Fibrates for CV prevention

References: ACCORD Lipid, FIELD

Bottom-line:

• In patients taking a statin, the addition of a fibrate does not significantly reduce the risk of CV events.

• In patients at intermediate-to-high CV risk who are absolutely not able to take a statin, fibrate therapy reduces the relative risk of non-fatal, but not fatal, CV events by ~20%.

  • In my opinion, ezetimibe & bile-acid sequestrants (& soon possibly PCSK9 inhibitors) should be considered before fibrates in these patients.

Patients

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Intervention

• FIELD: Fenofibrate vs matching placebo
  • Fenofibrate given as 200 mg (micronized formulation) PO once daily
  • Non-study lipid-lowering drug: Fenofibrate group 8%, placebo group 17%
  • ~20% in each group discontinued study drug by end of study
• ACCORD Lipid: Fenofibrate + simvastatin vs simvastatin + matching placebo
  • Fenofibrate given as 160 mg PO once daily
  • Average dose of simvastatin 20 mg/d in both groups (open-label, adjusted to lipid targets)
  • Fenofibrate discontinued in 22%, placebo discontinued in 19% by end of study; ~20% in each group discontinued simvastatin by end of study

Results @ ~5 years

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Internal validity

• Both trials at low risk of bias (including allocation, performance, detection, & attrition bias)
  • Central randomization
  • Patients, clinicians, investigators, adjudicators all blinded to treatment allocation
  • Loss-to-follow-up <1%
  • Analyzed using intention-to-treat principles

Generalizability

• FIELD represents the effects of fibrate monotherapy in a population with type 2 diabetes at mostly intermediate risk of CV events (estimated ~10-12% over 10 years)
  • Mechanistically, primarily testing the mechanistic effect of lowering triglycerides by ~30% over placebo, as effect on both LDL & HDL modest
• ACCORD Lipid represents the effects of adding a fibrate to a statin in a higher-risk population of patients with type 2 diabetes (estimated ~25% over 10 years without statin)
  • Again, primarily testing the mechanistic effect of lowering triglycerides, as no discernible effect on LDL or HDL

Other fibrate studies

• VA-HIT: In 2531 men with CAD not receiving a statin, gemfibrozil lowered trigs by ~30% more than placebo. At a median 5.1 years, this resulted in a 4.4% absolute risk reduction in MI or coronary death (NNT 23).
• BIP: In 3090 men with CAD not receiving a statin, bezafibrate increased HDL & lowered trigs by ~15% more than placebo. At a mean 6.2 years, this did not result in a statistically significant effect on MI or sudden death.
• Subgroup analyses from these various trials have provided more confusion than clarity. For example, some studies demonstrate an interaction by baseline triglycerides (VA-HIT, BIP), but not others (FIELD, ACCORD Lipid). The ACCORD Lipid study, but not the BIP trial, found a subgroup interaction based on the combination of low HDL and high trigs.
• A systematic review of 18 fibrate trials, including the ones already mentioned here, found results largely consistent with the FIELD trial:
  • No reduction in death or fatal CV events;
  • Reduction in CV events, entirely driven by non-fatal coronary events (i.e. non-fatal MI & coronary revascularization): Relative risk 0.81 (0.75-0.89);
  • 5% relative risk reduction in coronary events per 0.1 mmol/L reduction in triglycerides;
  • Notably, ACCORD Lipid was the only trial included in this systematic review which had routine statin administration.

HPS - Statins in secondary prevention & patients with diabetes

Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: A randomised placebo controlled trial. Lancet 2002;360:7-22.

Bottom-line: In patients with existing CVD or diabetes, statin therapy reduced the risk of death (NNT 56) & all major vascular events (NNT 19) over 5 years.

In this population that initially tolerated simvastatin during a 4-6 week run-in phase & was not taking other lipid-lowering therapy, moderate-dose simvastatin did not increase the risk of cancer, cognitive impairment, liver enzyme abnormalities, myalgias or myopathy. 

