Presentation on theme: "Nonglycemic Effects of Thiazolidinediones"— Presentation transcript:
1Nonglycemic Effects of Thiazolidinediones Thomas Repas D.O.Diabetes, Endocrinology and Nutrition Center, Affinity Medical Group, Neenah, WisconsinMember, Inpatient Diabetes Management Committee, St. Elizabeth’s Hospital, Appleton, WIMember, Diabetes Advisory Group, Wisconsin Diabetes Prevention and Control ProgramWebsite:
2Please Note:This presentation discusses investigational, off label and non-FDA indicated effects of thiazolidinediones (glitazones). Please be aware that TZDs are FDA approved for treatment of hyperglycemia in type 2 diabetes only. This presentation is for informational and educational purposes only and is not intended to encourage or recommend any off label uses of any pharmaceutical product (s).
3TZDs : Mechanisms of Action Intestine: glucose absorptionBlood glucosePancreas: insulin secretionSaltiel AR, Olefsky JM. Diabetes. 1996;45:Suter SL et al. Diabetes Care. 1992;15:Whitcomb RW et al. In: Diabetes Mellitus. 1996:
4Effects of thiazolidinediones on cardiovascular risk factors and atherosclerotic mechanisms triglycerides glycemia FFA BP HDLThiazolidinediones PAI-1 LDL oxidative stress monocytesubendothelial transmigrationVSMC migration and proliferation
5Peroxisome Proliferator-activated Receptors PPAR a Agonists PPAR aFatty AcidsFibratesFatty Acid, HDL MetabolismPPAR g Agonists PPAR gOxidized LipidsThiazolidinedioinesAdipogenesis, insulin sensitivityPPARs are mediators of vascular disease, inflammation and endothelial dysfunction
6Thiazolidinediones and PPAR g AdipogenesisGlucose TransportMonocyte DifferentiationInduction of Scavenger ReceptorInhibition of Cytokine ProductionThiazolidinedionePPARgRetinoic AcidX ReceptormRNARXRPromotorC3PCIII GenePPAR agonists affect glucose transport at the gene level as previously described. The therapeutic agents available to clinicians to modulate PPAR effects are rarely pure PPAR or PPAR agonists. Rather, there is usually some degree of overlap in effect.3
7Thiazolidinediones and “Insulin Resistance” XGlucoseGLUT-4Insulin has many actions in energy metabolism. (See the Core Curriculum Section of this site). Briefly, insulin inhibits the release of glucose from glycogen stores in the liver, increases peripheral glucose uptake by the GLUT-4 transporter, decreases the production of triglyceride-rich lipoproteins and increases peripheral triglyceride disposal. Insulin resistant patients have impaired activity of the GLUT-4 transporter, which leads to hyperglycemia.
8Thiazolidinediones and “Insulin Resistance” XGlucoseGLUT-1GLUT-4Thiazolidinediones (TZDs) are thought of as insulin sensitizers, but in actuality do not affect GLUT-4. Rather, TZDs open a “back door” for glucose transport into the intracellular space by activating the GLUT-1 transporter.
9Effect of Pioglitazone on Insulin Resistance: HOMA-IR Rosenstock J for the Pioglitazone HCl Study Group. Diabetologia. 2000;43(suppl 1):A192. Matthews DR et al. Diabetologia. 1985;28:
10Effect of Pioglitazone on Lipid Levels W/NDEI/2854/Therapy.ppt 3/8/02 4:47 PMEffect of Pioglitazone on Lipid LevelsRosenblatt S et al. Coron Artery Dis. 2001;12:10 NATIONAL DIABETES EDUCATION INITIATIVE™ FOR HEALTHCARE PROFESSIONALS
11Lipid Effects of Pioglitazone with Metformin Einhorn D et al. Clin Ther. 2000;22:
12Association Between sdLDL and Insulin Resistance 12(n=19)10(n=29)8plasma glucose (mmol/L) at identical plasma insulinMean steady state(n=52)642Association Between Small, Dense LDL and Insulin ResistanceThe goal of this study was to see if individuals who were classified as pattern B on the basis of their LDL particle diameter were also insulin resistant.The study population consisted of 100 adults, 52 women and 48 men, who had no history or symptoms of any known disease and had a normal physical examination and routine findings on general blood chemical analyses, hemogram, and resting electrocardiogram. Subjects were not receiving any medicine known to influence lipid metabolism or glucose tolerance.Pattern B subjects had higher total integrated glucose and insulin responses to oral glucose compared with glucose and insulin responses in those with either pattern A or an intermediate pattern.Pattern B individuals were shown to be more insulin resistant and had higher concentrations of triglycerides and lower HDL cholesterol than those with either pattern A or the intermediate.There were also significant correlation coefficients that existed between LDL diameter and steady state plasma glucose concentrations, glucose and insulin responses, triglycerides and HDL cholesterol concentrations, and systolic and diastolic blood pressure.Reaven GM, et al. J Clin Invest ;92:ALarger LDL particlepatternIntermediatepatternBSmall LDL particlepatternLDL-size phenotypeReaven GM, et al. J Clin Invest. 1993;92:
13Effect of Rosiglitazone on LDL Particle Density* Rf < (smaller, dense)Rf (larger, more buoyant)80706050% of Patients4030RF=Relative flotation2010Study EntryWeek 8 - Rosiglitazone*% of patients by particle size before and after 8 weeks of Rosiglitazone 4 mg bid in a randomized placebo-controlled pharmacodynamic study (N=234)Study 108. Data on file, GlaxoSmithKline.
