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Rosiglitazone-Associated Fractures in Type 2 Diabetes an Analysis from a Diabetes Outcome Progression Trial (ADOPT)

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Rosiglitazone-Associated Fractures in Type 2 Diabetes

An analysis from A Diabetes Outcome Progression Trial (ADOPT)

  • 1
  • 7

preclinical data and better understand the clinical implications of and possible interventions for these findings.

  • STEVEN E. KAHN, MB, CHB
  • DAHONG YU, PHD

  • 2
  • 7

  • BERNARD ZINMAN, MD
  • MARK A. HEISE, PHD

  • 3
  • 7

  • JOHN M. LACHIN, SCD
  • R. PAUL AFTRING, MD, PHD

  • 4
  • 8

STEVEN M. HAFFNER, MD WILLIAM H. HERMAN, MD
GIANCARLO VIBERTI, MD

5

Diabetes Care 31:845–851, 2008

FOR THE A DIABETES OUTCOME
PROGRESSION TRIAL (ADOPT) STUDY

GROUP*

6

RURY R. HOLMAN, MD

7

BARBARA G. KRAVITZ, MS

ype 2 diabetes is associated with an increased risk of fractures, with the risk increasing with longer duration

T

OBJECTIVE — The purpose of this study was to examine possible factors associated with the increased risk of fractures observed with rosiglitazone in A Diabetes Outcome Progression Trial (ADOPT).

of disease (1,2). These fractures affect predominantly the hip, arm, and foot (1–5) and occur despite the fact that bone mineral density is either normal or even increased in patients with type 2 diabetes compared with those who are not hyperglycemic (5–7). Although the reason for this increased risk is unclear, it has been postulated that in older patients some of the risk may be related to disability and falls (8). In the context of specific diabetes therapy, a recent report from the Health, Aging and Body Composition Study—an observational study—noted that older women with type 2 diabetes who were taking thiazolidinediones experienced increased bone loss compared with control subjects, whereas no differences were seen in men (9). However, a recent retrospective study suggested a greater loss of bone mineral density in men taking rosiglitazone (10).

RESEARCH DESIGN AND METHODS — Data from the 1,840 women and 2,511 men randomly assigned in ADOPT to rosiglitazone, metformin, or glyburide for a median of 4.0 years were examined with respect to time to first fracture, rates of occurrence, and sites of fractures.

RESULTS — In men, fracture rates did not differ between treatment groups. In women, at least one fracture was reported with rosiglitazone in 60 patients (9.3% of patients, 2.74 per 100 patient-years), metformin in 30 patients (5.1%, 1.54 per 100 patient-years), and glyburide in 21 patients (3.5%, 1.29 per 100 patient-years). The cumulative incidence (95% CI) of fractures in women at 5 years was 15.1% (11.2–19.1) with rosiglitazone, 7.3% (4.4–10.1) with metformin, and 7.7% (3.7–11.7) with glyburide, representing hazard ratios (95% CI) of 1.81 (1.17–2.80) and 2.13 (1.30–3.51) for rosiglitazone compared with metformin and glyburide, respectively. The increase in fractures with rosiglitazone occurred in pre- and postmenopausal women, and fractures were seen predominantly in the lower and upper limbs. No particular risk factor underlying the increased fractures in female patients who received rosiglitazone therapy was identified.

CONCLUSIONS — Further investigation into the risk factors and underlying pathophysiology for the increased fracture rate in women taking rosiglitazone is required to relate them to

A Diabetes Outcome Progression
Trial (ADOPT) was a randomized, controlled clinical trial comparing the effect of the thiazolidinedione rosiglitazone, the biguanide metformin, and the sulfonylurea glyburide on glucose control in drug-naive patients recently diagnosed (Ͻ3 years) with type 2 diabetes (11). In the study it was shown that treatment with rosiglitazone produced more durable glycemic control than metformin or glyburide as measured by fasting glucose and A1C. This effect resulted from a greater preservation of ␤-cell function with rosiglitazone. After unblinding and completion of the prespecified statistical analysis plan, a review of adverse events of special interest uncovered an increase in the number of fractures in women taking rosiglitazone; a brief description of the finding was added as a postscript to the primary manuscript then in press (11). In

