Evaluating the Cardiovascular Safety of New Medications for Type 2

Total Page:16

File Type:pdf, Size:1020Kb

Evaluating the Cardiovascular Safety of New Medications for Type 2 738 Diabetes Care Volume 39, May 2016 Robert J. Smith,1 Allison B. Goldfine,2 and Evaluating the Cardiovascular William R. Hiatt3 Safety of New Medications for CARDIOVASCULAR DISEASE AND DIABETES Type 2 Diabetes: Time to Reassess? Diabetes Care 2016;39:738–742 | DOI: 10.2337/dc15-2237 The U.S. Food and Drug Administration (FDA) issued a Guidance for Industry in 2008 defining preapproval and postapproval requirements for the demonstra- tion of cardiovascular safety for all new medications developed for glycemic management in type 2 diabetes. Seventeen large, prospective, randomized, controlled clinical trials involving more than 140,000 subjects thus far have been completed or are ongoing in accordance with this guidance. All five of the completed trials, involving three different drug classes, have met their primary objective to exclude an unacceptable level of ischemic cardiovascular risk as defined in the FDA guidance. Additionally, one trial found an increased risk of hospitalization for heart failure, and another demonstrated decreases in cardio- vascular mortality and hospitalization for heart failure. Given that a heightened risk of cardiovascular ischemic events has not been demonstrated across several classes of new diabetes drugs, we believe it is time for the scientificcommunityand the FDA to consider a more targeted approach to what is, in effect, a global cardiovascular safety trial requirement for all new type 2 diabetes medications in development. Multiple new medications for glycemic management of type 2 diabetes have re- cently been approved by the U.S. Food and Drug Administration (FDA), with addi- tional drugs in development. In the regulatory process, all agents for treatment of hyperglycemia in diabetes are evaluated for efficacy in lowering blood glucose levels 1Department of Medicine, Alpert Medical School and overall safety and are subjected to particularly rigorous screening for cardio- and Department of Health Services, Policy & vascular safety. The approach to these cardiovascular studies is largely directed by a Practice, School of Public Health, Brown Univer- sity, and Ocean State Research Institute, Provi- Guidance for Industry issued by the FDA in 2008 stating that all new type 2 diabetes dence VA Medical Center, Providence, RI drug development programs should rule out unacceptable cardiovascular risk by 2Research Division, Joslin Diabetes Center, demonstrating an upper bound of the two-sided 95% CI of the risk ratio ,1.8 Harvard Medical School, Boston, MA preapproval for a composite end point of major adverse cardiac events (MACE), 3Division of Cardiology, University of Colorado consisting of at least cardiovascular death, nonfatal myocardial infarction, and School of Medicine, and CPC Clinical Research, Aurora, CO stroke (1). For drugs in which the upper bound of the CI is between 1.3 and 1.8, the guidance states that subsequent postapproval trials of the same composite Corresponding author: Robert J. Smith, robert_ [email protected]. MACE end point should be conducted to continue marketing. These recommendations Received 13 October 2015 and accepted 23 were motivated by the high prevalence of cardiovascular disease in diabetes (accounting February 2016. for approximately 70% of deaths) and, in part, by concerns about a signal of potentially © 2016 by the American Diabetes Association. increased cardiovascular risk for the thiazolidinedione rosiglitazone (2) occurring on a Readers may use this article as long as the work is background of additional cardiac safety concerns with antihyperglycemic medications properly cited, the use is educational and not for for type 2 diabetes. The latter included evidence for increased deaths and major profit, and the work is not altered. cardiovascular events during the development program of the peroxisome proliferator– See accompanying articles, pp. 664, 668, activated receptor (PPAR) agonist muraglitazar (3), persistent uncertainty about cardio- 677, 686, 694, 701, 709, 717, 726, and vascular safety with sulfonylureas (4), increased mortality with intense glucose control 735. care.diabetesjournals.org Smith, Goldfine, and Hiatt 739 in the Action to Control Cardiovascular Sitagliptin [TECOS] trial) (10), the sodium– In addition to concerns about ischemic Risk in Diabetes (ACCORD) trial (5), and glucose cotransporter 2 (SGLT2) inhibitor cardiovascular events, as addressed by increased risk for congestive heart failure empagliflozin (BI 10773 [Empagliflozin] the recommendations for a composite with pioglitazone (6) and rosiglitazone (7). Cardiovascular Outcome Event Trial in MACE in the FDA guidance, there is an Seventeen large, randomized, controlled, Type 2 Diabetes Mellitus