1/19/2018 1 1/19/2018 2 Update on Prevention of Cardiovascular Disease in Adults With - PowerPoint Presentation

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2. 1/19/20182Update on Prevention of Cardiovascular Disease in Adults With Type 2 Diabetes Mellitus in Light of Recent EvidenceFarzad Hadaegh, MD, Professor of Internal Medicine & EndocrinologyPrevention of Metabolic Disorders Research Center, Research Institute for Endocrine SciencesShahid Beheshti University of Medical Sciences Tehran Jan 2018

3. Dyslipidemia in T2DMHypertension in T2DMAntithrombotic therapySmoking &T2DMGlucose-Lowering Agent Selection for CVD Risk ReductionScreening of cardiovascular disease in diabetes1/19/20183Agenda ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

4. ModifiableOverweightAbnormal lipid metabolismInflammation, hypercoagulationHypertensionSmokingPhysical inactivityUnhealthy dietInsulin resistance Non-modifiableAge Race/ethnicityGenderFamily history1/19/20184Cardiometabolic Risk Factorsــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

5. 1/19/20185Ray KK, et al. Lancet. 2009;373:1765–72Per 0.9% lowerHbA1cPer 4 mmHg lower SBPPer 1 mmol/L lower LDL-C50–5–10–15–20CV events–12.5–8.2–2.9Benefit of different interventions per 200 individuals with diabetes treated for 5 yearsــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

6. Dyslipidemia in Diabetes1/19/20186

7. Efficacy of statins in diabetic patients1/19/20187

8. n = 2838Age 40-75, no history of CVDT2DM plus one or more:RetinopathyAlbuminuriaHypertensionSmokingIntervention: Atorvastatin 10 mg vs. PlaceboOutcome: ACS, revascularization, strokeColhoun HM, et al. Lancet 2004;364:685.1/19/20188CARDS: Effect of Statin for PRIMARY Prevention in DMــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

9. Colhoun HM, et al. Lancet 2004;364:685.1/19/20189CARDS: Statins Reduced CVD in Patients with DMــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

10. Aim of study:Although statin therapy reduces the risk of occlusive vascular events in people with DM There is uncertainty about the effects on particular outcomes and whether such effects depend on the type of diabetes, lipid profile, or other factors.Methods: Data from 18686 individuals with diabetes (1466 type 1 and 17,220 type 2) in the context of a further 71,370 without diabetes in 14 randomised trials of statin therapy. Estimates effects on clinical outcomes per 1.0 mmol/L reduction in LDL cholesterol.Lancet 2008, Jan 12;371(9607):117-251/19/201810Efficacy of cholesterol-lowering therapy in diabetic patients in 14 RCT of statins : meta analysisــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

11. Result in Diabetic patients:All cause mortalityMI or Coronary DeathCoronary RevascularisationStrokeRisk Reduction %9 RR= 0.87 P<0.000122%RR=0.78P<0.000125%RR=0.75P<0.000121%RR=79P=0.00021/19/201811Meta Analyses (cont’d)ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ Lancet 2008, Jan 12;371(9607):117-25

12. After 5 years, 42 (95% CI 30–55) fewer people with diabetes had major vascular events per 1000 allocated statin therapy.1/19/201812Resultsــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

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15. 1/19/201815Meta Analyses (cont’d)ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ Lancet 2008, Jan 12;371(9607):117-25Among diabetic patients the proportional effects of statin therapy were similar irrespective of whether there was a :Prior history of vascular disease Other baseline characteristics Conclusion: Statin therapy should be considered for all diabetic individuals who are at sufficiently high risk of vascular events.

