DIABETOGENICIDAD DE LAS ESTATINAS

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

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: 3024878. Available at www.fda.gov. Accessed April 2014

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 2 0.02 Median 66.8 66.6 Interquartile range 59.1-76.5 58.8-76.2 Alanine aminotransferase >3xULN on consecutive visits no. (%) 23 (0.3) 17 (0.2) 0.34 Glycated haemoglobin at 24 mo - % P Value Median 5.9 5.8 0.001 Interquartile range 5.7-6.1 5.6-6.1 Fasting glucose at 24 mo mg/dl 0.12 Median 98 98 Interquartile range 91-107 90-106 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):2195-2207 *JUPITER: Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin

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: 735-42

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 0.15 1 or more risk factors Rosuvastatin 20mg Placebo Rosuvastatin 20mg Placebo 0.10 0.10 0.05 0.05 0 0 1 2 3 4 Follow up (years) Number at risk Rosuvastatin 3065 2969 2902 2477 1555 725 473 343 189 48 Placebo 3030 2944 2856 2448 1521 739 488 348 195 69 0 0 1 2 3 4 Follow up (years) Number at risk Rosuvastatin 5743 5564 5394 4515 2639 1330 870 624 365 126 Placebo 5765 5600 5442 4580 2685 1386 909 644 368 178 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 134 54 Ridker et al. Lancet 2012;380:565-71 *JUPITER: Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin

Patients with new onset diabetes (%) Independent Risk Factors for the Development of Diabetes with High Dose Atorvastatin Analysis from TNT* (n=7,595) 25 20 Characteristic absent Characteristic present 15 10 5 0 Fasting glucose >100 mg/dl Triglycerides >150 mg/dl BMI >30kg/m 2 History of hypertension Waters et al. JACC. 2011;57(14):1535-1545 *TNT: Treat to New Targets

% Patients with new onset diabetes Risk of T2DM with Atorvastatin is Strongly Correlated to the Presence of Risk Factors TNT 25 20 15 HR=5.78 p<0.0001 HR=2.04 p<0.0001 HR=2.73 p<0.0001 HR=1.64 p<0.0001 Risk Factor Absent Risk Factor Present 10 5 0 IDEAL 20 15 10 HR=4.72 p<0.0001 HR=1.88 p<0.0001 HR=2.59 p<0.0001 HR=1.60 p<0.0001 5 0 SPARCL 25 20 15 10 HR=3.49 p<0.0001 HR=2.37 p<0.0001 HR=2.36 p<0.0001 HR=1.91 p<0.0001 5 Waters et al. J Am Coll Cardiol 2011;57:1535-1545. 0 FPG>100mg/dL TG>150mg/dL BMI>30mg/m 2 History of hypertension

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 0 1.46 1.00 1.55 1.00 2.06 1.00 1 4.54 3.19 <0.0001 4.37 2.89 <0.0001 4.51 2.23 0.0034 2 9.89 7.15 <0.0001 8.10 5.48 <0.0001 8.39 4.28 <0.0001 3 19.6 14.91 <0.0001 14.9 10.54 <0.0001 15.8 8.58 <0.0001 4 30.0 25.40 <0.0001 24.8 18.78 <0.0001 34.3 20.16 <0.0001 Total 8.68 5.99 7.39 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

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

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

HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials HMGCR gene, rs17238484 (for the main analysis) and Rs12916 223 463 individuals from 43 genetic studies Swerdlow DI et al Lancet. September 24, 2014 http://dx.doi.org/10.1016/s0140-6736(14)61183-1

HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials Swerdlow DI et al Lancet. September 24, 2014 http://dx.doi.org/10.1016/s0140-6736(14)61183-1

Son todas las estatinas iguales?

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

Statins Exert Differential Effects on Insulin Sensitivity (IS) Among Non-diabetic Patients Pravastatin Koh 2008 0.441 (-0.088, 0.971) Sugyama 2007 0.485 (-0.144, 1.114) Gannage-Yared 2005 0.000 (-0.621, 0.621) Subtotal 0.342 (0.032, 0.651) Atorvastatin Huptes 2006-0.052 (-0.929, 0.824) Stalenhoef 2005-0.018 (-0963, 0.333) Watts 2003-0.434 (-1.279, 0.412) Costa 2003 0.308 (-0.379, 0.994) Chan 2002-0.059 (-0.844, 0.726) Subtotal -0.019 (-0.243, 0.205) Rosuvastatin Kastaganos 2008-0.116 (0.474, 0.243) Sviridov 2008 0.067 (0.512, 0.645) Ooi 2007a -0.030 (-1.008, 0.952) Ooi 2007b -0.094 (-1.060, 0.901) Tar Avest 2005-0.074 (0.727, 0.560) Stalenhoef 2005-0.006 (-0.357, 0.345) Subtotal -0.037 (-0.223, 0.148) Simvastatin Koh 2008-0.383 (-0.902, 0.143) Koh 2008a -0.515 (-1.303, 0.274) Koh 2008b -0.642 (-1.429, 0.146) Koh 2008c -0.503 (-1.288, 0.282) Koh 2008d -0.503 (-1.288, 0.282) Devaraj 2007 0.220 (-0.336, 0.776) Altunbas 2003-0.655 (-1.614, 0.285) Jula 2003-0.254 (-0.613, 0.106) Subtotal -0.321 (-0.526, 0.117) Excluding Pravastatin -0.149 (-0.284, -0.013) Overall -0.084 (-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 0.342 (95% CI 0.032 0.621); p=0.03] Simvastatin significantly worsened IS [SMD 0.321 (95% CI 0.526 to 0.117); p=0.03] -2.0-1.2 -.04 0.4 Standarized mean difference (95% CI) Baker et al. Diabetes Res Clin Pract. 2010 Jan;87(1):98-107 1.2

Short-Term Effect of Pitavastatin Treatment on Glucose Metabolism Kakuda H et al. Cholesterol. 2013;2013:314170. doi: 10.1155/2013/314170. Epub 2013 Dec 10.

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:10.1111

HbA1c (%) HbA1c Levels Significantly Decrease Over Time with Pitavastatin in Japanese Patients with T2DM Post marketing survey (n=1,843) 9.0 8.5 8.0 7.5 7.0 6.5 6.0 7.2±1.5 6.8±1.3-0.4±1.5 5.5 0 0 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;39:789-803.

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 2011. Published online August 03 2011.

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 2011. Published online August 03 2011.

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 2011. Published online August 03 2011.

Cumulative Incidence Rate Pitavastatin reduced the incidence of diabetes by 18% after a median of 2.8 years 1.00 0.75 HR 0.82 (95% CI: 0.68-0.99) p=0.041 (Stratified log-rank test) Control 0.50 Pitavastatin No. at Risk 0.25 0.00 Control Pitavastatin 0 6 12 18 24 30 36 42 48 54 60 66 72 Months since randomisation 556 534 500 475 405 385 Median follow up 2.8 years (range 2-6 years) Average pitavastatin dose 1.3mg 350 320 277 263 190 178 123 124 77 101 42 68 15 30 5 23 http://www.easdvirtualmeeting.org/resources/3645 http://mtpro.medical-tribune.co.jp/mtpronews/nct/nct130701. html73rd ADA 2013, Chicago, IL, USA: Late Breaking Studies 61-LB

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

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

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.