Patients increased risk of heart failure in patients multicenter postapproval trials involving [EMPA-REG OUTCOME] study) (11), and with diabetes (13). Increased heart failure more than 140,000 participants thus far the glucagon-like peptide 1 (GLP-1) recep- risk has previously been demonstrated have been initiated in accordance with tor agonist lixisenatide (Evaluation of Lix- with thiazolidinediones (6,7) but was not the FDA guidance (Tables 1 and 2). Results isenatide in Acute Coronary Syndrome apparent during the initial develop- from five of these trials now have been [ELIXA] study) (12). The sitagliptin and lix- ment of any of the agents for which reported, providing an opportunity to ex- isenatide studies demonstrated a hazard postmarketing safety trials were subse- amine the utility of this approach to eval- ratio for a composite MACE end point ap- quently performed under the 2008 FDA uate the safety of new antihyperglycemic proximating unity and an upper bound of guidance. Unexpectedly, exploratory medications for type 2 diabetes. the 95% CI ,1.30 for both drugs, while analysis of hospitalization for heart failure The FDA Endocrinologic and Metabolic the empagliflozin results provided evi- as an individual clinical end point revealed Drugs Advisory Committee was convened dence for cardiovascular benefit with a an elevated hazard ratio for saxagliptin at in April 2015 to review the results of hazard ratio of 0.86 and upper bound of 1.27 (95% CI 1.07–1.51) and a nonsignifi- postmarketing trials of the dipeptidyl the 95% CI 0.99 (Table 1). Thus, all five cant numerical increase in risk for peptidase 4 (DPP-4) inhibitors saxagliptin trials involving medications from three alogliptin with a hazard ratio of 1.19 (Saxagliptin Assessment of Vascular Out- different drug classes have excluded an (95% CI 0.90–1.58). The hazard ratios for comes Recorded in Patients with Diabetes unacceptable level of ischemic cardiovas- hospitalization for heart failure as a Mellitus–Thrombolysis in Myocardial In- cular risk (which was the primary analysis) prespecified, adjudicated individual end farction 53 [SAVOR-TIMI 53] trial) and as defined in the FDA 2008 guidance point approximated unity in the sitagliptin alogliptin (Examination of Cardiovascular document. and lixisenatide trials (Table 1), and in- Outcomes with Alogliptin versus Standard All-cause mortality, another important, creased risk for an expanded MACE end of Care [EXAMINE] trial) in type 2 diabe- prespecified secondary end point, raised point that included hospitalization for tes. The study data reviewed at those focused concerns by demonstrating in- heart failure was not evident with any of meetings demonstrated hazard ratios consistent findings across the DPP-4 in- these incretin-modulating drugs (10,12). for a composite MACE end point (cardio- hibitor trials. For saxagliptin, all-cause By contrast, the empagliflozin trial vascular death, nonfatal myocardial in- mortality in the intent-to-treat analysis showed a decreased hazard ratio for hos- farction, and nonfatal stroke) of 1.00 for population showed a hazard ratio of pitalization for heart failure as an individual saxagliptin and 0.96 for alogliptin. The up- 1.11 (95% CI 0.96–1.27), which increased end point at 0.65 (95% CI 0.50–0.85) and per bound of the 95% CI for the two drugs to 1.23 (95% CI 1.02–1.48) when evalu- as a component of an expanded MACE was 1.12 and 1.16, respectively, which ated in the on-treatment population. It is composite outcome combined with CV was below a threshold for concern based important to note that, consistent with death but excluding stroke at 0.66 (95% on the FDA guidance (Table 1) (8,9). The the lack of increased risk of MACE, the CI 0.55–0.79) (11). Thus, hospitalization advisory committee vote on whether ac- increased mortality risk was primarily for heart failure as a stand-alone explor- ceptable cardiovascular risk profiles were driven by noncardiovascular deaths, atory end point demonstrated inconsistent demonstrated was 13 “yes,” 1 “no,” and 1 with no specific identified causal con- results for the DPP-4 inhibitors, with a po- abstention for saxagliptin and was unan- cerns. By contrast, all-cause mortality tential concern observed for saxagliptin, a imous at 16 “yes” for alogliptin (note that was not numerically increased with less evident trend for alogliptin, and no there was not complete overlap in mem- alogliptin, sitagliptin, or lixisenatide, and numeric or statistical difference for bers attending each meeting). Results of all-cause mortality was significantly de- sitagliptin. Hospitalization for heart failure three additional cardiovascular outcome creased with empagliflozin (Table 1). It is risk was either neutral or decreased with trials conducted under the FDA guidance not possible to directly compare agents as the other two agents studied. On the basis