16. 1/19/2018161501 patients with diabetes and CHD, primary end point: time to first major cardiovascular event**CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal strokeTNT: Treating to New Target studyShepherd J, et al. Diabetes Care 2006;29:1220–6Cumulative incidence of major cardiovascular events*Relative risk reduction = 25%0.15HR = 0.75 (95% CI: 0.58, 0.97)P = 0.026Atorvastatin 10 mgAtorvastatin 80 mg0.200.100.0500123456YearsHigh intensity statins are better than moderate intensity in diabetes (TNT study)ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

17. 1/19/201817In adults with diabetes, it is reasonable to obtain a lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides) at the time of diagnosis, at the initial medical evaluation, and at least every 5 years thereafter in patients under the age of 40 years. Once a patient is taking a statin, LDL cholesterol levels should be assessed 4–12 weeks after initiation of statin therapy, after any change in dose, and on an individual basis (e.g., to monitor for medication adherence and efficacy).There is evidence for benefit from even extremely low, less than daily statin dosesADA 2018ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

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19. The Risk Calculator. The American College of Cardiology/American Heart Association ASCVD risk calculator may be a useful tool to estimate 10-year ASCVD (http://my .americanheart.org). 1/19/201819

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23. 1/19/201823However, as diabetes itself confers increased risk for ASCVD and risk calculators in general do not account for the duration of diabetes or the presence of other complications such as albuminuria, the risk calculator has limited use for assessing cardiovascular risk in individuals with diabetes.ADA 2018ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

24. 1/19/201824ADA 2018 Recommendations:ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

25. 1/19/201825For patients under the age of 40 years and/or who have type 1 diabetes with other ASCVD risk factors, we recommend that the patient and health care provider discuss the relative benefits and risks and consider the use of moderate-intensity statin therapy.ADA 2018ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

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27. Reduce LDL-C 18–55% & TG 7–30%Raise HDL-C 5–15%Major side effectsMyopathyIncreased liver enzymesContraindicationsAbsolute: liver diseaseRelative: use with certain drugs1/19/201827Statinsــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

28. HIV protease inhibitorsNefazodoneVerapamil and diltiazemAmiodaroneGrapefruit juice, >1 qt/d1/19/201828Concomitant Medications increasing Risk of Statin-associated Myopathyــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ Fibric acid derivatives, especially GemfibrozilNiacinCyclosporineAzole antifungalsMacrolide antibiotics

29. A meta-analysis of 13 randomized statin trials with 91,140 participants showed an odds ratio of 1.09 (9%) for a new diagnosis of diabetes, On average ,treatment of 255 patients with statins for 4 years resulted in 1 additional case of diabetes, while simultaneously preventing 5.4 vascular events among those 255 patients1/19/201829Statin and incident Diabetesــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

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31. Hypertriglyceridemia should be addressed with dietary and lifestyle changes including abstinence from alcohol; check for secondary causes!!Severe hypertriglyceridemia (>1,000 mg/dL) may warrant pharmacologic therapy (fibric acid derivatives and/or fish oil) to reduce the risk of acute pancreatitis. In a large trial in patients with diabetes, fenofibrate failed to reduce overall cardiovascular outcomes.Low levels of HDL cholesterol, often associated with elevated triglyceride levels, are the most prevalent pattern of dyslipidemia in individuals with type 2 diabetes.1/19/201831Treatment of Other Lipoprotein fractionsــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

32. Drug DoseGemfibrozil 600 mg BIDFenofibrate 200 mg QDClofibrate 1000 mg BID1/19/201832Fibric Acidsــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

33. 1/19/201833Fibric Acidsــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ Major actionsLower LDL-C 5–20% (with normal TG)May raise LDL-C (with high TG)Lower TG 20–50%Raise HDL-C 10–20%Side effects: dyspepsia, gallstones, myopathyContraindications: Severe renal or hepatic disease

34. If combination therapy necessary?1/19/201834Combination therapy (statin/fibrate) has not been shown to improve atherosclerotic cardiovascular disease outcomes and is generally not recommended. However, therapy with statin and fenofibrate may be considered for men with both triglyceride level ≥204 mg/dL (2.3 mmol/L) and HDL cholesterol level ≤ 34 mg/dL (0.9 mmol/L). Combination therapy (statin/niacin) has not been shown to provide additional cardiovascular benefit above statin therapy alone and may increase the risk of stroke and is not generally recommended.

