The Nutrition Prevention and Reversal of Cardiovascular Disease: Fact or

Fiction?Caldwell B. Esselstyn, Jr., MD

Highlights

• The world’s advanced countries have easy access to plentiful high fat

food; ironically, it is this rich diet that produces atherosclerosis

• In the world’s poorer nations, many people subsist on a primarily plant-

based diet, which is far healthier, especially in terms of heart disease

• The time is long overdue to offer cardiovascular disease patients

treatment for the causation of their disease

• The present standard cardiology approach cannot cure patients, nor halt

disease development, and is financially unsustainable

Highlights• All patients in a non-emergency situation should be offered the option of plant-

based nutrition to halt and reverse their disease by practitioners who are

knowledgeable with this approach

• Nutritional intervention, as shown in our study and others, has halted and even

reversed CAD

• The safety, diminished expense, and prompt, powerful, and persistent results in

treating the cause of vascular disease by whole-food plant-based nutrition offer

a paradigm shift from existing practice

• Arrest and Reversal outcomes with Diet

- No mortality

- No morbidity

- Benefits improve with time

Update on PCSK9 Inhibitors and New Therapies

Evan A. Stein, MD

Highlights• Elevated low-density lipoprotein cholesterol (LDLC) levels in the plasma is the

most important causative factor of atherosclerosis and associated ischemic

cardiovascular diseases

• The LDL receptor (LDLR) is the preferential pathway through which LDLs are

cleared from the circulation

• LDLs bound to the LDLR are internalized into clathrin-coated pits and

subsequently undergo lysosomal degradation, whereas the LDLR is recycled

back to the plasma membrane

• Circulating PCSK9 binds the LDLR on the cell surface and is subsequently

cointernalized together with the LDLR

• This promotes the degradation of the receptor in the lysosome, rather than

recycling to the plasma membrane. PCSK9 can also bind the LDLR intracellularly

Highlights• By virtue of its role as a major inhibitor of the LDLR, PCSK9 has emerged

as a hot new drug target to treat hypercholesterolemia and coronary

heart disease

• ODYSSEY, OSLER 1 & 2 trials have demonstrated that alirocumab and

evolucumab decrease LDL by ~60% and CVD events by ~50% at 12-18

months

• PCSK9 is a promising option for patients truly statin intolerant (or who

don’t have adequate LDL lowering despite statin therapy)

• But long term safety is still unknown and final CVD outcomes data

pending

New Treatments for Hypercholesterolemia: Apheresis, Mipomersen, Lomitapide & PCSK9

Inhibitors

James M Falco

Highlights• Apheresis has an important role in the management of two common

complex lipid disorders associated with a high risk of premature

atherosclerotic disease, familial hypercholesterolemia (FH) and Lp(a)

hyperlipidemia

• LDL apheresis is indicated in patients with LDL > 200 mg/dl with CHD,

asymptomatic patients with LDL >300 mg/dl and in selected CHD

patients with LDL >130 mg/dl with Lp(a) > 50-60 mg/dl

• Studies have shown significant reductions of CV event stabilization

and/or improvement of lesions and overall CV survival

Highlights• Mipomersen is a second generation antisense oligonucleotide that

targets apolipoprotein B

• Mipomersen reduces all apolipoprotein B containing atherogenic

particles and displays dose dependent reductions between 50-400

mg/week both as a single agent and in the presence of maximal lipid

lowering therapy

• Mipomersen is rapidly and extensively absorbed after subcutaneous

administration and has an elimination half-life of approximately 30

days across species

• No drug-drug interactions have been identified with Mipomersen

Highlights• Lomitapide is a microsomal transfer protein inhibitor indicated as an

adjunct to low fat diet and other lipid lowering therapies

• It reduces LDL, total cholesterol, apo B and HDl cholesterol in patients

with homozygous familial hypercholesterolemia (HoFH)

• Inhibitors of proprotein convertase subtilisin kexin type 9 (PCSK9)

represent a new therapeutic category of drugs for the treatment of

dyslipidemia and atherosclerotic cardiovascular disease

• Drugs which negate the action of PCSK9 can produce substantial

reductions in atherogenic lipoprotein cholesterol-carrying particles and

thereby hold the potential for further reducing events associated with

atherosclerotic cardiovascular disease

Statin Intolerance: Statin Side-Effects?

