2021 Primary Care Symposium Cardiometabolic Panel Discussion - James Smith MD Coastal Cardiology

2021 Primary Care Symposium
Cardiometabolic Panel Discussion
          James Smith MD
         Coastal Cardiology

Prevalence
• 425 million people worldwide
• In 2010 the International Diabetes Federation prediction was “430
  million by 2030”

• Compared with non-diabetics, patients
  with diabetes have a twofold to
  fourfold increased risk for development
  and dying of CHD

More than just CHD
• Twofold increase in stroke risk compared to non-diabetics
   • Sixfold increased risk for adverse outcomes after stroke
• 1/3 of all patients with symptomatic PAD
• Accounts for roughly 50% of all lower extremity
  amputations

More than just CHD
• Two to fivefold increased risk for heart
  failure
   • HFrEF
   • HFpEF
• Worse outcomes
• Multifactorial
   • Ischemic, metabolic, functional
     myocardial perturbations

Lesion morphology
• In atherectomy specimens of coronary cell rich areas, the extent of
  the necrotic plaque core, calcification and thrombus were increased
  in diabetics
• Associated with formation of vulnerable plaques and plaque rupture
• Post mortem studies demonstrate increased frequency of healed
  ruptures in patients with DM2 who died from acute coronary events

CAD
• DM is considered a CAD
  equivalent
• For patients with known
  CAD and diabetes, the rates
  of death approach 45% over
  7 years
• 75% over 10 years

Myocardial infarction
• 50% are dead 5 years after an MI
• 1 month mortality rate is 58% higher in diabetics than non-diabetics
• The SHOCK (Should we emergently revascularize Occluded Coronaries
  for cardiogenic shock) trial found a 36% increase in death for diabetic
  patients with cardiogenic shock from MI

Platelet abnormalities

Clotting
• Imbalance in the coagulation and fibrinolytic cascades that supports
  clot formation and stability
• Increases plasminogen activator inhibitor type 1 (PAI-1) levels
  impairing fibrinolytic capacity in atherosclerotic lesions
• Increases the expression of tissue factor and levels of plasma
  coagulation factors
• Decreases levels of endogenous anticoagulants

PAD
• DM increases incidence and severity of limb ischemic two to fourfold
• Often affects distal limb vessels – tibial and peroneal arteries which
  limits the potential for collateral vessel development
• May present with absent pedal pulses, diminished ABIs, claudication,
  non-healing ulcers, rest pain, cramping pain, numbness
• MAY BE SILENT

Disparities
• In the Framingham cohort, the presence of diabetes increased the
  frequency of intermittent claudication by more than 3-fold in men
  and more than 8-fold in women
• Most common cause of nontraumatic amputations in the US
• 1 in 20 Americans over 50 have PAD
• 1 in 3 diabetics over 50

Amputations
• 54% of patients undergo amputations without being assessed by
  angiograms
• Amputation rates decrease as revascularization increases

Diabetic Dyslipidemia

Lipid and lipoprotein abnormalities in NIDDM

Lipid and lipoprotein abnormalities in IDDM

Lipid Management—Lifestyle Intervention
• Lifestyle modification focusing on weight loss (if indicated);
  application of a Mediterranean style or Dietary Approaches to Stop
  Hypertension (DASH) eating pattern; reduction of saturated fat and
  trans fat; increase of dietary n-3 fatty acids, viscous fiber, and plant
  stanols/sterols intake; and increased physical activity should be
  recommended to improve the lipid profile and reduce the risk of
  developing atherosclerotic cardiovascular disease in patients with
  diabetes
• Intensify lifestyle therapy and optimize glycemic control for patients
  with elevated triglyceride levels (≥150 mg/dL [1.7 mmol/L]) and/or
  low HDL cholesterol (

Monitoring with Lipid Panel
• In adults not taking statins or other lipid-lowering therapy, it is
  reasonable to obtain a lipid profile at the time of diabetes diagnosis,
  at an initial medical evaluation, and every 5 years thereafter if under
  the age of 40 years, or more frequently if indicated.
• Obtain a lipid profile at initiation of statins or other lipid lowering
  therapy, 4–12 weeks after initiation or a change in dose, and annually
  thereafter as it may help to monitor the response to therapy and
  inform medication adherence.

