DIABETOGENICIDAD DE LAS ESTATINAS

Transcription

1 DIABETOGENICIDAD DE LAS ESTATINAS Lluís Masana Marín Unidad de Medicina Vascular y Metabolismo Hospital Universitario Sant Joan Universidad Rovira i Virgili, IISPV, CIBERDEM REUS

2 Statins and diabetes Google search: About 7,600,000 results Pubmed search: 4096 In 2012 the U.S. FDA changed the wording on all statins except pravastatin; Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including 1 1. Zocor label. FDA update Reference ID: Available at Accessed April 2014

3 Increased risk of diabetes in JUPITER Analysis from JUPITER* (n=17,802) Event Monitored adverse events Rosuvastatin (N=8901) Placebo (N=8901) Any serious event no. (%) 1352 (15.2) 1377 (15.5) 0.60 Muscular weakness, stiffness or pain no. (%) 1421 (16.0) 1375 (15.4) 0.34 Myopathy no. (%) 10 (0.1) 9 (0.1) 0.82 Rhabdomyolysis no. (%) 1 (<0.1) 0 Newly diagnosed cancer no. (%) 298 (3.4) 314 (3.5) 0.51 Death from cancer no. (%) 35 (0.4) 58 (0.7) 0.02 Gastrointestinal disorder no. (%) 1753 (19.7) 1711 (19.2) 0.43 Renal disorder no. (%) 535 (6.0) 480 (5.4) 0.08 Bleeding no. (%) 258 (2.9) 275 (3.1) 0.45 Hepatic disorder no. (%) 216 (2.4) 186 (2.1) 0.13 Laboratory values Creatinine, >100% increase from baseline no. (%) 16 (0.2) 10 (0.1) 0.24 Glomerular filtration rate at 12 mo ml/min/1.73m Median Interquartile range Alanine aminotransferase >3xULN on consecutive visits no. (%) 23 (0.3) 17 (0.2) 0.34 Glycated haemoglobin at 24 mo - % P Value Median Interquartile range Fasting glucose at 24 mo mg/dl 0.12 Median Interquartile range Trace of glucose in urine at 12 mo no. (%) 36 (0.5) 32 (0.4) 0.64 Other events Newly diagnosed diabetes (physician-reported) no. (%) 270 (3.0) 216 (2.4) 0.01 Haemorrhagic stroke no. (%) 6 (0.1) 9 (.01) 0.44 Ridker et al. NEJM 2008;359(21): *JUPITER: Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin

4 Statins increase the risk of T2D by 9% over 4 years (n=91,140) Decreased risk of diabetes Increased risk of diabetes Sattar et al. Lancet 2010; 375:

5 Incident diabetes Incident diabetes The Increased Risk of Diabetes Largely Occurs in Patients With 1 or More Risk Factor. Analysis from JUPITER* (n=17,603) Cumulative incidence of diabetes in those with or without 1 or more risk factors 0.15 No risk factors or more risk factors Rosuvastatin 20mg Placebo Rosuvastatin 20mg Placebo Follow up (years) Number at risk Rosuvastatin Placebo Follow up (years) Number at risk Rosuvastatin Placebo Population Deaths/CV events avoided New diabetes cases Those with no diabetes risk factors at baseline 86 0 Those with 1 or more diabetes risk factors at baseline Ridker et al. Lancet 2012;380: *JUPITER: Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin

6 Patients with new onset diabetes (%) Independent Risk Factors for the Development of Diabetes with High Dose Atorvastatin Analysis from TNT* (n=7,595) Characteristic absent Characteristic present Fasting glucose >100 mg/dl Triglycerides >150 mg/dl BMI >30kg/m 2 History of hypertension Waters et al. JACC. 2011;57(14): *TNT: Treat to New Targets

7 % Patients with new onset diabetes Risk of T2DM with Atorvastatin is Strongly Correlated to the Presence of Risk Factors TNT HR=5.78 p< HR=2.04 p< HR=2.73 p< HR=1.64 p< Risk Factor Absent Risk Factor Present IDEAL HR=4.72 p< HR=1.88 p< HR=2.59 p< HR=1.60 p< SPARCL HR=3.49 p< HR=2.37 p< HR=2.36 p< HR=1.91 p< Waters et al. J Am Coll Cardiol 2011;57: FPG>100mg/dL TG>150mg/dL BMI>30mg/m 2 History of hypertension

8 The Risk of New-Onset Diabetes is Affected by the Number of Metabolic Risk Factors in Patients with Established CVD Risk factors Incidence % TNT *Trial (n=7,595) IDEAL* Trial (n=7,595) SPARCL* Trial (n=3,803) HR (95% CI) P value Incidence % HR (95% CI) P value Incidence % HR (95% CI) P value < < < < < < < < < < < Total Waters et al. JACC 2011;57:1535 *TNT: Treat to New Targets; SPARCL: Stroke Prevention by Aggressive Reduction in Cholesterol Levels; IDEAL: Incremental Decrease in End Points Through Aggressive Lipid Lowering

9 The use of statins in people at risk of developing diabetes mellitus: Evidence and guidance for clinical practice The diabetogenic effects of statins appear to be dose-related. N.A. Sattar et al. / Atherosclerosis Supplements 15 (2014) 1e15

10 Role of diuretics, β blockers, and statins in increasing the risk of diabetes in patients with impaired glucose tolerance: reanalysis of data from the NAVIGATOR study Shen L et al. BMJ 2013;347:f6745

11 HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials HMGCR gene, rs (for the main analysis) and Rs individuals from 43 genetic studies Swerdlow DI et al Lancet. September 24,

