowering • Adverse effects • Durability (ADOPT) (edema, weight gain, • Insulin sensitizing CHF, fracture or rare effects (especially in MS, macular edema etc) NAFLD, PCOS etc) • Possible safety issues • Prevention of new- (risk of MI? – Rosi or onset diabetes (DREAM, bladder cancer? - Pio) ACT-NOW) • LessSo, hypoglycemiathere is a need to develop PPAR-γ • Few GI troubles agonist• Outcome with data balanced efficacy and safety (PROactive) Insulin Sensitizers : Several Issues Rosi, Peak sale ($3.3 billion) DREAM Dr. Nissen Dr. Nissen ADOPT META analysis BARI-2D (5,8) Rosi, lipid profiles RECORD 1994 1997 1999 2000 2002 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Tro out d/t FDA, All diabetes hepatotoxicity drug CV safety Rosi (5) FDA, Black box Rosi, Rosi , CV safety warning - REMS in USA = no evidence - Europe out Pio (7) PIO, bladder cancer CKD 501 Lobeglitazone 2000.6-2004.6 2004.11-2007.1 2007.3-2008.10 2009.11-2011.04 Discovery& Preclinical study Phase I Phase II Phase III Developmental Strategy Efficacy • PPAR activity Discovery & Preclinical study • In vitro & vivo efficacy • Potent efficacy 2000.06 - 2004.06 Phase I 2004.11 - 2007.01 • In vitro screening • Repeated dose toxicity • Metabolites • Geno toxicity • Phase II CYP 450 • Reproductive toxicity 2007.03 - 2008.10 • DDI • Carcinogenic toxicity ADME Phase III Safety 2009.11 - 2011.04 CV Safety / (Bladder) Cancer / Liver Toxicity / Bone loss Lobeglitazone (Duvie) 1.
    [Show full text]
  • (KPIC) PPO and Out-Of- Area Indemnity (OOA) Drug Formulary with Specialty Drug Tier
    Kaiser Permanente Insurance Company (KPIC) PPO and Out-of- Area Indemnity (OOA) Drug Formulary with Specialty Drug Tier This Drug Formulary was updated: September 1, 2021 NOTE: This drug formulary is updated often and is subject to change. Upon revision, all previous versions of the drug formulary are no longer in effect. This document contains information regarding the drugs that are covered when you participate in the California Nongrandfathered PPO and Out-of- Area Indemnity (OOA) Health Insurance Plans with specialty drug tier offered by Kaiser Permanente Insurance Company (KPIC) and fill your prescription at a MedImpact network pharmacy. Access to the most current version of the Formulary can be obtained by visiting kp.org/kpic-ca-rx-ppo-ngf. For help understanding your KPIC insurance plan benefits, including cost sharing for drugs under the prescription drug benefit and under the medical benefit, please call 1-800-788-0710 or 711 (TTY) Monday through Friday, 7a.m. to 7p.m. For help with this Formulary, including the processes for submitting an exception request and requesting prior authorization and step therapy exceptions, please call MedImpact 24 hours a day, 7 days a week, at 1-800-788-2949 or 711 (TTY). For cost sharing information for the outpatient prescription drug benefits in your specific plan, please visit: kp.org/kpic-ca-rx-ppo-ngf. For help in your preferred language, please see the Kaiser Permanente Insurance Company Notice of Language Assistance in this document. KPIC PPO NGF Table of Contents Informational Section................................................................................................................................2
    [Show full text]
  • Comparison of Clinical Outcomes and Adverse Events Associated with Glucose-Lowering Drugs in Patients with Type 2 Diabetes: a Meta-Analysis
    Online Supplementary Content Palmer SC, Mavridis D, Nicolucci A, et al. Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes: a meta-analysis. JAMA. doi:10.1001/jama.2016.9400. eMethods. Summary of Statistical Analysis eTable 1. Search Strategies eTable 2. Description of Included Clinical Trials Evaluating Drug Classes Given as Monotherapy eTable 3. Description of Included Clinical Trials Evaluating Drug Classes Given as Dual Therapy Added to Metformin eTable 4. Description of Included Clinical Trials Evaluating Drug Classes Given as Triple Therapy When Added to Metformin Plus Sulfonylurea eTable 5. Risks of Bias in Clinical Trials Evaluating Drug Classes Given as Monotherapy eTable 6. Risks of Bias in Clinical Trials Evaluating Drug Classes Given as Dual Therapy Added to Metformin eTable 7. Risks of Bias in Clinical Trials Evaluating Drug Classes Given as Triple Therapy When Added to Metformin plus Sulfonylurea eTable 8. Estimated Global Inconsistency in Networks of Outcomes eTable 9. Estimated Heterogeneity in Networks eTable 10. Definitions of Treatment Failure Outcome eTable 11. Contributions of Direct Evidence to the Networks of Treatments eTable 12. Network Meta-analysis Estimates of Comparative Treatment Associations for Drug Classes Given as Monotherapy eTable 13. Network Meta-analysis Estimates of Comparative Treatment Associations for Drug Classes When Used in Dual Therapy (in Addition to Metformin) eTable 14. Network Meta-analysis Estimates of Comparative Treatment Effects for Drug Classes Given as Triple Therapy eTable 15. Meta-regression Analyses for Drug Classes Given as Monotherapy (Compared With Metformin) eTable 16. Subgroup Analyses of Individual Sulfonylurea Drugs (as Monotherapy) on Hypoglycemia eTable 17.
    [Show full text]
  • Comparative Review of Oral Hypoglycemic Agents in Adults
    SECTION 18.5 Comparative Review of Oral Hypoglycemic Agents in Adults Harinder Chahal For WHO Secretariat Table of Contents Acronyms: ............................................................................................................................................................................... 3 I. Background and Rationale for the review: ....................................................................................................................... 4 II. Medications under comparative review: ......................................................................................................................... 4 Table 1 - New oral hypoglycemic agents for comparison with current EML agents .......................................................... 5 III. Literature searches and methodology: ............................................................................................................................ 5 1. Title Search Results: .................................................................................................................................................... 6 2. Statement about quality of evidence: ........................................................................................................................ 6 IV. Clinical efficacy and safety evaluation: ............................................................................................................................ 6 1. DPP-4 Inhibitors (Sitagliptin, Saxagliptin) and Metformin: ........................................................................................
    [Show full text]
  • The Opportunities and Challenges of Peroxisome Proliferator-Activated Receptors Ligands in Clinical Drug Discovery and Development
    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.
    [Show full text]
  • 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 ..................................................................................................................................................
    [Show full text]