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

From the 1Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, Washington; the 2Samuel Lunenfeld Research Institute, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada; the 3Biostatistics Center, George Washington University, Rockville, Maryland; the 4University of Texas Health Science Center at San Antonio, San Antonio, Texas; the 5Departments of Internal Medicine and Epidemiology, University of Michigan, Ann Arbor, Michigan; the 6Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, U.K.; 7GlaxoSmithKline, King of Prussia, Pennsylvania; and 8King’s College London School of Medicine, King’s College London, London, U.K. Corresponding author: Steven E. Kahn, MB, ChB, VA Puget Sound Health Care System (151), 1660 S. Columbian Way, Seattle, WA 98108. E-mail: [email protected]. Received for publication 30 November 2007 and accepted in revised form 22 January 2008. Published ahead of print at http://care.diabetesjournals.org on 5 February 2008. DOI: 10.2337/dc07-
2270. Clinical trial reg. no. NCT00279045, clinicaltrials.gov.
*A list of members of the ADOPT Study Group can be found in ref. 11. ADOPT was overseen by a steering committee comprising Steven Kahn and Giancarlo Viberti (cochairs), Steven Haffner, William Herman, Rury Holman, Paul Aftring, Nigel Jones, John Lachin, Colleen O’Neill, and Bernard Zinman. S.E.K., B.Z., J.M.L., S.M.H., W.H.H., R.R.H., and G.V. have received honoraria, consulting fees, and/or grant support from GlaxoSmithKline. G.V. holds stock in GlaxoSmithKline. B.G.K., D.Y., M.A.H., and R.P.A. are employees of GlaxoSmithKline and hold equity interest in the company. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/ dc07-2270. Abbreviations: ADOPT, A Diabetes Outcome Progression Trial. © 2008 by the American Diabetes Association.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

DIABETES CARE, VOLUME 31, NUMBER 5, MAY 2008

845

Rosiglitazone and fractures in type 2 diabetes

women we observed an increased occur- was defined as fasting plasma glucose considered statistically significant. Analyrence of bone fractures in the upper and Ͼ180 mg/dl on two successive occasions ses were conducted using SAS (SAS Instilower limbs, but an increase in hip or ver- or by independent adjudication (11). tebral fractures was not noted. An intute, Cary, NC). creased fracture risk was subsequently Concomitant medication use and reported in women receiving pioglitazone adverse event reporting (12), the other thiazolidinedione cur- Site investigators recorded all concomirently in clinical use. We now report in tant prescription medication use at basegreater detail the ADOPT findings related line and at each clinic visit. Medications

RESULTS

Demographic and clinical variables at baseline and follow-up

Women and men randomly assigned to the three treatment arms were well matched at baseline (Table 1). As anticipated, the majority of women in the study were aged Ͼ50 years (71%) and postmenopausal by self-report (77%). The proportions of patients at baseline using selected categories of medications related to bone health did not differ among the treatment groups within each sex (Table 1), although generally more women than men were using medications associated with better bone health (estrogen-containing hormones, calcium supplements, and bisphosphonates).

  • to fractures.
  • were classified using a validated coding

system (GSKDrug). Site investigators reported adverse events during the treatment portion of the study, and these were

RESEARCH DESIGN AND

METHODS — In ADOPT, 4,360 indi- categorized using the Medical Dictionary viduals with type 2 diabetes whose diabe- for Regulatory Activities (MedDRA). Fractes had been diagnosed within 3 years and tures included any preferred term with who were naive to oral hypoglycemic the text “fracture” within the higher-level drugs were randomly assigned. Nine of group term of “bone and joint injuries.” In the randomly assigned subjects never re- the case of fractures, the site of the fracceived study medication; 1,456 subjects tures was as reported to or determined by were assigned to rosiglitazone, 1,454 to the investigators with no adjudication or metformin, and 1,441 to glyburide ther- subsequent directed assessment perapy. The study was performed in 488 cen- formed as part of the study protocol. ters in 17 countries in North America and
The median duration of follow-up was 4.0 years for the rosiglitazone and metformin groups and 3.3 years for the glyburide group. The proportions of patients completing the study were 63, 62, and 56% for the rosiglitazone, metformin, and glyburide groups, respectively. Thus, the number of patient-years of medication exposure was 4,953.8 for the rosiglitazone group, 4,905.6 for the metformin cohort, and 4,243.6 for the glyburide group.
Europe. The protocol was reviewed and Methods, assays, and calculations approved by institutional review boards Fasting blood samples were drawn for for each center, and all subjects gave writ- measurement of fasting plasma glucose, ten, informed consent. The study was a A1C, and immunoreactive insulin levels.