Recommended publications
  • Diabetes Mellitus Typ 2 Medikamentöse Therapie
    Übersicht AMT Diabetes mellitus Typ 2 Medikamentöse Therapie L. Cornelius Bollheimer, Christiane Girlich, Ulrike Woenckhaus und Roland Büttner, Regensburg Arzneimitteltherapie 2007;25:175–86. Literatur NIDDM subjects. A study of two ethnic groups. Diabetes Care 1993;16: 621–9. 1. Deutsche Diabetes Gesellschaft. Evidenzbasierte Leitlinie: Epidemiologie 24. Akbar DH. Effect of metformin and sulfonylurea on C-reactive protein und Verlauf des Diabetes mellitus in Deutschland. http://www.deutsche- level in well-controlled type 2 diabetics with metabolic syndrome. En- diabetes-gesellschaft.de/redaktion/mitteilungen/leitlinien/EBL_Update_ docrine 2003;20:215–8. Epidemiologie_05_2004_neues_Layout.pdf. Internetdokument. 2004. 25. Krentz AJ, Bailey CJ. Oral antidiabetic agents: current role in type 2 dia- 2. Seufert J. Kardiovaskuläre Endpunktstudien in der Therapie des Typ-2- betes mellitus. Drugs 2005;65:385–411. Diabetes-mellitus. Dtsch Ärzteblatt 2006;103:A934–42. 26. Parhofer KG, Laubach E, Geiss HC, Otto C. Effect of glucose control on 3. Deutsche Diabetes Gesellschaft. Praxis-Leitlinien der Deutschen Diabe- lipid levels in patients with type 2 diabetes. Dtsch Med Wochenschr tes Gesellschaft. Diabetologie und Stoffwechsel 2006;1:S2. 2002;127:958–62. 4. Häring HU, Matthaei S. Behandlung des Diabetes mellitus Typ 2. Diabe- 27. DeFronzo RA, Barzilai N, Simonson DC. Mechanism of metformin ac- tologie und Stoffwechsel 2006;1:S205–10. tion in obese and lean noninsulin-dependent diabetic subjects. J Clin 5. Brueckel J, Kerner W. Definition, Klassifikation und Diagnostik des Dia- Endocrinol Metab 1991;73:1294–301. betes mellitus. Diabetologie und Stoffwechsel 2006;1:S177–80. 28. Cryer DR, Nicholas SP, Henry DH, Mills DJ, et al. Comparative outcomes 6.
    [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]
  • Comparative Effectiveness, Safety, and Indications of Insulin Analogues in Premixed Formulations for Adults with Type 2 Diabetes
    Comparative Effectiveness Review Number 14 Comparative Effectiveness, Safety, and Indications of Insulin Analogues in Premixed Formulations for Adults With Type 2 Diabetes This report is based on research conducted by the Johns Hopkins Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-02-0018). The findings and conclusions in this document are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of the Agency for Healthcare Research and Quality or of the U.S. Department of Health and Human Services. This report is intended as a reference and not as a substitute for clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information. This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied. Comparative Effectiveness Review Number 14 Comparative Effectiveness, Safety, and Indications of Insulin Analogues in Premixed Formulations for Adults With Type 2 Diabetes Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 540 Gaither Road Rockville, MD 20850 www.ahrq.gov Contract No.
    [Show full text]
  • Modifications to the Harmonized Tariff Schedule of the United States To
    U.S. International Trade Commission COMMISSIONERS Shara L. Aranoff, Chairman Daniel R. Pearson, Vice Chairman Deanna Tanner Okun Charlotte R. Lane Irving A. Williamson Dean A. Pinkert Address all communications to Secretary to the Commission United States International Trade Commission Washington, DC 20436 U.S. International Trade Commission Washington, DC 20436 www.usitc.gov Modifications to the Harmonized Tariff Schedule of the United States to Implement the Dominican Republic- Central America-United States Free Trade Agreement With Respect to Costa Rica Publication 4038 December 2008 (This page is intentionally blank) Pursuant to the letter of request from the United States Trade Representative of December 18, 2008, set forth in the Appendix hereto, and pursuant to section 1207(a) of the Omnibus Trade and Competitiveness Act, the Commission is publishing the following modifications to the Harmonized Tariff Schedule of the United States (HTS) to implement the Dominican Republic- Central America-United States Free Trade Agreement, as approved in the Dominican Republic-Central America- United States Free Trade Agreement Implementation Act, with respect to Costa Rica. (This page is intentionally blank) Annex I Effective with respect to goods that are entered, or withdrawn from warehouse for consumption, on or after January 1, 2009, the Harmonized Tariff Schedule of the United States (HTS) is modified as provided herein, with bracketed matter included to assist in the understanding of proclaimed modifications. The following supersedes matter now in the HTS. (1). General note 4 is modified as follows: (a). by deleting from subdivision (a) the following country from the enumeration of independent beneficiary developing countries: Costa Rica (b).
