Learning Objectives 1) Recognize the risk of diabetes associated with statin therapy in a population at high risk for diabetes 2) Compare and contrast statin benefit to risk when treating patients in a population at high risk for diabetes 3) Evaluate risk for diabetes as a result of statin therapy 4) Compare and contrast risk for new onset diabetes amongst individual statins Abbreviations: ADA = American Diabetes Association ASCVD = atherosclerotic cardiovascular disease ARR = absolute risk reduction CHD = coronary heart disease CHF = congestive heart failure CVA = cerebrovascular accident CVD = cardiovascular disease DM = diabetes mellitus FPG = fasting plasma glucose GLUT4 = glucose transporter type 4 HFpEF = heart failure with preserved ejection fraction HTN = hypertension HDL = high-density lipoprotein IFG = impaired fasting glucose IGT = impaired glucose tolerance LDL = low-density lipoprotein OGTT = oral glycose tolerance test OR = odds ratio PAD = peripheral artery disease NNH = number needed to harm NNT = number needed to treat NODM = new onset diabetes mellitus RCT = randomized control trials RR = relative risk RRR = relative risk reduction SLC2A4 = solute carrier family 2 member 4 TG = triglycerides TLC = therapeutic lifestyle changes Guidelines and Advisement American Diabetes Association 1 Pre-diabetes (aka increased risk for diabetes): o Definitions: FPG 100-125 mg/dl (IFG); OGTT 140-199 mg/dl (IGT); A1c 5.7-6.4% IFG/IGT should not be viewed as clinical entities in their own right but risk factors for DM Risk factors for DM: BMI > 25 kg/m 2 (> 23 kg/m 2 for Asian American), physical inactivity, hypertension, HDL <35, TG >250, High-risk ethnicity (i.e. AA, Hispanic), other clinical conditions (i.e. PCOS) DM screening for individuals with pre-existing risk for DM who are starting new statin therapy Food and Drug Administration 3 Based on clinical trial meta-analyses and epidemiological data from the published literature, information concerning an effect of statins on incident diabetes [new onset diabetes or NODM] and increases in HbA1c and/or fasting plasma glucose was added to statin labels National Lipid Association: Statin Diabetes Safety Taskforce 21 No changes to clinical practice are recommended other than the measurement of HbA1C or fasting glucose in those deemed to also be at elevated diabetes risk after initiating statin therapy, and potentially before initiation in selected patients considered to be at elevated risk of developing diabetes. Pending [A1c, fasting glucose, OGTT] results should not delay statin therapy Randomized Control Trials West of Scotland Coronary Prevention Study (WOSCOPS) 5,6 WOSCOPS: Pravastatin vs. placebo HR: 0.70 (0.50-0.99) Pravastatin conferred 30% reduction in risk for developing diabetes mellitus
Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein (JUPITER) 7,8 JUPITER: Rosuvastatin vs. placebo HR: 1.28 (1.07-1.54) Rosuvastatin conferred 28% increased risk for developing diabetes mellitus Meta-Analyses and Systematic Reviews (Rajpathak, 2009) 9 Primary outcome: incidence of DM; included 6 randomized placebo-controlled trials: N=57,593 patients with mean follow-up of 4 years Statin therapy was associated with a 13% higher risk for diabetes (RR 1.13 (1.03-1.24))* *the WOSCOPS trial was excluded in this analysis (Sattar, 2010) 10 Primary outcome: incidence of DM; included 13 randomized placebo-controlled trials N=91,140 participants with mean follow-up x 4years Statin therapy was associated with a 9% higher risk for diabetes (1.09 (1.02-1.17)) o NNH 255 persons treated x4 years with any statin (1 case NODM per 1000 person years) o However, statins will prevent 5.4 fewer deaths from CHD within the same group generating 1 case