Patients (n=20,536)

• Included
  • Age 40-80 y
  • Total cholesterol (non-fasting) 3.5+ mmol/L
  • High risk for coronary death based on a past medical history of any of:
    • CAD (past ACS, stable angina, CABG or PCI)
    • Cerebrovascular disease (non-disabling non-hemorrhagic stroke, TIA, carotid endarterectomy)
    • PAD (intermittent claudication)
    • Other arterial surgery or angioplasty
    • Diabetes (type 1 or 2)
    • None of the above, but >65 y/o male with treated HTN
• Excluded
  • Statin "clearly indicated"
  • Severe HF
  • Chronic liver disease (cirrhosis, hepatitis or ALT >1.5x ULN)
  • Creatinine >200 umol/L
  • Muscle disease (inflammatory muscle disease or CK >3x ULN)
  • Concurrent treatment with cyclosporine, fibrates or high-dose niacin
• 63,603 screened -> 32,145 entered run-in -> 20,536 randomized -> 20,469 analyzed
• "Typical" study patient
  • Age >64 y 46%
  • Female 25%
  • PMHx
    • MI 41%
    • Other CAD 24%
    • No coronary hx 35%
      • Cerebrovascular disease 9%
      • PAD 13%
      • Diabetes 19%
      • HTN as only inclusion criterion 1%
  • Lipids: Total cholesterol 5.9 mmol/L, LDL 3.4 mmol/L, apoB 1.14 g/L
  • Meds (CAD subgroup)
    • ASA 63% (77%)
    • ACEI 20% (10%)
    • Beta-blocker 26% (23%)

Interventions

• I: Simvastatin 40 mg PO once daily
  • Adherence to >80% of doses: 89% @ 1 y, 82% @ 5 y
• C: Matching placebo
  • Open-label statin use: 4% @ 1 y, 32% @ 5 y

Results @ mean 5 years

• LDL
  • @ baseline: 3.4 mmol/L
  • Difference: -1.3 mmol/L @ 1 y, -0.7 mmol/L @ 5 y
• Death: Simvastatin 12.9%, placebo 14.7% (hazard ratio 0.87, 0.81-0.94), NNT 56
• Major vascular event (components below): 19.8% vs 25.2% (HR 0.76, 0.72-0.81), NNT 19
  • Non-fatal MI or coronary death: 8.7% vs 11.8%
  • Stroke: 4.3% vs 5.7%
  • Coronary revascularization: 5.0% vs 7.1%
  • Non-coronary revascularization: 4.4% vs 5.2%
• Adverse effects
  • Cancer: 7.9% vs 7.8%
  • Cognitive impairment: 23.7% vs 24.2%
  • ALT >4x ULN: 0.4% vs 0.3%
  • Unexplained muscle pain/weakness reported at least once: 32.9% vs 33.2%
  • CK
    • 4-10x ULN: 0.2% vs 0.1%
    • >10x ULN: 0.11% vs 0.06%
  • Subgroup analyses demonstrated consistent relative risk reduction in major vascular event across different high-risk inclusion criteria, so absolute benefit dependent on baseline risk. 5-year risk in placebo group (NNT with statin) in relevant subgroups:
    • CAD only: 22.5% (NNT 16)
    • No CAD
      • Cerebrovascular disease: 23.6% (NNT 18)
      • PAD: 30.5% (NNT 14)
      • Diabetes: 18.6 (NNT 23)

Generalizability

• Represents a wide spectrum of patients with existing vascular disease or diabetes with poor use of other secondary CV prevention interventions, particularly in the CAD subgroup
• Run-in phase: Placebo x4 weeks, then simvastatin 40 mg/d x4-6 weeks
  • To ensure long-term adherence + "responsiveness" to LDL lowering
  • 36% who entered run-in did not undergo randomization, mostly due to unwillingness or inability to adhere for a planned 5 years
  • Therefore, represents a population that did not have intolerable adverse events after a month of statin therapy

Internal validity

• Low risk of allocation, performance, detection & attrition bias

  • Central telephone randomization

  • Patients, clinicians, adjudicators unaware of treatment allocation

  • Loss-to-follow-up <0.5%

  • Intention-to-treat analysis

• High risk of contamination bias

  • By year 5, 32% of patients in placebo group were receiving an open-label statin

  • This acts as a conservative bias, as it attenuates the apparent benefit of statin therapy

EMPA-REG - Empagliflozin for CV risk reduction in T2DM with hx of CVD

Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.

Bottom line: In patients with T2DM and CVD, empagliflozin (at either dose of 10 mg or 25 mg daily) reduced the risk of death (NNT 39) & CV events (NNT 63) over 3 years.