    [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]
  • Muraglitazar Bristol-Myers Squibb/Merck Daniella Barlocco
    Muraglitazar Bristol-Myers Squibb/Merck Daniella Barlocco Address Originator Bristol-Myers Squibb Co University of Milan . Istituto di Chimica Farmaceutica e Tossicologica Viale Abruzzi 42 Licensee Merck & Co Inc 20131 Milano . Italy Status Pre-registration Email: [email protected] . Indications Metabolic disorder, Non-insulin-dependent Current Opinion in Investigational Drugs 2005 6(4): diabetes © The Thomson Corporation ISSN 1472-4472 . Actions Antihyperlipidemic agent, Hypoglycemic agent, Bristol-Myers Squibb and Merck & Co are co-developing Insulin sensitizer, PPARα agonist, PPARγ agonist muraglitazar, a dual peroxisome proliferator-activated receptor-α/γ . agonist, for the potential treatment of type 2 diabetes and other Synonym BMS-298585 metabolic disorders. In November 2004, approval was anticipated as early as mid-2005. Registry No: 331741-94-7 Introduction [579218], [579221], [579457], [579459]. PPARγ is expressed in Type 2 diabetes is a complex metabolic disorder that is adipose tissue, lower intestine and cells involved in characterized by hyperglycemia, insulin resistance and immunity. Activation of PPARγ regulates glucose and lipid defects in insulin secretion. The disease is associated with homeostasis, and triggers insulin sensitization [579216], older age, obesity, a family history of diabetes and physical [579218], [579458], [579461]. PPARδ is expressed inactivity. The prevalence of type 2 diabetes is increasing ubiquitously and has been found to be effective in rapidly, and the World Health Organization warns that, controlling dyslipidemia and cardiovascular diseases unless appropriate action is taken, the number of sufferers [579216]. PPARα agonists are used as potent hypolipidemic will double to over 350 million individuals by the year compounds, increasing plasma high-density lipoprotein 2030. Worryingly, it is estimated that only half of sufferers (HDL)-cholesterol and reducing free fatty acids, are diagnosed with the condition [www.who.int].
    [Show full text]
  • 7-Azaindoles and Their Use As Ppar Agonists 7-Azaindole Und Ihre Verwendung Als Ppar-Agonisten 7-Azaindoles Et Leur Utilisation Comme Agonistes De Ppar
    (19) TZZ___T (11) EP 1 794 159 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 471/04 (2006.01) A61K 31/437 (2006.01) 01.08.2012 Bulletin 2012/31 A61P 3/10 (2006.01) (21) Application number: 05778246.8 (86) International application number: PCT/EP2005/009269 (22) Date of filing: 27.08.2005 (87) International publication number: WO 2006/029699 (23.03.2006 Gazette 2006/12) (54) 7-AZAINDOLES AND THEIR USE AS PPAR AGONISTS 7-AZAINDOLE UND IHRE VERWENDUNG ALS PPAR-AGONISTEN 7-AZAINDOLES ET LEUR UTILISATION COMME AGONISTES DE PPAR (84) Designated Contracting States: • GLIEN, Maike AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 65195 Wiesbaden (DE) HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI • SCHAEFER, Hans-Ludwig SK TR 65239 Hochheim (DE) • WENDLER, Wolfgang (30) Priority: 11.09.2004 EP 04021667 65618 Selters (DE) • BERNARDELLI, Patrick (43) Date of publication of application: F-78450 Villepreux (FR) 13.06.2007 Bulletin 2007/24 • TERRIER, Corinne F-93190 Livry Gargan (FR) (73) Proprietor: Sanofi-Aventis Deutschland GmbH • RONAN, Baptiste 65929 Frankfurt am Main (DE) F-92140 Clamart (FR) (72) Inventors: (56) References cited: • KEIL, Stefanie EP-A- 1 445 258 WO-A-2004/074284 65719 Hofheim (DE) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations.
