Summary : This flowchart provides a stepwise clinical decision algorithm for adults with clinical ASCVD at very high risk and baseline LDL-C ≥190 mg/dL (not due to secondary causes), with clinical diagnosis or genetic confirmation of familial hypercholesterolemia (FH), who are on statin therapy for secondary prevention. The chart guides clinicians through statin optimization, nonstatin agent selection, and referral pathways to achieve LDL-C targets. flowchart: # Nodes : • Start (rounded rectangle): "Adults with clinical ASCVD at very high risk* and baseline LDL-C ≥190 mg/dL not due to secondary causes† with clinical diagnosis or genetic confirmation of FH, on statin therapy for secondary prevention" • Decision (diamond): "≥50% LDL-C reduction and LDL-C <55 mg/dL (or non-HDL-C <85 mg/dL) on maximally-tolerated statin therapy‡" • If YES: "Monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy. If persistent hypertriglyceridemia,‖ refer to the 2021 ACC ECDP on Management of Hypertriglyceridemia45" • If NO: (rectangle with steps) 1. "Evaluate and optimize lifestyle modifications, adherence to guideline-recommended statin therapy, risk factor control, and SASES" 2. "Increase to high-intensity statin therapy if not already taking" 3. "Consider referral to lipid specialist and RD/RDN for all patients, especially for HoFH‖" • Decision (diamond): "≥50% LDL-C reduction and LDL-C <55 mg/dL (or non-HDL-C <85 mg/dL) on maximally-tolerated statin therapy‡" • If YES: "Monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy. If persistent hypertriglyceridemia,‖ refer to the 2021 ACC ECDP on Management of Hypertriglyceridemia45" • If NO: (rectangle) "Consider the following as the initial nonstatin agent and addition of other agents as needed to achieve adequate reduction of LDL-C‖" 1. "Consider ezetimibe and/or PCSK9 mAb" 2. "May consider bempedoic acid or inclisiran**" 3. "May consider evinacumab, lomitapide, and/or LDL apheresis for HoFH under care of lipid specialist‖" • Decision (diamond): "≥50% LDL-C reduction and LDL-C <55 mg/dL (or non-HDL-C <85 mg/dL) on maximally-tolerated statin therapy‡" • If YES: "Monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy. If persistent hypertriglyceridemia,‖ refer to the 2021 ACC ECDP on Management of Hypertriglyceridemia45" • If NO: (rectangle) "1. Referral to lipid specialist 2. Referral to RD/RDN" • Decision (gray rectangle): "Decision for no additional medication" # Connectors : • Downward arrows connect each node in sequence. • Decision diamonds split into YES and NO branches. • YES branches loop to monitoring node. • NO branches proceed to next intervention or referral. • Nonstatin agent selection node splits into three parallel options (numbered 1, 2, 3). • All branches ultimately converge on either monitoring or referral. # Layout : • Vertical flow, top-to-bottom. • Decision diamonds create branch points. • Parallel options for nonstatin agents are horizontally arranged. • Monitoring node is a common endpoint for successful LDL-C reduction. • Referral node is the endpoint for unsuccessful LDL-C reduction after all interventions. # Analysis : • The flowchart emphasizes a stepwise escalation: starting with statin therapy, optimizing lifestyle and statin intensity, then adding nonstatin agents if LDL-C targets are not met. • Multiple nonstatin options are provided, with more advanced therapies reserved for patients with homozygous familial hypercholesterolemia (HoFH) under specialist care. • The algorithm ensures regular monitoring and referral to specialists if targets remain unmet, supporting a comprehensive approach to secondary prevention in very high-risk ASCVD patients with FH.

Summary : This flowchart outlines the recommended management for adults with clinical ASCVD and baseline LDL-C ≥190 mg/dL not due to secondary causes, without clinical or genetic diagnosis of familial hypercholesterolemia, focusing on statin therapy for secondary prevention. flowchart: # Nodes : • Start (rounded rectangle): "Adults with clinical ASCVD and baseline LDL-C ≥190 mg/dL not due to secondary causes* without clinical or genetic diagnosis of FH, on statin therapy for secondary prevention" • Decision (diamond): "≥50% LDL-C reduction and LDL-C <70 mg/dL (or non-HDL-C <100 mg/dL) on maximally-tolerated statin therapy†" • If YES: (rounded rectangle) "Monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy. If persistent hypertriglyceridemia,†† refer to the 2021 ACC ECDP on Management of Hypertriglyceridemia††" • If NO: (rectangle) "1. Evaluate and optimize lifestyle modifications, adherence to guideline-recommended statin therapy, risk factor control, and SAEs 2. Increase to high-intensity statin therapy, if not already taking 3. Consider referral to lipid specialist and RD/RDN for all patients, especially for HoFH‡‡" • Decision (diamond): "≥50% LDL-C reduction and LDL-C <70 mg/dL (or non-HDL-C <100 mg/dL) on maximally-tolerated statin therapy†" • If YES: (rounded rectangle) "Monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy. If persistent hypertriglyceridemia,†† refer to the 2021 ACC ECDP on Management of Hypertriglyceridemia††" • If NO: (rectangle) "Consider the following as the initial nonstatin agent and addition of other agents as needed to achieve desired reduction of LDL-C§§" - Sub-nodes (rectangles): 1. "Consider