  • registered clinical trial.
  • All assays were performed at a central lab-

The study protocol has been pub- oratory (13). lished previously (13). In brief, ADOPT was a randomized, double-blind, parallel- Statistical methods group trial. Eligible patients with diabetes The cumulative incidence of time-towere aged 30–75 and had a fasting plasma event variables was estimated by the glucose concentration between 126 and Kaplan-Meier method (14), with with180 mg/dl with lifestyle therapy. Exclu- drawals from study medication right cension criteria included clinically significant sored. The relative risk (hazard ratio liver disease, renal impairment, a history [HR]) was estimated from the Cox pro- Bone fractures by treatment of lactic acidosis, unstable or severe an- portional hazards model (14). These assignment gina, known congestive heart failure methods allow for differential duration of Of the 4,351 treated patients, 200 re(New York Heart Association classes exposure among groups. Treatment com- ported a fracture during the course of the I–IV) requiring pharmacological inter- parison of time to first fracture by body study: 92 (6.3%) among those randomly vention, uncontrolled hypertension, or site was also based on Cox proportional assigned to rosiglitazone, 59 (4.1%) in the chronic diseases requiring periodic or in- hazards regression but with Fisher’s exact metformin group, and 49 (3.4%) in the termittent treatment with oral or intrave- test if there were zero counts (i.e., no frac- glyburide group. Accounting for differ-

  • nous corticosteroids or continuous use of tures) in one of the treatment groups.
  • ences in treatment exposure, the inci-

inhaled corticosteroids. Wilcoxon’s rank-sum tests were used dence of a fracture was 1.86 per 100
Subjects were randomly assigned to to compare baseline variables between patient-years with rosiglitazone, 1.20 per receive double-blind treatment with ei- groups on the basis of treatment assign- 100 patient-years with metformin, and ther rosiglitazone, metformin, or gly- ment (15). Differences in proportions 1.15 per 100 patient-years with glyburide. The initial daily doses were 4 mg were tested using the contingency ␹2 test, buride. Figure 1A presents the Kaplanrosiglitazone, 500 mg metformin, and 2.5 and differences in quantitative or ordinal Meier estimated cumulative incidence of a mg glyburide, and the dose was titrated to variables were tested using the Kruskal- fracture (95% CI), reaching 9.8% (7.7– the maximum effective daily dose (4 mg Wallis test (15). Cox proportional haz- 11.9) at 5 years with rosiglitazone, 5.6% rosiglitazone twice daily, 1 g metformin ards models were used to assess the effect (4.1–7.1) with metformin, and 5.7% twice daily, and 7.5 mg glyburide twice of the updated current values of weight, (3.9–7.6) with glyburide. With the Cox daily). Forced titration of the dose of serum creatinine, hematocrit, calcium, proportional hazards model, estimated medication occurred at each visit when A1C, and waist circumference as time- HRs (95% CI) for risk of fracture with the fasting plasma glucose level was Ն140 dependent covariates on the risk of rosiglitazone versus metformin and glymg/dl. The primary outcome was time to fractures. monotherapy failure with the maximum Data are presented as means Ϯ SD 0.0073) and 1.61 (1.14 –2.28; P ϭ tolerated dose of the study drug, which unless specified. Two-sided P Յ 0.05 was 0.0069), respectively. Interestingly, the buride were 1.57 (1.13–2.17; P ϭ

846

DIABETES CARE, VOLUME 31, NUMBER 5, MAY 2008

Kahn and Associates

Table 1—Baseline demographic characteristics, clinical measures, and prior medication use in men and women by treatment assignment

  • Women
  • Men

  • Rosiglitazone
  • Metformin
  • Glyburide
  • Rosiglitazone
  • Metformin
  • Glyburide

n

645
56.1 Ϯ 10.2
498 (77.2)
590
56.7 Ϯ 10.0
463 (78.5)
605
56.3 Ϯ 10.7
449 (74.2)
811
56.4 Ϯ 9.9
NA
864
57.0 Ϯ 9.9
NA
836
56.6 Ϯ 9.8
NA
Age (years) Postmenopausal Time since diagnosis of diabetes

  • Ͻ1 year
  • 275 (42.6)