Statin Treatment—Primary Prevention
• For patients with diabetes aged 40–75 years without atherosclerotic
  cardiovascular disease, use moderate-intensity statin therapy in addition to
  lifestyle therapy.
• For patients with diabetes aged 20–39 years with additional atherosclerotic
  cardiovascular disease risk factors, it maybe reasonable to initiate statin
  therapy in addition to lifestyle therapy.
• In patients with diabetes at higher risk, especially those with multiple
  atherosclerotic cardiovascular disease risk factors or aged 50–70 years, it is
  reasonable to use high-intensity statin therapy.
• In adults with diabetes and 10-year ASCVD risk of 20% or higher, it may be
  reasonable to add ezetimibe to maximally tolerated statin therapy to
  reduce LDL cholesterol levels by 50% or more.

Statin Treatment—Secondary Prevention
• For patients of all ages with diabetes and atherosclerotic
  cardiovasculardisease, high intensity statin therapy should be added
  to lifestyle therapy.
• For patients with diabetes and atherosclerotic cardiovascular disease
  considered very high risk using specific criteria, if LDL cholesterol is
  ≥70 mg/dL on maximally tolerated statin dose, consider adding
  additional LDL-lowering therapy (such as ezetimibe or PCSK9
  inhibitor).
• For patients who do not tolerate the intended intensity, the
  maximally tolerated statin dose should be used.

Statin Treatment Intensity

Overwhelming benefit for the use of statins

Residual risk
• 65-70% of events occur in the setting of statins

Lower is better
• The LDL hypothesis
• 2004 PROVE-IT
   • Significantly reduced CVD events following MI with high-dose atorva vs. prava
• As early as 1995 Cholesterol Treatment Trialists began publishing
  meta-analyses based on the statin trials
   • In 2005 (based on 14 trials at the time) they reported that on average, a
     reduction of 1 mmol per liter (38.7 mg per deciliter) in LDL cholesterol levels
     yields a consistent 23% reduction in the risk of major coronary events over 5
     years

Lower is better?
• 2008 ENHANCE trial
   • Failed to show the addition of ezetimibe in carotid intimal medial thickness
     despite a reduction in LDL
• Several negative trials using combination lipid therapy despite
  lowering LDL in many cases
• The statin hypothesis
   • Pleiotropic effects of statins including:
      •   Amelioration of endothelial dysfunction
      •   Enhancing stability of atherosclerotic plaques
      •   Increased nitric oxide bioavailability
      •   Anti-oxidant properties
      •   Anti-inflammation

Lower is Better!
• Published in 2015
• Simvastatin 40mg vs simvastatin 40mg + ezetimibe 10mg in patients
  who had been hospitalized in the preceeding 10 days with acute
  coronary syndrome
• Lowered LDL cholesterol by approximately 24%
• First outcome trial of a non-statin to show benefit with further LDL
  reduction

What is PCSK-9?
• Pro-protein convertase subtilisin-like kexin type 9
• A secreted protease which is a 692 amino acid mature protein,
  consisting of 3 domains: prodomain, catalytic, and C-terminal
• Primarily expressed in liver, intestine and kidney
• Rapid turnover in plasma (

Discovery of PCSK-9
• Identified in 2003 at the Necker-Enfants Malades Hospital in Paris.
• Gain-of-function mutations were identified in two French families (HC92
  and HC60) who presented with severely elevated LDL-C levels and were
  diagnosed with autosomal dominant hypercholesterolemia
• It was determined with linkage analysis that these patients had PCSk9 gain-
  of-function mutations on chromosome 1 which results in increased
  expression of the PCSK9 protein, increased serum LDL-C, and the
  expression of the FH phenotype.
• Further investigation with animal models revealed that overexpression of
  the PCSK9 gene results in a dropout in the LDLR and a subsequent increase
  in LDL-C levels proving the relationship between the two.