Lisa Tannock, MD

Highlights• In clinical practice 10-25% of patients report statin associated muscle

symptoms (SAMS) or intolerance like Myalgia, myopathy and

rhabdomyolysis

• Patient related factors that can increase the risk of statin induced

myopathy include: increasing age, female sex, renal insufficiency,

hepatic dysfunction, hypothyroidism, diet (i.e grapefruit juice) and

polypharmacy

• The properties of statins that can increase the risk of statin induced

myopathy include: high systemic exposure, lipophilicity, high

bioavailability, limited protein binding, potential for drug-drug

interactions metabolized by CYP pathways (particularly CYP450 3A4)

Highlights• Statins may decrease LFTs that are high due to fatty liver.

• If AST/ALT < 3 times ULN, it is ok to continue statin therapy

• If muscle symptoms occur, measure CK and TSH

• CK >10 x ULN: discontinue all lipid meals. CK <10 x ULN: measure weekly, if it

is increasing discontinue medicines and if decreasing ok to continue statins

• In case of SAMS, European Atherosclerosis Society (EAS) recommends to

• Discontinue the statin and then retry

• Try at least 3 different statins

• Use maximum tolerated statin dose combined with non-statin lipid

therapies

Advanced Lipid Testing: LDL Particles for the Clinicians

Peter Jones

Highlights• Advanced lipid testing consisting of biomarkers which are lipid or non-lipid

parameters beyond those included in a routine lipid profile enables clinicians

to effectively measure and treat lipid abnormalities.

• Biomarkers can be useful in determining disease state, rate and trait and

helps to assess the initial ASCVD risk, before starting lipid-altering therapy but

also to monitor the progress of therapy

• Following tests which can be useful for assessing baseline risk and for on-

treatment decisions

– Evolved LDL cholesterol testing consisting of non-HDL, apoprotein B, LDL-P

– Evolved HDL cholesterol testing consisting of HDL-P, apoprotein A1

– Lipoprotein (a)

Highlights• Basic lipid panel (preferably fasting), with LDL and non HDL is required.

A nonfasting non-HDL cholesterol still be useful

• Further measures of atherogenic particle number (apo B, LDP-P) are

not necessary since non-HDL is equivalent and sufficient even in

discordant situations

• Routine measurement of Lp(a) is not needed. It can be done for

patients with a personal history of premature CVD, a family history of

premature CVD, or familial hypercholesterolemia.

• A high risk level for Lp(a) is >50 mg/dl

• Lipid particle size and/or density is not helpful if the overall particle

number is known

Triglyceride Lowering Agents: Should they be used outside Lipid clinic?

Eliot Brinton

Highlights• Mendelian randomization data strongly suggest that

hypertriglyceridemia (HTG) causes atherosclerotic cardiovascular

disease (ASCVD)

• Hence, triglyceride (TG) lowering treatment in HTG is now more

strongly recommended to address the residual ASCVD risk than

has been the case in earlier published guidelines

• Fasting TG measurement is standard. Non-fasting TG predicts

CVD risk in populations but is too variable in individuals

• If non-fasting TG <200 mg/dl, fasting TG is not necessary.

Remnant particle testing is controversial

Highlights• Statins are the best-established agents for ASCVD prevention,

and so are usually used as first-line treatment of TG levels less

than 500 mg/dL

• Statin monotherapy may fail to normalize high triglycerides and

low high-density lipoprotein cholesterol, and it prevents only a

minority of CVD events

• Fibrates are the best-established agents for TG level lowering

and are generally used as first-line treatment of TG levels greater

than 500 mg/dL

Highlights• Further treatment of lipid disorders that remain after statin

monotherapy should help reduce the residual CVD risk

• Fibrate monotherapy lowers high triglyceride levels, raises low

high-density lipoprotein cholesterol, and reduces CVD risk

• Hence, fibrates are recommended as an adjunct to statins for

treatment of residual dyslipidemia and residual CVD risk

Metformin: The Role of Its Non-Glycemic Effects in Cardiovascular Risk Reduction

John Miles, MD

Highlights• Metformin has proven itself as a front runner in the therapeutic

armamentarium of type 2 diabetes and various other metabolic

diseases

• Metformin exerts most varied effects on both large and small

vessels, as well as on haemostatic parameters

• Metformin has remarkable and partly unique properties in the

microcirculation, which can largely explain its long-term

superiority in the UKPDS trial

Highlights• Metformin has been associated with less CV morbidity and

mortality, at least in part independently of improvement in

glycaemic control and other risk factors, such as hypertension,

obesity and dyslipidaemia

• Metformin use has been associated with reduced mortality in

patients with diabetes and heart failure

• Metformin has demonstrated beneficial effects on systolic BP,

heart rate, LV mass, stroke volume, cardiac index and cardiac

work

Dual-acting Saroglitazar effective for diabetic dyslipidemia with fewer side effects