35. 1/19/201835If combination therapy necessary?Combination therapy (statin/fibrate) has not been shown to improve atherosclerotic cardiovascular disease outcomes and is generally not recommended. ACombination therapy (statin and fibrate) is associated with an increased risk for abnormal transaminase levels, myositis, and rhabdomyolysis. The risk of rhabdomyolysis is more common with higher doses of statins and renal insufficiency and appears to be higher when statins are combined with Gemfibrozil (compared with fenofibrate)

36. If combination therapy necessary?1/19/201836Clinicians should attempt to find a dose or alternative statin that is tolerable, if side effects occur. There is evidence for benefit from even extremely low, less than daily, statin doses . The addition of Ezetimibe to moderate-intensity statin therapy has been shown to provide additional cardiovascular benefit compared with moderate-intensity statin therapy alone and may be considered for patients :with a Recent ACS with LDL –C >50 mg/dL or for those patients who cannot tolerate high intensity statin therapy. A

37. 1/19/201837The IMProved Reduction of Outcomes:(IMPROVE-IT)ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ Individuals were 50 years of age who experienced an ACS within the preceding 10 days and had an LDL –C level> 50 mg/dL.In those with diabetes (27%), the combination of moderate intensity Simvastatin (40mg) and Ezetimibe (10 mg) showed a significant reduction of major adverse cardiovascular events with an absolute risk reduction of 5% (40% vs. 45%) and RR reduction of 14% (RR 0.86 [95% CI 0.78–0.94]) over moderate-intensity simvastatin (40 mg) alone.

38. The addition of the novel PCSK9 inhibitors, Evolocumab and Alirocumab, To maximally tolerated doses of statin therapy in participants who were at high risk for ASCVD Decrese the LDL cholesterol ranging from 36% to 59%.  1/19/201838Statins and PCSK9 Inhibitors (adjunctive therapy)ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

39. Hypertensive Disorders in Type 2 Diabetic Patients1/19/201839

40. 1/19/201840Recommendations:Blood pressure should be measured at every routine clinical visit. Patients found to have elevated blood pressure (≥140/90 mmHg) should have blood pressure confirmed using multiple readings, including measurements on a separate day, to diagnose hypertension. BAll hypertensive patients with diabetes should monitor their blood pressure at home. B Check BP in a correct way and control for orthostatic hypotensionADA 2018ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

41. 1/19/201841Most patients with diabetes and hypertension should be treated to a SBP < 140 mmHg and a DBP <90 mmHg. ALower systolic and diastolic blood pressure targets, such as 130/80 mmHg, may be appropriate for individuals at high risk of cardiovascular disease, if they can be achieved without undue treatment burden. CIn pregnant patients with diabetes and preexisting hypertension who are treated with antihypertensive therapy, blood pressure targets of 120–160/80–105 mmHg are suggested in the interest of optimizing long-term maternal health and minimizing impaired fetal growth. ETreatment Goals , ADA 2018ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

42. In type 1 diabetes, hypertension is often the result of underlying nephropathy, while in type 2 diabetes it usually coexists with other cardiometabolic risk factors.1/19/201842

43. JAMA. 2015 Feb 10;313(6):603-15. Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis.OBJECTIVE: To determine the associations between BP-lowering treatment and vascular disease in type 2 diabetes.DATA SOURCES AND STUDY SELECTION: We searched MEDLINE for large-scale randomized controlled trials of BP-lowering treatment including patients with diabetes, published between January 1966 and October 2014.MAIN OUTCOMES AND MEASURES: All-cause mortality, cardiovascular events, coronary heart disease events, stroke, heart failure, retinopathy, new or worsening albuminuria, and renal failure.1/19/201843ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

44. JAMA. 2015 Feb 10;313(6):603-15. Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis.RESULTS: 100,354 participants were included. Each 10-mm Hg lower systolic BP was associated with a significantly lower risk of :Mortality (relative risk [RR], 0.87; 95% CI, 0.78-0.96); 13% CVD(RR, 0.89 [95% CI, 0.83-0.95]; 11% CHD(RR, 0.88 [95% CI, 0.80-0.98]; 12% Stroke (RR, 0.73 [95% CI, 0.64-0.83]; 27% Albuminuria (RR, 0.83 [95% CI, 0.79-0.87]; 17% Retinopathy (RR, 0.87 [95% CI, 0.76-0.99]; 13% When trials were stratified by mean baseline ,lower RRs observed among those with baseline BP of ≥ 140 mm Hg1/19/201844ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