Figure 1. Pedigree of family HC92 and genetic analysis with markers spanning the 1p34.1−p32 region.
Affected individuals present with a history of tendon xanthomas (individuals HC92-II-7 and HC92-III-3), coronary heart disease, early myocardial infarction (individuals
HC92-II-2 and HC92-II-6) and stroke (individual HC92-II-4). Filled bars indicate the mutated allele. Age (in years) at lipid measurement, total cholesterol (TC) and low-
density lipoprotein cholesterol (LDL-C; in g per liter; untreated values for affected individuals) are given.

Mean LDL-C levels in patients with GOF PCSK9
Mutations

Loss of Function
• The hypothesis originated that if gain of function of PCSK9 is associate with elevated
  levels of LDL-C and CHD, then loss of function of PCSK9 is associated with low LDL-C
  levels
• This was affirmed by the Dallas Heart study in 2004 that evaluated a diverse population
  (50% African Americans) in which two nonsense mutations (Y142X and C679X) were
  identified in PCSK9 among African Americans with 40% lower LDL-C levels.
• Subsequently, PCSK9 was sequenced in the Atherosclerosis Risk in Communities (ARIC)
  study participants which found that 2.6% of 3363 African American subjects had similar
  PCSK9 nonsense mutations (Y142X and C679X).
• These mutant carriers had a 28% LDL-C reduction and an 88% reduction in coronary
  events over a 15-year observation period
• 3.2% of white subjects had the PCSK9R46L sequence variant, which was associated with a
  15% reduction in mean LDL-C and a 47% reduction in CHD
• In 2005, a PCSK9 knockout (KO) mice model also showed decreased levels of cholesterol

Mean LDL-C levels in patients with LOF PCSK9
mutations

Loss of function homozygous mutation case
reports
• 32 year old Caucasian woman had no measurable PCSK9 and a LDL-C of 14
  (Am J Hum Genet. 2006;79: 514-523)

• 21 year old Zimbabwean woman had no measurable PCSK9 and a LDL-C of
  15
  (Atherosclerosis. 2007;193: 445-448)

• 49 year old French male had no detectable PCSK9 levels and a LDL-C of 16
  (Arterioscler Thromb Vasc Biol. 2009;29:2192-2197)

Regression?

Treatment of Other Lipoprotein Fractions or
Targets
• In patients with atherosclerotic cardiovascular disease or other
  cardiovascular risk factors on a statin with controlled LDL cholesterol
  but elevated triglycerides (135–499 mg/dL), the addition of
  icosapent ethyl can be considered to reduce cardiovascular risk .

Lipoprotein(a)
• “We recommend screening for elevated Lp(a) in those at intermediate
  or high CVD/CHD risk, a desirable level

Inflammation
• Proinflammatory HDL
   • During states of inflammation HDL can be converted to proinflammatory HDL
     which promotes LDL oxidation
   • McMahon et al. found that >85% of patients with SLE and carotid plaques had
     measurable piHDL, compared with around 40% of those without detectable
     plaques
• Oxidative stress
   • an excess of ROS not counterbalanced by an adequate antioxidant defense
     system is associated with accelerated atherosclerosis in the general
     population
   • Increased oxidative stress has been identified in patients with SLE, and is
     often elevated independent of disease activity

SCAI Statement on Meta-Analysis of Elective
Coronary Revascularization vs. Medical Therapy
Alone
• A rigorous meta-analysis of randomized clinical trials (RCTs) that
  compared the effects of medical therapies alone with medical
  therapies plus revascularization in patients with stable ischemic heart
  disease (SIHD) was presented at EuroPCR on May 18, 2021.
• concluded that adding revascularization was associated with a
  statistically important reduction in cardiovascular death associated
  with a statistically important reduction in spontaneous myocardial
  infarction (MI)

   • Syntax, Bari2D, FAME, ischemia, courage