351 (54.4)
18 (2.8)
33.6 Ϯ 7.2
103.4 Ϯ 15.3 0.90 Ϯ 0.09 132.2 Ϯ 15.8
79.0 Ϯ 8.8
281 (47.6) 288 (48.8)
21 (3.6)
33.8 Ϯ 6.8
104.4 Ϯ 15.2 0.91 Ϯ 0.09 132.9 Ϯ 15.2
79.3 Ϯ 8.5
278 (46.0) 309 (51.1)
18 (3.0)
33.8 Ϯ 7.1
103.8 Ϯ 16.3 0.90 Ϯ 0.09 132.3 Ϯ 15.1
79.2 Ϯ 8.7
375 (46.2) 407 (50.2)
29 (3.6)
31.1 Ϯ 6.1
106.7 Ϯ 13.9 0.99 Ϯ 0.07
133.65 Ϯ 15.5
80.4 Ϯ 8.5
392 (45.4) 436 (50.5)
36 (4.2)
31.0 Ϯ 5.2
106.4 Ϯ 13.6 0.98 Ϯ 0.09 132.8 Ϯ 15.6
80.0 Ϯ 9.2
359 (42.9) 442 (52.9)
35 (4.2)
31.0 Ϯ 5.3
106.8 Ϯ 14.2 0.98 Ϯ 0.07 133.0 Ϯ 15.6
79.4 Ϯ 9.1
1–2 years Ͼ2 years BMI (kg/m2) Waist circumference (cm) Waist-to-hip ratio Systolic blood pressure (mmHg) Diastolic blood pressure
(mmHg)
Fasting plasma glucose (mg/dl) A1C (%)
150.9 Ϯ 23.3 7.37 Ϯ 0.89 154.2 Ϯ 99.1
125 (19.4)
41 (6.4) 12 (1.9) 47 (7.3)
120 (18.6)
20 (3.1)
150.6 Ϯ 25.6 7.36 Ϯ 0.93
162.6 Ϯ 113.4
137 (23.2)
52 (8.8) 11 (1.9) 41 (6.9)
123 (20.8)
27 (4.6)
151.9 Ϯ 27.6 7.35 Ϯ 0.88
167.8 Ϯ 132.3
114 (18.8)
40 (6.6) 8 (1.3) 51 (8.4)
126 (20.8)
23 (3.8)
152.0 Ϯ 27.6 7.36 Ϯ 0.97
146.4 Ϯ 114.9
1 (0.1) 11 (1.4) 1 (0.1) 61 (7.5)
109 (13.4)
9 (1.1)
151.9 Ϯ 25.6 7.36 Ϯ 0.94
144.5 Ϯ 109.9
1 ( 0.1)
152.8 Ϯ 27.1 7.34 Ϯ 0.95 137.9 Ϯ 95.1
0
5 (0.6) 1 (0.1) 53 (6.3) 94 (11.2) 16 (1.9)
Fasting insulin (pmol/l) Estrogen-containing hormones Calcium supplements Bisphosphonates Glucocorticoids* Thiazide diuretics Loop diuretics
15 (1.7) 2 (0.2) 50 (5.8) 96 (11.1) 18 (2.1)

Data are means Ϯ SD or n (%). *Includes all routes of administration. NA, not applicable.

increased risk of fracture with rosiglita- 2.74 per 100 patient-years with rosiglita- ceiving rosiglitazone, 6.8% (10 of 147) zone was first apparent after ϳ12 months zone, 1.54 per 100 patient-years with reported a fracture versus 3.2% (4 of 127)

  • of therapy.
  • metformin, and 1.29 per 100 patient- receiving metformin (P ϭ 0.1709) and

years with glyburide. The cumulative in- 1.9% (3 of 156) receiving glyburide (P ϭ cidence of a fracture (Fig. 1C) reached 0.0362). Among postmenopausal

Bone fractures in men

Among the 2,511 men, 89 reported a frac- 15.1% (95% CI 11.2–19.1) at 5 years women, 10.0% (50 of 498) receiving rosture, with no difference among the with rosiglitazone, 7.3% (4.4–10.1) with iglitazone, 5.6% (26 of 463) receiving groups: 32 (4.0%) of those treated with metformin, and 7.7% (3.7–11.7) with metformin, and 4.0% (18 of 449) receivrosiglitazone, 29 (3.4%) with metformin, glyburide. With the Cox proportional ing glyburide reported a fracture (P ϭ and 28 (3.4%) with glyburide. The inci- hazards model, estimated HR (95% CI) 0.0111 for rosiglitazone versus metdence allowing for the period of exposure for risk of fracture with rosiglitazone ver- formin and P ϭ 0.0003 versus glyburide).