45. Tight BP Control : Large RCTs1/19/201845

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47. 1/19/201847

48. Average after 1st year: 133.5 Standard vs. 119.3 Intensive, Delta = 14.2Mean # Meds Intensive: 3.2 3.4 3.5 3.4 Standard: 1.9 2.1 2.2 2.31/19/201848Systolic Pressures (mean + 95% CI)ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

49. Intensive Events (%/yr)StandardEvents (%/yr)HR (95% CI)P Primary208 (1.87)237 (2.09)0.88 (0.73-1.06)0.20Total Mortality150 (1.28)144 (1.19)1.07 (0.85-1.35)0.55Cardiovascular Deaths60 (0.52)58 (0.49)1.06 (0.74-1.52)0.74Nonfatal MI126 (1.13)146 (1.28)0.87 (0.68-1.10)0.25Nonfatal Stroke34 (0.30)55 (0.47)0.63 (0.41-0.96)0.03Total Stroke36 (0.32)62 (0.53)0.59 (0.39-0.89)0.01Also examined Fatal/Nonfatal HF (HR=0.94, p=0.67), a composite of fatal coronary events, nonfatal MI and unstable angina (HR=0.94, p=0.50) and a composite of the primary outcome, revascularization and unstable angina (HR=0.95, p=0.40)1/19/201849Primary & Secondary Outcomes ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

50. Primary Outcome Nonfatal MI, Nonfatal Stroke or CVD DeathHR = 0.8895% CI (0.73-1.06)1/19/201850

51. Nonfatal StrokeTotal StrokeHR = 0.6395% CI (0.41-0.96)HR = 0.5995% CI (0.39-0.89)1/19/201851

52. Intensive BP management reduced the rate of two closely correlated secondary end points: total stroke (p=0.01) and nonfatal stroke (p=0.03)Assuming that this finding was real, the number needed to treat to the lower SBP level to prevent one stroke over 5 years was 89 1/19/201852 Stroke Resultsــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

53. The ACCORD BP trial evaluated the effect of targeting a SBP goal of 120 mm Hg, compared to a goal of 140 mm Hg, in patients with type 2 diabetes at increased cardiovascular risk. The results provide no conclusive evidence that the intensive BP control strategy reduces the rate of a composite of major CVD events in such patients.1/19/201853Conclusionsــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

54. 1/19/201854We assessed the effects of the routine administration of an angiotensin converting enzyme (ACE) inhibitor-diuretic combination on serious vascular events in patients with diabetes, irrespective of initial blood pressure levels or the use of other blood pressure lowering drugs.The primary endpoints were composites of major macrovascular and microvascular events, defined as death from CVD analysis ,non-fatal stroke or non-fatal MI, and new or worsening renal or diabetic eye disease, and was by intention-to-treat.

55. 1/19/201855

56. 1/19/201856NNT=66 over 5 years

57. 1/19/201857NNT=79 over 5 years

58. 1/19/201858

59. Tight BP control Tight BP control 1/19/201859

60. Tight Glu controlTight Glu control 1/19/201860

61. 1/19/201861Meta-Analyses of RCTs

62. 1/19/201862Based on these analyses, antihypertensive treatment appears to be beneficial when mean baseline blood pressure is ≥140/90 mmHg or mean attained intensive blood pressure is ≥ 130/80 mmHg .Among trials with lower baseline or attained blood pressure, antihypertensive treatment reduced the risk of stroke, retinopathy, and albuminuria, but effects on other ASCVD outcomes and heart failure were not evident.ADA 2018ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

63. 1/19/201863Specific factors to consider are 1. Absolute risk of cardiovascular events2. Risk of progressive kidney disease, as reflected by albuminuria,3. Adverse effects,4. Age, 5. Overall treatment burdenPatients who have higher risk of CVD events (particularly stroke) or albuminuria and who can attain intensive blood pressure control relatively easily and without substantial adverse effects may be best suited to intensive blood pressure control. In contrast, patients with conditions more common in older adults, such as functional limitations, polypharmacy, multimorbidity , loss of autonomy and orthostatic hypotension may be best suited to less intensive blood pressure control. (higher SBP goals should be considered e.g., 145–160 mmHg, lowering DBP below 65-70 mmHg may increase the risk for CVD and mortality)Diabetes Care 2017;40:1273–1284 Individualization of Treatment Targetsــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