ezetimibe and/or PCSK9 mAb" 2. "May consider bempedoic acid or inclisiran§§" 3. "May consider LDL apheresis under care of lipid specialist**" 4. "Decision for no additional medication" • Decision (diamond): "≥50% LDL-C reduction and LDL-C <70 mg/dL (or non-HDL-C <100 mg/dL) on maximally-tolerated statin therapy†" • If YES: (rounded rectangle) "Monitor adherence to lifestyle modifications, medications, and LDL-C response to therapy. If persistent hypertriglyceridemia,†† refer to the 2021 ACC ECDP on Management of Hypertriglyceridemia††" • If NO: (rectangle) "1. Referral to lipid specialist 2. Referral to RD/RDN" # Connectors : • Arrows connect each decision diamond to YES/NO branches. • YES branches loop to monitoring node. • NO branches proceed to next intervention or referral. • Sub-nodes for nonstatin agents are parallel options. • Final NO branch leads to referral options. # Layout : • Vertical flow, starting from top. • Decision diamonds split into YES (right) and NO (downward) branches. • Parallel options for nonstatin agents are horizontally arranged. • Monitoring node is a common endpoint for all YES branches. • Referral is the endpoint for persistent failure to reach targets. # Analysis : • The flowchart provides a stepwise escalation for LDL-C management in high-risk patients, starting with statin therapy and progressing to nonstatin agents and specialist referral if targets are not met. • The process emphasizes repeated assessment of LDL-C reduction and adherence, with multiple opportunities for intervention. • The chart highlights the importance of lifestyle modification, medication optimization, and specialist involvement for refractory cases. • Monitoring and referral are key endpoints, ensuring ongoing management and escalation as needed.

Summary : This flowchart provides a decision tree for treating hypercholesterolemia in persons with diabetes mellitus, focusing on statin therapy initiation and management based on ASCVD risk and lipid panel results. flowchart: # Nodes : • Individuals with DM and LDL-C ≥100 mg/dL (rectangle) • Optimize enduring healthy lifestyles* (rectangle) • Shared decision to initiate statin therapy based on ASCVD risk? (rectangle) • YES (decision branch) – Very High Risk (10-year risk 10% to 20%, includes T2D with ≥2 additional RFs), or Extreme Risk (>20%, includes established ASCVD or TOD). Begin high-intensity statin. (rectangle) – High Risk (10-year risk <10%, includes T2D with <2 additional RFs and no TOD). Begin moderate-intensity statin. (rectangle) – Monitor lipid panel** to goal with maximally tolerated statin dose. Check Apo B for residual risk. (rectangle) – Monitor lipid panel. Goal LDL-C <100 mg/dL, Apo B <90 mg/dL, and non-HDL-C <130 mg/dL. (rectangle) – Apo B <80 mg/dL for very high risk or <70 mg/dL for extreme risk (rectangle) – Apo B >80 mg/dL for very-high risk or >70 mg/dL for extreme risk (rectangle) – Monitor lipid panel. (rectangle) – A. Add ezetimibe and monitor lipids. (rectangle) – B. If not at goal, add PCSK9 agent, bile acid sequestrant, or bempedoic acid. (rectangle) – A. If at goal, monitor lipid panel. (rectangle) – B. If not at goal, intensify statin therapy and add ezetimibe as needed. (rectangle) • NO (decision branch) – Offer low-intensity statin or monitor lipid panel. (rectangle) • Increased ASCVD risk? (decision diamond) • Utilize ASCVD risk calculator. Assess Apo B and non-classical RFs (CAC, hs-CRP, etc.) as needed. (rectangle) • Uncertain (decision branch) # Connectors : • Arrows connect each node in a top-down, left-to-right branching structure. • Decision points split into YES, NO, and Uncertain branches. • YES branch further splits into risk categories and subsequent management steps. • NO branch leads to low-intensity statin or monitoring. • Uncertain branch leads to risk calculator and further assessment. # Layout : • The flowchart is organized in a vertical hierarchy, starting from the top with initial patient criteria, then branching based on ASCVD risk assessment. • The YES branch is subdivided into risk levels and corresponding treatment steps, with feedback loops for monitoring and intensifying therapy. • The NO and Uncertain branches provide alternative pathways for lower or unclear risk. # Figure Legend : • Lifestyle changes include healthy diet, activity, regular exercise, and weight maintenance. • Lipid panel includes total cholesterol, LDL-C, HDL-C, triglycerides, and calculated non-HDL-C; monitor every 6 to 12 weeks. • Apo B = apolipoprotein B; ASCVD = atherosclerotic cardiovascular disease; CAC = coronary artery calcification; DM = diabetes mellitus; hs-CRP = high-sensitivity C-reactive protein; LDL-C = low-density lipoprotein cholesterol; PCSK9 agent = PCSK9 inhibitor; RF = risk factor; TOD = target organ damage. # Analysis : • The flowchart provides a structured approach to statin therapy initiation and management in diabetic patients with elevated LDL-C, emphasizing risk stratification and stepwise intensification based on lipid panel results and residual risk markers. • The decision tree ensures individualized therapy, with clear escalation steps for patients not meeting lipid goals, and incorporates non-classical risk factors for uncertain cases. • The process is cyclical, with repeated monitoring and adjustment to achieve optimal lipid control.