  • was 1.16 per 100 patient-years with ros- sus metformin was 1.81 (1.17–2.80; P ϭ
  • Table 2 presents demographics, clin-

iglitazone, 0.98 per 100 patient-years 0.008) and for rosiglitazone versus gly- ical characteristics, and selected prior with metformin, and 1.07 per 100 pa- buride was 2.13 (1.30 –3.51; P ϭ medication use at baseline among women tient-years with glyburide. Figure 1B pre- 0.0029). There was no apparent in- who did and did not report a fracture sents the Kaplan-Meier estimated creased risk of fractures with rosiglitazone within each treatment group. Women in cumulative incidence of a fracture, dem- over the first 12 months of exposure, the the glyburide group who reported fraconstrating no significant difference in risk increased risk being manifest beyond 12 tures were older at baseline; in the rosiglias estimated from the Cox proportional months of exposure. Fracture risk did not tazone group, more women who reported hazards model. Greater detail of the sites appear to be related to ethnicity, but a fracture were receiving treatment for hyof fractures by treatment assignment in numbers in the subgroups were small. pertension at baseline.

  • men is listed in Table 1 of the online ap- Among women with a fracture, 11.7% in
  • Table 2 of the online appendix pre-

pendix, available at http://dx.doi.org/ the rosiglitazone, 16.7% in the met- sents the proportions of selected concom-

  • 10.2337/dc07-2270.
  • formin, and 23.8% in the glyburide itant medications used by women with a

groups reported an accidental limb injury fracture (up until the time of first fracture) or fall within 30 days before the fracture. and those without a fracture (at any time

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  • Utah Medicaid Pharmacy and Therapeutics Committee Drug

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    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 ..................................................................................................................................................
  • Muraglitazar Bristol-Myers Squibb/Merck Daniella Barlocco

    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].
  • Thiazolidinedione Derivatives in Type 2 Diabetes Mellitus

    Thiazolidinedione Derivatives in Type 2 Diabetes Mellitus

    r E v i E w Thiazolidinedione derivatives in type 2 diabetes mellitus C.J.J. Tack, P. Smits*# Department of Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands, *corresponding author: [email protected] A b s T r act in Europe, the thiazolidinedione derivatives pioglitazone approved for use in combination therapy. Unlike the situation and rosiglitazone have been approved for the treatment of in the USA, TZDs are not approved, but even contraindicated type 2 diabetes mellitus either as monotherapy for patients for use in combination with insulin in Europe. From the day with intolerance or contraindications to metformin or in of approval onwards, there has been discussion concerning combination therapy. This class of drugs seems particularly the exact place of TZDs within the pharmacotherapy of suited for obese patients, but is currently not considered as type 2 diabetes mellitus. Different views have resulted in a first choice for monotherapy. The efficacy with respect to differences in guidelines and treatment standards. The lack blood glucose lowering is comparable with sulphonylurea of data on long-term clinical studies with ‘hard’ endpoints (SU) derivatives and with metformin. long-term data with (mortality and new macrovascular events) definitively plays respect to efficacy and side effects are still limited. an important role in this discussion. Recently, the first outcome study was published (the PROactive study),1 but this study has also raised several questions.2-5 K E y w o r d s With respect to glucose regulation, TZDs do not seem to be superior to the conventional drugs metformin or Combination therapy, monotherapy, pioglitazone, sulphonylurea (SU) derivatives.
  • Thiazolidinedione Drugs Down-Regulate CXCR4 Expression on Human Colorectal Cancer Cells in a Peroxisome Proliferator Activated Receptor Á-Dependent Manner

    Thiazolidinedione Drugs Down-Regulate CXCR4 Expression on Human Colorectal Cancer Cells in a Peroxisome Proliferator Activated Receptor Á-Dependent Manner