64. Nonpharmacological therapy is reasonable in individuals with diabetes and mildly elevated blood pressure (SBP .120 mmHg or DBP .80 mmHg).Smoking cessationWeight reduction (The loss of 1 kg in body weight has been associated with a decrease in blood pressure of 1 mmHg )Reduction of salt intake (<2,300 mg/day)Increase physical activityPsychological factors and stressDietary changes1/19/201864Look medication lists for agents that may raise blood pressure, including over-the-counter and herbal ones. NSIAD drugs increase systolic blood pressure on average by 5 mmHgADA 2018ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

65. 1/19/201865Combination therapy and management of REFRACTORY hypertension among diabetic patientsPharmacologic Antihypertensive Treatment

66. 1/19/201866When RASBs prefer to other medications among patients with type 2 diabetes

67. 1/19/201867An ACE inhibitor or ARB, at the maximum tolerated dose indicated forblood pressure treatment, is the recommended first-line treatmentfor hypertension in patients with diabetes and urine albumin-to creatinineratio ≥300 mg/g creatinine (A) or 30–299 mg/g creatinine (B) If one class is not tolerated, the other should be substituted. B management Diabetes Care 2017;40:1273–1284 In order to reduce risk of progressive kidney disease

68. ABSTRACTObjective :To evaluate the outcomes with use of renin angiotensin system (RAS) blockers compared with other antihypertensive agents in people with diabetes.DesignMeta-analysisData sources and study selection: PubMed, Embase, and the Cochrane central register of controlled trials databases for randomized trials of RAS blockers versus other antihypertensive agents in people with diabetes mellitus.Outcomes: were death, cardiovascular death, myocardial infarction, angina, stroke, heart failure, revascularization, and ESRD. 1/19/201868BMJ. 2016 Feb 11;352:i438.

69. 1/19/201869

70. 1/19/201870

71. 1/19/201871

72. 1/19/201872In the absence of albuminuria, risk of progressive kidney disease is low, and ACE inhibitors and ARBs have not been found to afford superior cardioprotection when compared with other antihypertensive agents .β Blockers may be used for the treatment of CAD or heart failure buthave not been shown to reduce mortality as other blood pressure–lowering agents in the absence of these conditions . The combination of both ACE inhibitors and ARBs is not recommended given the lack of added ASCVD benefit and increased rate of hyperkalemia, syncope, and acute kidney injury.Diabetes Care 2017;40:1273–1284 Based on these analyses, antihypertensive treatment appears to be beneficial when mean baseline blood pressure is ≥140/90mmHg or mean attained intensive blood pressure is ≥130/80 mmHg.

73. J Am Coll Cardiol. 2010 Jun 29;56(1):77-85Aim: To determine which combination therapy in patients with hypertension and diabetes most effectively decreases cardiovascular eventTrial compared the outcomes effects of a renin-angiotensin system blocker, benazepril, combined with amlodipine (BA) or hydrochlorothiazide (BH). A total of 6,946 patients with diabetes were randomized to treatment with BA or BH. A subgroup of 2,842 diabetic patients at very high risk (previous cardiovascular or stroke events) was also analyzed, as were 4,559 patients without diabetesAvoiding Cardiovascular Events Through COMbination Therapy in Patients Living With Systolic Hypertension1/19/201873

74. The starting doses were benazepril 20 mg/day + either amlodipine 5 mg/day or HCT 12.5 mg/day. The study protocol then mandated an increase in the benazepril dose to 40 mg/day in both treatment arms.Thereafter, the amlodipine dose could be increased to 10 mg/day or the HCT dose to 25 mg/day if required to achieve a target blood pressure goal of 140/90 mm Hg. For the diabetic patients (who represent the principal cohort of this report) or for patients with chronic kidney disease, a target blood pressure of 130/80 mm Hg was recommended, but not mandated.1/19/201874Study proceduresــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

75. Data obtained by ambulatory monitoring in patients with diabetes treated with BA or BH after 2 years of treatment. 1/19/201875