14020: LDL/ApoB Ratio Baseline to Wk 26 GlyburideRSG 2mg bdRSG 4mg bdMean Change in LDL/ApoB-0.04-0.020.000.020.040.060.08(ROSIGLITAZONE/020 - ITT Population)(Error Bars = 95% CI)
15Rosiglitazone Effects on HDL Sub-fractions 25Week 820Week 2415Mean percentage change95% CI)10+(5-5HDL-2HDL-3Data on File (Study 108). GlaxoSmithKline.Geometric Mean (ITT, LOCF)
16Pioglitazone effects on Small, Dense LDL Winkler, K et al. Diabetes Care. 2003;26:
17Atherogenic Index of Plasma Atherogenic index of plasma = the logarithmic transformation of the triglyceride:HDL cholesterol ratio (correlates inversely with the LDL particle size)Lee, C. et al. Abstract 688-P . American Diabetes Association 63rd Scientific Sessions. 6/03
18Satoh, et al. Diabetes Care. 2003; 26: 2493-2499. Potential Antiatherogenic Effects of PioglitazoneSatoh, et al. Diabetes Care. 2003; 26:
19Occur Independent of Antidiabetic Effect Satoh, et al. Diabetes Care. 2003; 26:
20Multiple Factors May Drive Progressive Decline of -Cell Function “Glucotoxicity”(hyperglycemia)Insulin Resistance-cell“Lipotoxicity”(elevated FFA, TG)Multiple Factors May Drive Progressive Decline of Beta-Cell FunctionInsulin resistance can lead to hyperglycemia, elevated free fatty acids, and increased triglycerides. These, along with protein glycation, can contribute to beta-cell decline and apoptosis.Reaven GM. Physiol Rev. 1995;73:Adapted from Reaven GM. Physiol Rev 1995;73:473–486.
21Effect of TZD’s on Free Fatty Acids Treatment Weeks24681216263852Free Fatty Acids (mg/dL)1820222428No. at No. atBaseline wk 52GlyburideRSG 4 mg*RSG 8 mg*ITT without LOCF*Given in divided dosesStudy 020. Data on file; GlaxoSmithKline.
22Thiazolidinedione Increases Islet Insulin in db/db Mice 28 days treatment with RSG 1.42 mg/kg MET 100 mg/kg GLI mg/kg Mice treated for 28 days ~6–7 wk of age.Lister CA, Moore GBT, Piercy V, et al. 35th Annual EASD, Brussels, Belgium, Sept 28, 1999: Poster.
24Visceral Fat Distribution: Normal vs Type 2 Diabetes Slide 13Visceral Fat Distribution:Normal vs Type 2 DiabetesAs seen in computed tomographic (CT) scans, the distribution of visceral fat (white areas) differs in a subject with normal glucose tolerance (left) and in a subject with type 2 diabetes (right). The two subjects had similar waist circumferences, but the individual with type 2 diabetes had a larger amount of visceral fat than did the subject with normal glucose tolerance. The amount of subcutaneous fat was larger in the subject with normal glucose tolerance than in the subject with type 2 diabetes.
25Fat Distribution Study 083 Intra-abdominal Fat Area (MRI) Subcutaneous Fat Area (MRI)Mean Change from Baseline (cm2)40Mean Change from Baseline (cm2)4035p=0.0223530302525202015p=0.652p=0.695p=0.55915101055PlaceboRSG 4 mg bdn=14n=10PlaceboRSG 4 mg bdn=14n=10Intrahepatic Fat (MRS)64p=0.6922Fat DistributionStudy 083Mean Change from Baseline (%)-2-4-6-8-10p=0.036-12Carey D et al. Diabetologia 2000.PlaceboRSG 4 mg bdn=16n=12
26Effects of TZDs on Hepatic Fat Type 2 diabetics on 45 mg/d pioglitazone for 16 weeks21 + 4%Percent Hepatic Fat Content11 + 2%N=11P< 0.01Bajaj, M. et al. Abstract P-597-P.ADA 63rd Scientific Sessions. 6/03.
27Effects of Pioglitazone on Microalbuminuria Four long-term studies-the "Quartet studies" involved more than 3,700 patients from 28 countries across EuropeMet-1%Met/SU+6%Change in Urinary Alb/Cr Ratio from BaselinePio/SUSU-10%-17%PioPio/Met-20%-15%Urquhart, R. et al. Abstract 585-P . American Diabetes Association 63rd Scientific Sessions. 6/03
28Effects of Rosiglitazone on Microalbuminuria All patientsPatients with MA at baseline30n = 132*20-10Placebo10-20RSG (4 mg/day)*n = 33-30RSG (8 mg/day)Mean change in albumin:creatinine at 26 weeks (%)Mean change in albumin:creatinine at 26 weeks (%)-10-40-20-50-30*n = 142*n = 36*n = 145P < 0.001-60*n = 35-40* Error bars = 94% confidence intervalsLebovitz HE, et al. J Clin Endocrinol Metab 2001; 86:280–288.
29Mean Ambulatory Blood Pressure 5RSG (8 mg/day)4Optimally titrated SU32Change in blood pressure at 52 weeks (mmHg)1-1-2-3P =Systolic BPDiastolic BPBakris GL, et al. Diabetes 2000; 49 (Suppl. 1):A96.
30Effect of RSG on Fibrinolysis Study 127 PAI-1 AntigenPAI-1 Activity40p=0.3573020p=0.03710Mean Change (%)-10-20-30-40D= -33.8% (95CIs: -50.5, -11.6)p=0.006SUSU + RSGStudy 127 ITT LOCF Freed et al. Diabetologia 2000.