    [Show full text]
  • The Leading Source of Diabetes Business News the Long View Fall
    The Leading Source of Diabetes Business News The Long View Fall 2011 • No. 108 Although change isn’t literally in the air for me – here in San Francisco, we still get a few more weeks of summer – autumn brings some notable shifts in the world of diabetes, and I’m looking forward to hearing all about them in companies’ third-quarter financial updates. Perhaps most importantly, Amylin/Lilly/Alkermes’ Bydureon, the first once-weekly diabetes therapy, has now made its debut in several European countries. That means this earnings’ season will be the first chance to hear how the launch has gone, and we’ll get our first real indicator of what to expect in the quarters to come. Will patients flock to the every-seven-days dosage schedule, forcing rival GLP-1 companies to accelerate development of their own once-weekly products (and encouraging Amylin/Lilly/Alkermes to stay on course with their phase 2 once-monthly exenatide)? Or will factors like needle size, injection simplicity – and even the regularity of daily dosing, considered an advantage by some – give the edge to Victoza? (Novo Nordisk certainly isn’t resting on the success of this soon-to- be-blockbuster, having most recently launched Victoza in the swiftly growing Chinese market – a topic we explore in this issue’s interview with Novo Nordisk’s head of China, Ron Christie.) The global GLP-1 contest was already intensely competitive and has become more so, even before Bydureon’s entry to the US or the arrival of new players (e.g., Sanofi’s Lyxumia).
    [Show full text]
  • S 26948: a New Specific Peroxisome Proliferator–Activated Receptor
    ORIGINAL ARTICLE S 26948: a New Specific Peroxisome Proliferator–Activated Receptor ␥ Modulator With Potent Antidiabetes and Antiatherogenic Effects Maria Carmen Carmona,1 Katie Louche,1 Bruno Lefebvre,2 Antoine Pilon,3 Nathalie Hennuyer,3 Ve´ronique Audinot-Bouchez,4 Catherine Fievet,3 Ge´rard Torpier,3 Pierre Formstecher,2 Pierre Renard,5 Philippe Lefebvre,2 Catherine Dacquet,5 Bart Staels,3 Louis Casteilla,1 and Luc Pe´nicaud1 on behalf of the Consortium of the French Ministry of Research and Technology OBJECTIVE—Rosiglitazone displays powerful antidiabetes benefits but is associated with increased body weight and adipo- genesis. Keeping in mind the concept of selective peroxisome he peroxisome proliferator–activated receptors proliferator–activated receptor (PPAR)␥ modulator, the aim of this (PPARs) (1) are transcription factors belonging study was to characterize the properties of a new PPAR␥ ligand, S to the nuclear receptor transcription factor fam- 26948, with special attention in body-weight gain. Tily (1). Three isoforms, PPAR␣,-␦, and -␥, have RESEARCH DESIGN AND METHODS—We used transient been described to have tissue-specific patterns of expres- transfection and binding assays to characterized the binding sion and function—the latter being highly expressed in characteristics of S 26948 and GST pull-down experiments to adipocytes and macrophages among other cell types (2–5). investigate its pattern of coactivator recruitment compared with The role of PPAR␥ on adipocyte differentiation has been rosiglitazone. We also assessed its adipogenic capacity in vitro extensively studied in vitro and in vivo (2,3,6,7). Forced using the 3T3-F442A cell line and its in vivo effects in ob/ob mice ␥ (for antidiabetes and antiobesity properties), as well as the expression of PPAR in nonadipogenic cells is sufficient to homozygous human apolipoprotein E2 knockin mice (E2-KI) (for induce adipocyte differentiation on treatment with specific antiatherogenic capacity).