12 HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials Swerdlow DI et al Lancet. September 24,

13 Son todas las estatinas iguales?

14 Statins vary in chemical structure O HO CO 2 Na OH O HO O O HO CO 2 Na OH O O F N HO Pravastatin Simvastatin Fluvastatin HO - CO 2 OH HO - CO 2 OH HO - CO 2 OH F N Ca 2+ F Ca 2+ F Ca 2+ HN O N N N N S Atorvastatin Pitavastatin O 2 Rosuvastatin

15 Statins Exert Differential Effects on Insulin Sensitivity (IS) Among Non-diabetic Patients Pravastatin Koh (-0.088, 0.971) Sugyama (-0.144, 1.114) Gannage-Yared (-0.621, 0.621) Subtotal (0.032, 0.651) Atorvastatin Huptes (-0.929, 0.824) Stalenhoef (-0963, 0.333) Watts (-1.279, 0.412) Costa (-0.379, 0.994) Chan (-0.844, 0.726) Subtotal (-0.243, 0.205) Rosuvastatin Kastaganos (0.474, 0.243) Sviridov (0.512, 0.645) Ooi 2007a (-1.008, 0.952) Ooi 2007b (-1.060, 0.901) Tar Avest (0.727, 0.560) Stalenhoef (-0.357, 0.345) Subtotal (-0.223, 0.148) Simvastatin Koh (-0.902, 0.143) Koh 2008a (-1.303, 0.274) Koh 2008b (-1.429, 0.146) Koh 2008c (-1.288, 0.282) Koh 2008d (-1.288, 0.282) Devaraj (-0.336, 0.776) Altunbas (-1.614, 0.285) Jula (-0.613, 0.106) Subtotal (-0.526, 0.117) Excluding Pravastatin (-0.284, ) Overall (-0.210, 0.042) Meta analysis of 16 placebo-controlled trials among non-diabetics involving atorvastatin, pravastatin, rosuvastatin or simvastatin (n=1146) Pravastatin significantly improved IS [SMD (95% CI ); p=0.03] Simvastatin significantly worsened IS [SMD (95% CI to 0.117); p=0.03] Standarized mean difference (95% CI) Baker et al. Diabetes Res Clin Pract Jan;87(1):

16 Short-Term Effect of Pitavastatin Treatment on Glucose Metabolism Kakuda H et al. Cholesterol. 2013;2013: doi: /2013/ Epub 2013 Dec 10.

17 Changes in blood glucose after 12 and 44 weeks of Pitavastatin or Atorvastin treatment Gumprecht J et al DIABETES, OBESITY AND METABOLISMVolume 13 No. 11 November 2011 doi:

18 HbA1c (%) HbA1c Levels Significantly Decrease Over Time with Pitavastatin in Japanese Patients with T2DM Post marketing survey (n=1,843) ± ± ± Mean±S.D. p<0.001(repeated measures ANOVA) 3 month 6 month 1 year 2 year 3 year 4 year 5 year Teramoto T et al. Jn Pharmacol Ther 2011;39:

19 J-PREDICT: First Prospective Trial to Evaluate Statin-induced T2DM in an At-Risk Population An open-label randomised controlled study to evaluate the effect of pitavastatin on new onset of diabetes in a population with impaired glucose tolerance (IGT) Study hypothesis: The treatment group receiving pitavastatin 1 2 mg/day will show a lower incidence of new-onset diabetes compared with the control group receiving lifestyle modification alone Yamazaki et al. Diabetol Int Published online August

20 Design and Methods 1240 adult patients with IGT (WHO criteria) Randomly assignment in a 1:1 ratio to either lifestyle modification (control) or pitavastatin 1 2 mg/day in addition to lifestyle modification Pre-screening IC Screening 75-g OGTT Randomisation Lifestyle intervention alone Lifestyle intervention+ pitavastatin 1 2 mg/day < 6 months <2 months 60 months (max.108 months) WHO IGT criteria: 2h plasma glucose 140 and <200 mg/dl and fasting plasma glucose <126 mg/dl Yamazaki et al. Diabetol Int Published online August

21 Study recruitment Assessed or eligibility (n=8,472) Screening (n=3,462) Randomisation (n=1,269) Excluded (n=5,010) Did not meet screening criteria (n=1,303) Refused to participate (n=3,512) Other reasons (n=138) Excluded (n=2,193) Did not meet screening criteria (n=1,619) Refused to participate (n=572) Other reasons (n=2) Allocated to lifestyle modification only (n=635) Allocated to Pitavastatin 1-2 mg/day (n=634) Yamazaki et al. Diabetol Int Published online August

22 Cumulative Incidence Rate Pitavastatin reduced the incidence of diabetes by 18% after a median of 2.8 years HR 0.82 (95% CI: ) p=0.041 (Stratified log-rank test) Control 0.50 Pitavastatin No. at Risk Control Pitavastatin Months since randomisation Median follow up 2.8 years (range 2-6 years) Average pitavastatin dose 1.3mg html73rd ADA 2013, Chicago, IL, USA: Late Breaking Studies 61-LB

23 The use of statins in people at risk of developing diabetes mellitus: Evidence and guidance for clinical practice N.A. Sattar et al. / Atherosclerosis Supplements 15 (2014) 1e15

24 The use of statins in people at risk of developing diabetes mellitus: Evidence and guidance for clinical practice Recommendations for glycaemia testing pre- and post- statin commencement in individuals without known diabetes N.A. Sattar et al. / Atherosclerosis Supplements 15 (2014) 1e15

25 Conclusiones El efecto beneficioso de las estatinas sobre el riesgo cardiovascular supera sus posibles efectos adversos Las estatinas tienen diferencias a nivel molecular que condicionan su farmacocinética y farmacodinámica. Estas diferencias moleculares pueden comportar una distinta interacción con el metabolismo glucídico Ciertas estatinas (P-P) parecen tener un efecto neutro singular sobre el metabolsimo glucídico.