of NODM (for each 39 mg/dl reduction in LDL-C) Meta-analyses comparing individual statin, statin-intensity, and LDL goals (Preiss, 2011) 11 High-intensity statin therapy was associated with a 12% higher risk for diabetes versus moderateintensity therapy (OR 1.12 (1.04 1.22)) NNH 498 (to create 1 case of NODM) vs. NNT 155 (to prevent 1 CV event) (Navarese, 2013) 12 Pravastatin 40mg/day had the lowest risk versus placebo (OR 1.07 (0.86 1.30)) Rosuvastatin 20mg/day had the highest risk versus placebo (OR 1.25 (0.82 1.90)) (Cai, 2014) 13 Pooled NODM target LDL < 70 mg/dl vs. control OR 1.33 (1.14 1.56) Pooled NODM target LDL > 100 mg/dl vs. control OR 1.01 (0.92 1.10), NS More intense LDL goals (< 70) conferred significantly higher risk for NODM compared to less intense (>100) (Vallejo-Vaz, 2015) 16 Primary Outcome: glycemia and risk for diabetes; included 15 trials with non-diabetic participants taking pitavastatin or control N=4,815 participants with mean follow-up x 4years Pitavasatin therapy was associated with a 30% lower risk for diabetes (RR 0.70 (0.30-1.61), not significant)
NODM Risk Factors and Review (Waters, 2013) 18 NODM Risk Factors (covariates associated with NODM from secondary prevention atorvastatin trial data): 1. FPG > 100 mg/dl 2. TG > 150 mg/dl 3. BMI > 30 kg/m 2 4. History of HTN Risk was 24% higher with > 2 NODM RFs versus 0-1 with Atorvastatin 80mg/day (HR: 1.24 (1.08-1.42)) (Navarese, 2014) 19 Risk from meta-analyses may underestimate NODM due to lack of standardized DM identification and underpowered results Recommend tailored approach for statin therapy: 1. Assess NODM risk factors: FPG >100, HTN, BMI > 30kg/m 2, TG >150 2. Assess whether primary versus secondary prevention 3. If for primary prevention & > 2 RFs for NODM pravastatin 40mg/day + glycemic control Risk versus Benefit discussion points There is overwhelming support for statins, which have been shown to prolong life and prevent MI/CVA in those taking them, even without having elevated levels of cholesterol In persons at high risk for CVD, statins are an excellent way to reduce risk over the next 10 years There is a small risk for diabetes associated with statins I. 9% higher risk compared to no treatment or placebo. II. About 1 case for every 1000 persons treated, per year III. People who developed diabetes in the studies often had other risk factors for diabetes (i.e. IFG, BMI >30) IV. There are other ways to reduce your risk for a MI/CVA within a 10-year period that may not raise your risk for DM (i.e. smoking cessation), but these strategies don t necessarily replace statin therapy It s unclear whether certain statins put you at higher risk. I. Some statins including pravastatin and pitavastatin may have a neutral or risk reducing effect on diabetes risk (Not applicable when indicated for high-intensity statin. Depends on insurance) II. Stronger statins and more aggressive cholesterol goals seem to increase risk, but, when appropriate, the benefits of stronger, more aggressive therapies far outweigh the increased risk Monitoring and preventing progression to diabetes is key References (presentation + handout): *Bolded references indicate high importance to this topic 1. Standards of Medical Care in Diabetes-2017 Abridged for Primary Care Providers. Clin Diabetes. 2017;35(1):5-26. 2. Taylor F, Huffman MD, Macedo A, Moore THM, Burke M, Davey Smith G, Ward K, Ebrahim S. Statins for the primary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews 2013, Issue 1. Art. No.: CD004816. DOI: 10.1002/14651858.CD004816.pub5 3. FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs. Food and Drug Administration website. http://www.fda.gov/drugs/drugsafety/ucm293101.htm. Accessed September 1, 2017.
4. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013. 5. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. The New England journal of medicine. Nov 16 1995;333(20):1301-1307. 6. Freeman DJ, Norrie J, Sattar N, et al. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation. Jan 23 2001;103(3):357-362. 7. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. The New England journal of medicine. Nov 20 2008;359(21):2195-2207. 8. Ridker PM. The JUPITER trial: results, controversies, and implications for prevention. Circulation. Cardiovascular quality and outcomes. May 2009;2(3):279-285. 9. Rajpathak SN, Kumbhani DJ, Crandall J, Barzilai N, Alderman M, Ridker PM. Statin therapy and risk of developing type 2 diabetes: a meta-analysis. Diabetes care. Oct 2009;32(10):1924-1929. 10. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. Feb 27 2010;375(9716):735-742. 11. Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA : the journal of the American Medical Association. Jun 22 2011;305(24):2556-2564. 12. Navarese EP, Buffon A, Andreotti F, et al. Meta-analysis of impact of different types and doses of statins on new-onset diabetes mellitus. The American journal of cardiology. Apr 15 2013;111(8):1123-1130. 13. Cai R, Yuan Y, Zhou Y, et al. Lower intensified target LDL-c level of statin therapy results in a higher risk of incident diabetes: a meta-analysis. PloS one. 2014;9(8):e104922. 14. Budinski D, Arneson V, Hounslow N, Gratsiansky N. Pitavastatin compared with atorvastatin in primary hypercholesterolemia or combined dyslipidemia. Clin Lipidol 2009; 4: 291 302. 15. Abstracts of the 49th EASD (European Association for the Study of Diabetes) Annual Meeting. September 23-27, 2013. Barcelona, Spain. Diabetologia. 2013;56 Suppl 1:S 59. 16. Vallejo-Vaz AJ, Kondapally Seshasai SR, Kurogi K, et al. Effect of pitavastatin on glucose, HbA1c and incident diabetes: A meta-analysis of randomized controlled clinical trials in individuals without diabetes. Atherosclerosis. 2015;241(2):409-418. 17. Baker WL, Talati R, White CM, Coleman CI. Differing effect of statins on insulin sensitivity in non-diabetics: a systematic review and meta-analysis. Diabetes Res Clin Pract. 2010;87(1):98-107. 18. Waters DD, Ho JE, Boekholdt SM, et al. Cardiovascular event reduction versus new-onset diabetes during atorvastatin therapy: effect of baseline risk factors for diabetes. Journal of the American College of Cardiology. Jan 15 2013;61(2):148-152. 19. Navarese EP, Szczesniak A, Kolodziejczak M, Gorny B, Kubica J, Suryapranata H. Statins and risk of new-onset diabetes mellitus: is there a rationale for individualized statin therapy? American journal of cardiovascular drugs : drugs, devices, and other interventions. Apr 2014;14(2):79-87. 20. Robinson JG, Ray K. Moving Toward the Next Paradigm for Cardiovascular Prevention. Circulation. 2016;133(16):1533-1536 21. Maki KC, Ridker PM, Brown WV, Grundy SM, Sattar N. An assessment by the Statin Diabetes Safety Task Force: 2014 update. Journal of clinical lipidology. May-Jun 2014;8(3 Suppl):S17-29. 22. Swerdlow DI, Preiss D, Kuchenbaecker KB, et al. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet. Sep 24 2014. 23. Swerdlow DI, Preiss D, Kuchenbaecker KB, et al. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet. Sep 24 2014. 24. Nakata M, Nagasaka S, Kusaka I, Matsuoka H, Ishibashi S, Yada T. Effects of statins on the adipocyte maturation and expression of glucose transporter 4 (SLC2A4): implications in glycaemic control. Diabetologia. Aug 2006;49(8):1881-1892
Cases: Questions: (Part1) 1. What additional information is needed / wanted to assess ASCVD risk in this individual? 2. What is this person s statin benefit group? 3. What are the benefits of statin therapy in understandable / layman s terms? 4. What are the risks of statin therapy in understandable / layman s terms? (Part 2)
1. How many risk factors for NODM are present? 2. Does risk for NODM change initial thoughts about statin choice / dose? 3. What ongoing monitoring is recommended? Questions: 1. Is this patient indicated for statin therapy / what is her statin benefit group? 2. Is this patient at risk for new onset diabetes? 3. How does this change the risk/benefit discussion?
Questions: 1. What is this person s statin benefit group? 2. Could statin therapy negatively impact glucose management efforts? 3. How does this change the risk/benefit conversation?