Highlights• In a 9-month, postmarketing study among Indians, Saroglitazar

was well tolerated and effective in diabetes patients whose

dyslipidemia was not controlled by statins

• The 9-month study included 787 patients in India with diabetic

dyslipidemia treated with 4 mg daily of Saroglitazar

• Glycemic parameters were evaluated at baseline and at 3

months, 6 months, and 9 months. At 9-month follow-up:

- Triglyceride levels were reduced by 43.8%

- LDL cholesterol was reduced by 18.5%

- Total cholesterol was reduced by 23.1%

Highlights• A significant improvement was seen in HDL cholesterol, which

rose from 41.0 ± 14.73 mg/ dL at baseline to 44.5 ± 8.31 mg/dL

• HbA1C dropped from 8.5 ± 1.37% to 7.0 ± 0.78% at 9-month

follow-up (P<0.0001), and fasting and postprandial blood sugar

were also significantly reduced at 9-month follow-up by 28.1%

and 35.2% (P<0.0001) respectively

• Treatment with the drug was not found to be associated with an

increase in body weight (73.9 ± 11.92 kg at baseline to 72.4 ±

11.55 kg at 9-month follow-up) and there were no reports of

serious adverse events among users

Insulin pump therapy superior to multiple daily injections for HbA1c levels

Highlights• Lee and colleagues conducted a run-in period for the OpT2mise trial for

dose optimization on 495 individuals with poor glycemic control on

multiple daily injections

• Following the run-in phase, 331 participants with HbA1c levels of 8% to

12% either continued multiple daily injections (n = 163) or switched to

pump therapy (n = 168) for 6 months to compare the two treatment

types

• After 6 months, HbA1c levels decreased by 1.1% in the pump therapy

group and by 0.4% in the multiple daily injections group (P < .001)

• Compared with participants in the injections group, participants in the

pump therapy group were more likely to achieve HbA1c levels below

8% (P < .001)

Highlights• Total daily insulin doses were greater in the injections group (122 U)

compared with the pump therapy group (97 U) after 6 months (P

< .0001)

• The pump therapy group had significantly lower 24-hour sensor

glucose values at 6 months compared with the injections group (P

< .05) after comparing results to the first CGM study

• The pump therapy group also spent fewer minutes per day in

hyperglycemia compared with the injections group (P < .001)

• Improved treatment satisfaction was significantly associated with

greater HbA1c reductions at 6 months for the pump therapy group but

not the injections group (P < .05)

Analysing Endothelial Dysfunction In Type2 Diabetes Mellitus Patients Using Flow Mediated

Dilatation Score

Highlights• A study was performed to determine early stage CVD risk in type

2 DM patient using FMD (flow mediated dilatation) score –

correlating it with acceleration of inflammatory process of

vascular injury.

• A total of 50 (36 F and 14 M) patients with type 2 DM of more

than 10 years with age above 50years were screened for FMD

score along with 30 (17 F 13 M) healthy controls, using

Angiodefender.

Highlights• The FMD score in 50 type 2 DM patients showed that 70% (n=35)

patients suffered from impaired endothelial function and

increased arterial thickness; 16% (n=8) patients suffered from

endothelial dysfunction, arterial stiffness and atherosclerosis

whereas the remaining 14% had normal endothelial function.

• On the other hand in the healthy counterparts, the FMD score

was normal in 80% (n=24) patients.

• Flow mediated dilatation score can be effectively used as a

marker to determine the vascular injury and endothelial

dysfunction in patients with type2 DM.

Correlation of left ventricular hypertrophy & left ventricular diastolic dysfunction with HbA1c in

newly diagnosed type 2 diabetics

Highlights

• This study was carried out to assess the frequency of left ventricular

hypertrophy (LVH) and left ventricular diastolic dysfunction (LVDD)

in normotensive newly diagnosed type 2 diabetic patients by using

2D echocardiography and correlation with HbA1C.

• 100 newly diagnosed normotensive type 2 diabetes mellitus

patients between 30 - 60 year of age were enrolled from endocrine

OPD of a tertiary care center during a period of 1 year.

Highlights

• Results: 41 % patients had LVDD and 37 % patients had LVH.

• The mean HbA1C of population with LVDD was 7.67 ± 0.90 % and

that with LVH was 7.74 ± 0.91 %. The LVDD and LVH were positively

correlated with HbA1C (p value = 0.0057 & p value = 0.0011)

respectively

• Left ventricular diastolic dysfunction & left ventricular hypertrophy

were positively correlated with HbA1C in newly diagnosed T2DM

population