76. NNT= 48NNT=46NNT=281/19/201876

77. In patients with diabetes and hypertension, combining a renin-angiotensin system blocker with amlodipine, compared with hydrochlorothiazide, was superior in reducing cardiovascular events and could influence future management of hypertension in patients with diabetes.Other such trials are needed to confirm these outcomes and assess other antihypertensive medication combinations1/19/201877 Key messagesــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

78. 1/19/201878Thiazide-like diuretics are only effective down to an eGFRof 30 mL/min/1.73 m2.). Below an eGFR of 30mL/min/1.73m2, a long-acting loop diuretic should be prescribed.To prevent inadvertent declines in eGFR, patients treated with an ACE inhibitoror ARB should be aware of volumestatus and avoid volume depletion to reducethe risk for acute kidney injury

79. Resistant hypertension is defined as blood pressure ≥140/90 mmHg despite a therapeutic strategy that includes appropriate lifestyle management plus a diuretic and two other antihypertensive drugs belonging to different classes at adequate doses. 1/19/201879

80. 1/19/201880Diabetes Care 2017;40:1273–1284

81. 1/19/201881Reduce sympatheticnerve activity Reducealbuminuria and have additional cardiovascularbenefitsIn patients receiving pharmacologic antihypertensive treatment, home blood pressure should be measured to promote patient engagement in treatment and adherence and may better correlate with ASCVD risk than office measurements .B

82. 1/19/201882β-Blockers may be used for the treatment of prior myocardial infarction (MI), active angina, or heart failure but have not been shown to reduce mortality as blood pressure-lowering agents in the absence of these conditions.Initial treatment for hypertension should include any of the drug classes demonstrated to reduce cardiovascular events in patients with diabetes: ACE inhibitors, angiotensin receptor blockers (ARBs) ,thiazide-like diuretics or dihydropyridine calcium channel blockers.ADA 2018ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

83. 1/19/201883Use of both ACE inhibitors and ARBs in combination, or the combination of an ACE inhibitor or ARB and a direct renin inhibitor, is not recommended given the lack of added ASCVD benefit and increased rate of adverse events namely, hyperkalemia, syncope, and acute kidney injury (AKI) Adding a mineralocorticoid receptor antagonist to a regimen including an ACE inhibitor or ARB may increase the risk for hyperkalemia, emphasizing the importance of regular monitoring for serum creatinine and potassium in these patients.ADA 2018ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

84. 1/19/201884In people with diabetic kidney disease, hyperkalemia risk dramatically increases when the eGFR is < 45 mL/min/1.73 m2 or serum K is > 4.5 mEq/L while the patient is already receiving a diuretic.The combination of reduced eGFR and elevated K in a given patient can raise the risk 8 fold for hyperkalemia development if spironolactone and an ACE inhibitor or ARB are addedDiabetes Care 2017;40:1273–1284

85. 1/19/201885Growing evidence suggests that there is an association between the absence of nocturnal blood pressure dip-ping and the incidence of ASCVD. Moving at least one antihypertensive medication to bedtime significantly reduced CVD , but results were based on a small number of events .Serum CRETININ and K should be monitored during treatment with an ACE inhibitor, ARB, or diuretic, particularly among patients with reduced GFR who are at increased risk of hyperkalemia and AKI ; both of these conditions increase the risk of CVD and mortality events.ADA 2018ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

86. Then study shows that spironolactone was by far the most effective blood pressure-lowering treatment for patients with resistant hypertension. These findings suggest that the predominant underlying pathophysiological cause of resistant hypertension is sodium retention, despite existing baseline diuretic therapy. This conclusion is supported by our finding that the response to spironolactone had a clear inverse relation with plasma renin, was especially effective at lower plasma renin levels, and yet the most effective drug throughout the range of plasma renin1/19/201886Key Message ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

87. Anti- thrombotic therapy in Diabetes1/19/201887

88. 95,000 participants, 4,000 = T2DM Aspirin  the risk of vascular events by 12% (RR 0.88 [95% CI 0.82–0.94]). The largest  was for nonfatal MI with little effect on CHD death (RR 0.95 [95% CI 0.78–1.15]) or total stroke.The effects of aspirin on major CVD were similar for patients with RR 0.88 (95% CI 0.67–1.15) or without diabetes RR 0.87 (95% CI 0.79– 0.96), respectively.1/19/201888