    [Show full text]
  • Role of Dual PPAR Gamma and Alpha Agonists in Diabetes Mellitus
    23 Role of Dual PPAR γ and α Agonists in Diabetes Mellitus—Have They Met a Road Block or They Are Dead? Mohd Ashraf Ganie, Abdul Hamid Zargar Abstract: There are three peroxisome proliferator-activated receptors (PPARs) subtypes which are commonly designated PPAR alpha, PPAR gamma and PPAR beta/delta. PPAR alpha activation increases high density lipoprotein (HDL) cholesterol synthesis, stimulates “reverse” cholesterol transport and reduces triglycerides. PPAR gamma activation results in insulin sensitization and antidiabetic action. Combined treatments with PPAR gamma and alpha agonists may potentially improve insulin resistance and alleviate atherogenic dyslipidemia, whereas PPAR delta properties may prevent the development of overweight which typically accompanies “pure” PPAR gamma ligands. The new generation of dual-action PPARs—the glitazars, which target PPAR-gamma and PPAR-alpha (like muraglitazar and tesaglitazar) were on deck in late-stage clinical trials for sometime and were considered effective in reducing cardiovascular risk, but their long-term clinical effects were unknown. Thus glitazars offered a hope of a new approach to diabetes care addressing not just glycemia, but dyslipidemia and other components of the metabolic syndrome, though the side effect profile remains unknown. No human data is available, and so it remains highly speculative. The glitazars and on the newly published results for muraglitazar and tesaglitazar. “The PPAR-alpha is a good target and is being developed to yield more potent drugs that work through PPAR-alpha, and at the same time, improve on the PPAR-gamma. Efforts is on to get the glucose lowering with few of the adverse effects. This thinking has met with problems as many clinical trials have been terminated due to dominant side effects.
    [Show full text]
  • George Grunberger, M.D., F.A.C.P., F.A.C.E
    GEORGE GRUNBERGER, M.D., F.A.C.P., F.A.C.E. Chairman, Grunberger Diabetes Institute Clinical Professor, Department of Internal Medicine Clinical Professor, Center for Molecular Medicine & Genetics Wayne State University School of Medicine Professor, Department of Internal Medicine Oakland University William Beaumont School of Medicine Visiting Professor, First Faculty of Medicine Charles University, Prague (Czech Republic) Phone: (248) 335-7740 43494 Woodward Ave, ste 208, Bloomfield Hills, MI 48302 Fax: (248) 338-7979 e-mail: [email protected] EDUCATION 1973 BA degree (Biochemistry), Columbia College, New York, NY 1977 MD degree, New York University School of Medicine, New York, NY TRAINING 1977-1980 Residency, Internal Medicine Case Western Reserve University University Hospitals of Cleveland, Cleveland, Ohio 1980-1983 Fellowship (clinical and basic research), Endocrinology and Metabolism, Diabetes Branch, National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases National Institutes of Health, Bethesda, Maryland FACULTY APPOINTMENTS, Wayne State University, Detroit, Michigan 1986-1992 Associate Professor (tenured), Department of Internal Medicine Associate Professor (tenured), Department of Molecular Biology and Genetics 1992-2002 Professor (tenured), Department of Internal Medicine 1995-1996 Interim Chairman, Department of Internal Medicine 1992-1994 Professor (tenured), Department of Molecular Biology & Genetics 1994-present Professor (tenured), Center for Molecular Medicine & Genetics 1986-present Regular member
    [Show full text]
  • Oral Hypoglycemic Drugs in the Management of Type 2 Diabetes Mellitus: a Review
    Journal of Health, Medicine and Nursing www.iiste.org ISSN 2422-8419 An International Peer-reviewed Journal Vol.44, 2017 Oral Hypoglycemic Drugs in the Management of Type 2 Diabetes Mellitus: A Review Nikesh Mani Shrestha 1* Bang Zhu Meng 2 1.School of Clinical Medicine, Inner Mongolia University for the Nationalities,536 West Huo Lin He Street, Horqin District, Tongliao City, Inner Mongolia, China 2.Affiliated Hospital of Inner Mongolia University for the Nationalities, 1742 Huo Lin He Street, Horqin District, Tongliao City, Inner Mongolia, China Abstract Diabetes mellitus is a chronic, progressive, heterogeneous group of metabolic disorder mainly characterized by hyperglycemia. T2DM results due to insulin resistance or secretory defects of a beta cell or both and gradually progress to a state characterized by complete loss of pancreatic beta cells secretion. 2hour oral glucose tolerance test or HbA1c testing is performed for the screening for diabetes mellitus. In this review, we attempt to outline the basic pharmacological and non-pharmacological principles for the management of T2DM. Keywords: diabetes, clinical management, non-pharmacological management, primary care 1. Introduction Diabetes mellitus is one of the common chronic metabolic diseases which is mainly characterized by hyperglycemia. It is a progressive disease. So, as a disease progresses there is a high chance of developing microvascular and macrovascular complications. Many studies have been conducted to find the effective measure to reduce these complications. Based on the pathology, there are different types of diabetes mellitus. Among them, type 2 diabetes (T2D) is very common accounting for approximately 90% of diabetic cases worldwide. The prevalence rate of T2DM is increasing due to a sedentary lifestyle, increasing obesity and an aging population (Johnson JA et al, 2006).
    [Show full text]