Patients

• Inclusion
  • Adults with T2DM
    • No glucose-lowering agents in previous 12 weeks: 7-9%
    • Receiving glucose-lowering agents, stable x12 weeks: 7-10%
  • Established CVD, defined as any of the following:
    • MI >2 months ago
    • CAD (confirmed with angiography)
    • Stroke >2 months ago
    • PAD documented by
      • Limb revascularization or amputation
      • Peripheral artery stenosis >50% on angiography or non-invasive evaluation
      • ABI <0.9 on at least 1 side
• Key exclusion criteria
  • Cancer within last 5 y
  • Stroke/TIA within 2 months
  • Planned cardiac surgery or PCI in next 3 months
  • BMI >45
  • Blood dyscrasias or any disorder causing hemolysis or unstable RBCs
  • eGFR <30 mL/min/1.73 m^2
  • ALT, AST or ALP >3x ULN
• 11,531 individuals screened across 590 sites in 42 countries -> 7028 randomized -> 7020 analyzed
• "Average" patient
  • Age 63 y
  • Male 72%
  • White 72%, Asian 22%, Black 5%, other 1%
  • Geography: Europe 41%, North America 20%, Asian 19%, Latin America 15%, Africa 4%
  • CV risk factors
    • CAD 76% (multivessel 47%)
    • MI 46%
    • CABG 24%
    • Stroke 24%
    • PAD 20%
  • Time since T2DM dx: >10 y (57%), 5-10 y (25%), 1-5 y (16%)
  • Wt 87 kg, BMI 31
  • BP 136/77
  • Lipids: total 4.2, LDL 2.2, HDL 1.1 mmol/L
  • A1c 8%
  • Meds
    • Metformin 74%
    • Insulin 49%
    • Sulfonylurea 43%
    • DPP-4 inhibitor 11%
    • Antihypertensives 95%
      • ACEI 80%
      • Beta-blocker 64%
    • ASA 83%
    • Statin 76%

Interventions & co-interventions (median 2.6 y)

• I: Empagliflozin 10 mg or 25 mg
  • A1c lowered by 0.5-0.6% at 12 weeks vs placebo
• C: Matching placebo
• Co-interventions:
  • 1st 12 weeks after randomization: No change to glycemic management unles fasting glucose >13.3 mmol/L
  • After 12 weeks: Adjustment to glucose-lowering therapy according to local guidelines

Results @ median 3.1 y

• Results for both doses of empaglifozin were similar, and therefore pooled
• Statistically significant reduction in:
  • The primary outcome (CV death, MI, stroke): Hazard ratio (HR) 0.86, 95% confidence interval 0.74-0.99 (p=0.04)
    • 10.5% vs 12.1% (NNT 63)
  • Death: HR 0.68 (0.57-0.82)
    • 5.7% vs 8.3% (NNT 39)
  • HF hospitalization: HR 0.65 (0.50-0.85)
    • 2.7% vs 4.1% (NNT 72)
• No statistically significant difference:
  • MI: HR 0.87 (0.70-1.09) - 4.8% vs 5.4%
  • Stroke: HR 1.18 (0.89-1.56) - 3.5% vs 3.0%
  • Coronary revascularization: HR 0.86 (0.72-1.04) - 7.0% vs 8.0%
• Safety
  • Serious adverse events: 38.2% vs 42.3% (NNT 25, p<0.001)
  • Premature discontinuation: 23.4% vs 29.3%
  • Hypovolemia: 5.1% vs 4.9%
  • Acute kidney injury: 1.0% vs 1.6%
  • UTI: 18.0% vs 18.1% (complicated 1.7% vs 1.8%)
  • Genital infection: 6.4% vs 1.8% (NNH 22)
  • DKA: 0.1% vs <0.1%
  • Hypoglycemia (glucose <3.9 mmol/L or requiring assistance): 27.8% vs 27.9%
• Numerous subgroup analyses were performed, which demonstrated inconsistent subgroup interactions with the primary outcome and CV death

Issues with internal validity?

• No: Randomized, allocation-concealed, blinded trial with low loss-to-follow-up (<0.1%) analyzed using intention-to-treat principles 
• Run-in: 2-week open-label placebo run-in

Additional considerations

• The reduction of CV events became apparent after only 3 months. Previous trials of diabetes drugs or glycemic control goals have never demonstrated a benefit this early, suggesting that the apparent benefit of empagliflozin may have resulted from another mechanism. 
• The reduction int the primary CV event resulted mainly from a reduction in CV death, but not MI or stroke. This further argues against glycemic control as the beneficial mechanism of empagliflozin.