89. 1/19/201889

90. Meta-analysis of trials examining the effects of aspirin on risk of CVD events in patients with diabetesCHD events (A) and Stroke (B)1/19/201890

91. 1/19/201891Use aspirin therapy (75–162 mg/day )as a secondary prevention strategy in those with diabetes and a history of atherosclerotic cardiovascular disease. AAspirin therapy (75–162 mg/day) may be considered as a primary prevention strategy in those with type1 or type 2 diabetes who are at increased CVD. This includes most men and women with diabetes aged ≥50 years who have at least one additional major risk factor (family history of premature CVD, hypertension, dyslipidemia, smoking, or albuminuria) and are not at increased risk of bleeding. CADA 2018ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

92. Smoking and Diabetes1/19/201892

93. METHODS:We searched Medline and Embase databases through May 2015, and multivariate-adjusted relative risks were pooled by using random-effects models. A total of 89 cohort studies were included1/19/201893

94. 1/19/201894The pooled adjusted relative risk associated with smoking 1.55 (1.46-1.64) for total mortality 1.49 (1.29-1.71) for CVD mortality 1.44 (1.34-1.54) CVD1.51 (1.41-1.62) CHD1.54 (1.41-1.69) for stroke 2.15 (1.62-2.85) for PAD1.43 (1.19-1.72) for heart failure  

95. 1/19/201895In comparison with never smokers, former smokers 1.19 (1.11-1.28 )for total mortality, 1.15 (1.00-1.32,) CVD mortality1.09 (1.05-1.13 )for CVD,1.14 (1.00-1.30) for CHD 1.04 ( 0.87-1.23) but not for stroke  

96. 1/19/201896Active smoking is associated with significantly increased risks of total mortality and cardiovascular events among diabetic patients, whereas smoking cessation is associated with reduced risks in comparison with current smoking. The findings provide strong evidence for the recommendation of quitting smoking among diabetic patients.

97. Smoking cessation was associated with a 19% reduction in CVD risk, irrespective of diabetes status.1/19/201897

98. Glucose-Lowering Agent Selection for CVD Risk Reduction1/19/201898

99. A small UKPDS substudy involving 753 overweight patients,which found a relative risk reduction of 39% in MI in the group assigned to metformin versus conventional therapy .Meta-analyses also found evidence with metformin therapy of reduced CVD .An adjusted HR of 0.54 for a composite CVD outcome in patients with type 2 diabetes mellitus and CAD who received metformin compared with glipizide.1/19/201899Metforminــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ Diabetes Care 2015;38:1777–1803 | DOI: 10.2337/dci15-0012

100. 1/19/2018100

101. 1/19/2018101

102. 1/19/2018102In patients with type 2 diabetes with stable congestive heart failure, metformin may be used if eGFR rate remains >30 mL/min but should be avoided in unstable or hospitalized patients with congestive heart failure. BIn patients with type 2 diabetes and established atherosclerotic cardiovascular disease, antihyperglycemic therapy should begin with lifestyle management and metformin and subsequently incorporate an agent proven to reduce major adverse cardiovascular events and cardiovascular mortality (currently Empagliflozin and Liraglutide), after considering drug-specific and patient factors. AIn patients with type 2 diabetes and established atherosclerotic cardiovascular after lifestyle management and metformin, the anti-hyperglycemic agent Canagliflozin may be consideredto reduce major adverse cardiovascular events, based on drug-specific and patient factors .C Metforminــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