    1215-1222 26/3/07 18:16 Page 1215 INTERNATIONAL JOURNAL OF ONCOLOGY 30: 1215-1222, 2007 Thiazolidinedione drugs down-regulate CXCR4 expression on human colorectal cancer cells in a peroxisome proliferator activated receptor Á-dependent manner CYNTHIA LEE RICHARD and JONATHAN BLAY Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, B3H 1X5, Canada Received October 26, 2006; Accepted December 4, 2006 Abstract. Peroxisome proliferator activated receptor (PPAR) Introduction Á is a nuclear receptor involved primarily in lipid and glucose metabolism. PPARÁ is also expressed in several cancer types, Peroxisome proliferator activated receptors (PPARs) are and has been suggested to play a role in tumor progression. nuclear hormone receptors that are involved primarily in PPARÁ agonists have been shown to reduce the growth of lipid and glucose metabolism (1). Upon ligand activation, colorectal carcinoma cells in culture and in xenograft models. these receptors interact with the retinoid X receptor (RXR) Furthermore, the PPARÁ agonist thiazolidinedione has been and bind to peroxisome proliferator response elements (PPREs), shown to reduce metastasis in a murine model of rectal cancer. leading to transcriptional regulation of target genes. Members Since the chemokine receptor CXCR4 has emerged as an of the thiazolidinedione class of antidiabetic drugs act as important player in tumorigenesis, particularly in the process ligands for PPARÁ (2), as does endogenously produced 15- 12,14 of metastasis, we sought to determine if PPARÁ agonists deoxy-¢ -prostaglandin J2 (15dPGJ2) (3). might act in part by reducing CXCR4 expression. We found In addition to regulation of glucose metabolism, PPARÁ that rosiglitazone, a thiazolidinedione PPARÁ agonist used appears also to be involved in tumorigenesis, although its primarily in the treatment of type 2 diabetes, significantly exact role has yet to be elucidated (4).
  • DPP-4 Inhibitors and Combinations Step Therapy and Quantity Limit

    DPP-4 Inhibitors and Combinations Step Therapy and Quantity Limit

    DPP-4 Inhibitors and Combinations Step Therapy and Quantity Limit Program Summary Preferred agents in this program are Januvia, Janumet, Janumet XR. Non-preferred agents in this program are Jentadueto, Jentadueto XR, Kazano, Kombiglyze XR, Nesina, Onglyza, Oseni, Tradjenta. All agents are subject to Quantity Limits. FDA APPROVED INDICATIONS AND DOSAGE2-11, 13 Dosage and Drug Indication Limitations for use Administration DPP-4 Inhibitors Januvia® Indicated as an • Should not be used in 25 mg, 50 mg, 100 (sitagliptin) adjunct to diet and patients with type 1 mg; 1 tablet per day, exercise to improve diabetes or for the maximum daily dose tablet glycemic control in treatment of diabetic of 100 mg adults with type 2 ketoacidosis, as it would diabetes mellitus not be effective in these settings. • Has not been studied in patients with a history of pancreatitis. Nesina® Indicated as an • Is not indicated for the 6.25 mg, 12.5 mg, 25 (alogliptin) adjunct to diet and treatment of type 1 mg; 1 dose per day, exercise to improve diabetes mellitus or maximum daily dose tablet glycemic control in diabetic ketoacidosis, as it of 25 mg adults with type 2 would not be effective in diabetes mellitus these settings. Onglyza® Indicated as an • Is not indicated for the 2.5 mg, 5 mg; 1 dose (saxagliptin) adjunct to diet and treatment of type 1 per day, maximum exercise to improve diabetes mellitus or daily dose of 5 mg tablet glycemic control in diabetic ketoacidosis, as it adults with type 2 would not be effective in diabetes mellitus these settings.
  • Pioglitazone, a Peroxisome Proliferator-Activated Receptor

    Pioglitazone, a Peroxisome Proliferator-Activated Receptor

    0023-6837/03/8312-1715$03.00/0 LABORATORY INVESTIGATION Vol. 83, No. 12, p. 1715, 2003 Copyright © 2003 by The United States and Canadian Academy of Pathology, Inc. Printed in U.S.A. Pioglitazone, a Peroxisome Proliferator-Activated Receptor-␥ Agonist, Attenuates Myocardial Ischemia/Reperfusion Injury in a Rat Model Haruyasu Ito, Atsushi Nakano, Makoto Kinoshita, and Akira Matsumori The Department of Cardiovascular Medicine, Kyoto University, Graduate School of Medicine, Kyoto, Japan SUMMARY: Thiazolidinediones are insulin-sensitizing drugs, ligands for peroxisome proliferator-activated receptor-␥ (PPAR-␥), which play an important role in the modulation of inflammatory responses. Myocardial ischemia/reperfusion (MI/R) injury is associated with inflammation, in which various cells, particularly monocytes and macrophages, are involved. This study examined the effects of the thiazolidinedione peroxisome proliferator-activated receptor-␥ ligand, pioglitazone, in a rat model of MI/R injury. Pioglitazone at 3 mg/kg/day or the vehicle was administered for 7 days before rats were subjected to 30 minutes of coronary ligation followed by 24 hours of reperfusion. The mRNA expression [monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule-1] in the ischemic region, the number of infiltrating macrophages in the ischemic region, and the myocardial infarct size were examined. The inhibitory effects of pioglitazone on activated macrophages were studied in vitro. Phorbol 12-myristate 13-acetate–induced MCP-1 production, in the absence or presence of pioglitazone, were assayed in cultured macrophages. Compared with the control group, (1) mRNA levels of MCP-1 and intercellular adhesion molecule-1 and the number of infiltrating macrophages in the ischemic region were significantly lower in the pioglitazone-treated group; and (2) myocardial infarct size was significantly smaller in the pioglitazone-treated group.
  • Peroxisome Proliferator-Activated Receptors and Their Novel Ligands As Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease

    Peroxisome Proliferator-Activated Receptors and Their Novel Ligands As Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease

    cells Review Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease Anne Fougerat 1,*, Alexandra Montagner 1,2,3, Nicolas Loiseau 1 , Hervé Guillou 1 and Walter Wahli 1,4,5,* 1 Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; [email protected] (A.M.); [email protected] (N.L.); [email protected] (H.G.) 2 Institut National de la Santé et de la Recherche Médicale (Inserm), Institute of Metabolic and Cardiovascular Diseases, UMR1048 Toulouse, France 3 Institute of Metabolic and Cardiovascular Diseases, University of Toulouse, UMR1048 Toulouse, France 4 Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Clinical Sciences Building, 11 Mandalay Road, Singapore 308232, Singapore 5 Center for Integrative Genomics, Université de Lausanne, Le Génopode, CH-1015 Lausanne, Switzerland * Correspondence: [email protected] (A.F.); [email protected] (W.W.); Tel.: +33-582066376 (A.F.); +41-79-6016832 (W.W.) Received: 29 May 2020; Accepted: 4 July 2020; Published: 8 July 2020 Abstract: Non-alcoholic fatty liver disease (NAFLD) is a major health issue worldwide, frequently associated with obesity and type 2 diabetes. Steatosis is the initial stage of the disease, which is characterized by lipid accumulation in hepatocytes, which can progress to non-alcoholic steatohepatitis (NASH) with inflammation and various levels of fibrosis that further increase the risk of developing cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is influenced by interactions between genetic and environmental factors and involves several biological processes in multiple organs. No effective therapy is currently available for the treatment of NAFLD.
  • Pharmacy Medical Necessity Guidelines: Thiazolidinediones

    Pharmacy Medical Necessity Guidelines: Thiazolidinediones

    Pharmacy Medical Necessity Guidelines: Thiazolidinediones (TZDs) Effective: March 9, 2021 Prior Authorization Required √ Type of Review – Care Management Not Covered Type of Review – Clinical Review √ Pharmacy (RX) or Medical (MED) Benefit RX Department to Review RXUM These pharmacy medical necessity guidelines apply to the following: Fax Numbers: Commercial Products RXUM: 617.673.0988 Tufts Health Plan Commercial products – large group plans Tufts Health Plan Commercial products – small group and individual plans Tufts Health Freedom Plan products – large group plans Tufts Health Freedom Plan products – small group plans • CareLinkSM – Refer to CareLink Procedures, Services and Items Requiring Prior Authorization Tufts Health Public Plans Products Tufts Health Direct – A Massachusetts Qualified Health Plan (QHP) (a commercial product) Tufts Health Together – MassHealth MCO Plan and Accountable Care Partnership Plans Tufts Health RITogether – A Rhode Island Medicaid Plan Note: This guideline does not apply to Medicare Members (includes dual eligible Members). OVERVIEW FOOD AND DRUG ADMINISTRATION-APPROVED INDICATIONS ActoPlus Met XR (pioglitazone/metformin extended release tablet) is a thiazolidinedione and biguanide combination product indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both pioglitazone and metformin is appropriate. Avandia (rosiglitazone) is a thiazolidinedione indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Neither Avandia nor ActoPlus Met XR is indicated for the treatment of type 1 diabetes or diabetic ketoacidosis. Thiazolidinediones (TZDs) have a Black Box Warning regarding heart failure; TZDs have been associated with causing or exacerbating congestive heart failure.