103. What should be do ?1/19/2018103

104.  Prevalence (%)CIPrevalenceHazard ratioCIhazard ratiop-valuePAFCIPAFCVD events        Age ــــــ1.041.02-1.05<0.0001ــــــ Sex (women as reference)ــــــ1.731.36-2.21<0.0001ــــــ FPG < 7.22 (mmol/l)ــــــ1ــــــــــــ FPG 7.22 - <10 (mmol/l)31.0025.52-36.391.461.12-1.960.0119.762.67- 17.63 FPG ≥ 10 (mmol/l)35.5829.95-41.212.041.53-2.72<0.000117.8410.04-25.92 WHR64.4160.22-71.831.300.99-1.700.05114.76(-0.6)- 29.23 Hypertension60.4954.76-66.221.651.28-2.13<0.000123.2611.81-35.01 High TC ≥ 5.20 (mmol/l) 85.4081.25-89.561.961.40-2.75<0.000141.6323.14-56.63Mortality events        Age ــــــ1.111.09-1.130.000ــــــ Sex (women as reference)ــــــ1.591.05-2.040.006ــــــ BMI < 25 (kg/m2)  1     BMI 25 - <30 (kg/m2)43.0235.54-50.490.610.43-0.890.010-27.49(-46.39)-(-6.17) BMI ≥ 30 (kg/m2)28.523.67-32.300.620.41-0.920.020-17.16(-33.09)-(-2.76) FPG < 7.22 (mmol/l)ــــــ1ــــــــــــ FPG 7.22 - <10 (mmol/l)29.0622.21-35.921.400.94-2.040.0978.13-1.40-17.84 FPG ≥ 10 (mmol/l)38.3731.03-45.712.311.55-3.200.00020.8813.48-30.93 Hypertension62.7055.53-70.041.701.23-2.360.00125.8110.38-40.36 Smoking36.0428.79-43.291.451.03-2.040.03311.180.83-22.061/19/2018104Prevalence, multivariate hazard ratio and population attributable fraction (PAF) of risk factors for CVD and mortality events in participants with type 2 diabetes (Tehran lipid and Glucose Study; 1999-2012)

105. NEJM 2003; 348: 383-93NEJM 2008; 358: 580-911/19/2018105

106. 160 patients (mean age: 55 yr) with DM2 and microalbuminuriaConventional strategyIntensive strategy: A1C <6.5% BP <130/80 mmHg Total Chol <175 mg/dL TG <150 mg/dLThe primary end point: Composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, revascularization, and amputation1/19/2018106Steno-2 Studyــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

107. Steno -2 Study (CVD)1/19/2018107

108. Steno-2 Follow-up (13.3 years)(Cumulative incidence of death) 1/19/2018108

109. Screening of CVD in Diabetes1/19/2018109

110. 1/19/2018110

111. There was NO significant difference between the screening and the usual care group for the main outcome1/19/2018111

112. Screening:In asymptomatic patients, routine screening for CAD is not recommended because it does not improve outcomes as long as CVD risk factors are treated. (A)Candidates for advanced or invasive cardiac testing include those with: 1) typical or atypical cardiac symptoms: e.g., unexplained dyspnea, chest discomfort; 2) Signs or symptoms of associated vascular disease including Carotid Bruits, TIA, Stroke, Claudication or PAD; or electrocardiogram abnormalities (e.g., Q waves). E 1/19/2018112ADA 2018 Recommendations:ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

113. The screening of Asymptomatic Patients with high CVD risk is NOT recommended ,in part because these high-risk patients should already be receiving intensive medical therapy, an approach that provides similar benefit as invasive revascularizationThe ultimate balance of benefit, cost, and risks of newer noninvasive CAD screening methods, such as CT and CTA, to identify patient subgroups for different treatment strategies remains unproven; Particularly in the modern setting of Aggressive ASCVD risk factor control1/19/2018113Screening of asymptomatic patients with high CVD risk ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

114. TreatmentIn patients with known CVD, consider ACE inhibitor therapy (C) and use aspirin and statin therapy (A) (if not contraindicated) to reduce the risk of cardiovascular events.In patients with a prior MI, beta-blockers should be continued for at least 2 years after the event. (B) In all patients with diabetes, cardiovascular risk factors (dyslipidemia, hypertension, smoking, a positive family history of premature coronary disease, albuminuria) should be assessed at least annually. Abnormal risk factors should be treated.1/19/2018114ADA 2018 Recommendations:ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

115. In patients with symptomatic CHF, TZD treatment should not be used. AIn patients with type 2 diabetes with stable CHF, metformin may be used if renal function is normal but should be avoided in unstable or hospitalized patients with CHF. B1/19/2018115ADA 2018 Recommendations:ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

116. 1/19/2018116Thanks for your patience, dear colleagues!