Cardiovascular

Oral semaglutide demonstrates cardiovascular safety

Oral semaglutide demonstrates cardiovascular safety

FDA approved subcutaneous semaglutide (ozempic) in December 2017. Clinical trials and experience have shown that semaglutide helps with A1c lowering and weight loss. Additionally, SUSTAIN 6 trial proved its cardiovascular safety.

The current study PIONEER 6, published in the New England Journal of Medicine, addresses the cardiovascular safety of oral semaglutide in diabetes patients at “high risk” for adverse ASCVD events. Age greater than 50 with established cardiovascular disease or chronic kidney disease, or age greater than 60 with CVD risk factors defined the “high risk” status in study participants.

A group of 3200 adults was randomized to receive oral semaglutide or placebo. Patients’ mean age was 66 years. Investigators followed subjects for about 16 months. Final analysis revealed that participants receiving oral semaglutide experienced 20% less major adverse cardiovascular events (MACE) than placebo counterparts. Lower rates of CV death and death from any cause seem to be the main drivers of the reduced primary endpoint.

Although MACE occurred less frequently in the semaglutide group, the trial was designed to evaluate non-inferiority (safety) and not superiority (benefits). These findings are reassuring towards a positive FDA approval for the oral semaglutide. Such an endorsement would place the first oral GLP-1 agonist on the market.

GT

2019 Endocrine Society Guidelines on Metabolic Risk

2019 Endocrine Society Guidelines on Metabolic Risk

Endocrine Society recently published new guidelines on metabolic risk. Metabolic risk is characterized similarly to metabolic syndrome (syndrome X) but with the name change to emphasize action rather than description. Presence of three or more of the following entities defines high metabolic risk: high blood pressure, high glucose, high triglycerides, low HDLc, and increased waist circumference.

Although guidelines are similar to those of other national association such as ACC/AHA, ADA, AACE, and NLA; they introduce or emphasize the following elements:

  • Should measure waist circumference routinely.

  • Include A1c in the definition of metabolic risk (vs. fasting glucose only). 

  • Be more aggressive in using statin therapy for primary prevention. 

  • Can add fenofibrate rather than ezetimibe if triglycerides are above 200 mg/dL and HDLc is low.

These guidelines are essential as they further raise awareness of the real cardiovascular and diabetes risk associated with metabolic syndrome, and more importantly encouraging providers to act upon it.

I anticipate elaboration and incorporation of the above critical changes in other national guidelines.  Prevention, always first.

GT

High natural testosterone production in men is associated with blood clots and heart disease

High natural testosterone production in men is associated with blood clots and heart disease

Analysis of two major Mendelian randomization studies revealed that endogenous testosterone production in men is positively correlated with blood clots, heart attack, and heart failure. Data from at least 200,000 participants were included in the analysis. A proposed mechanism for such a risk is the testosterone conversion into estrogen, in turn contributing to thromboembolism. Testosterone can also increase platelet aggregation via the thromboxane A2 pathway.

Data from these “natural experiments” overall follow the observed increased risk of deep venous thrombosis and heart disease in men who are over-supplemented with exogenous testosterone. On the contrary, low Testosterone levels are also associated with visceral adiposity, low muscle mass, and insulin resistance.  From a cardiovascular perspective, future clinical research is needed to identify the balancing point of how much or little testosterone men should have.

GT

Blood pressure and cardiovascular disease

Blood pressure and cardiovascular disease

This major observational study affirms the notion that the lower the blood pressure the lower the cardiovascular outcomes. A group of 1.3 million outpatient adults was observed and analyzed over 8 years. The study finds that both systolic and diastolic blood pressure are independent contributors to increased CVD. In addition to guideline-driven blood pressure targets, the BP goal should be individualized based on the patient’s comorbidities, medication burden, and side effects.

GT

2019 NLA scientific statement: Lp(a) - key points

2019 NLA scientific statement: Lp(a) - key points

The various large meta-analysis, Mendelian randomizations, and prospective population-based studies have found the Lipoprotein (a) to be an independent risk factor for atherosclerosis, aortic valve stenosis, and thrombosis. Lp(a) test is considered to be high when its value is >50 mg/dL or >100 nmol/L. These measures correspond to the top 20th percentile of the general population.

Currently, there are no approved specific therapies for Lp(a). The NLA does not recommend the use of Niacin, HRT (hormonal replacement therapy) or Lomitapide (microsomal triglyceride transfer protein inhibitor). Recent trials such as FOURIER and ODYSSEY have shown that addition of PCSK9 inhibitors to Statin therapy can lower Lp(a) by 30%.

However, various guidelines including 2018 AHA/ACC and 2019 NLA scientific statement recommend the use of PCSK9 inhibitors only in the context of uncontrolled LDLc/non-HDLc in patients at high-risk or very-high-risk for ASCVD events.

GT

Coronary microvascular dysfunction in women

Coronary microvascular dysfunction in women

It is important to be aware of the atypical pathology and manifestation of coronary artery disease in women. This case shows the inappropriate withholding of heart medications in an 83-year-old female due to ischemic nonobstructive coronary artery disease, also called INOCA. Coronary microvascular dysfunction (CMD) is considered the main pathogenesis of INOCA.

GT

Lipoprotein(a) is an independent ASCVD risk

Lipoprotein(a) is an independent ASCVD risk

Blood Lipoprotein(a) measurements are genetically determined.  Lifestyle, physical activity or dietary habits do not change its levels.  Epidemiologically, Lp(a) has been found to be an independent risk factor for poor ASCVD outcomes.  Lp(a) is a promoter of atherosclerosis, thrombosis and aortic valve stenosis.

In this meta-analysis of 7 statin-outcome randomized clinical trials, authors showed that baseline and on-statin treatment Lp(a) levels correlated positively and linearly with ASCVD events: the higher the Lp(a) measurements, the higher the cardiovascular outcomes.

Development of specific drug therapies in reducing Lp(a) are needed.  These therapies would then be tested in outcome driven ASCVD clinical trials.

GT

New drug development for hypercholesterolemia

New drug development for hypercholesterolemia

The study shows that bempedoic acid, when added to statin therapy, reduces LDLc levels further. Bempedoic acid is an inhibitor of ATP citrate lyase, an important enzyme of cholesterol and fatty acid synthesis.

A group of 2300 patients with either established cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) were followed for about 12 months.  Baseline LDLc was 103 mg/dL.  Mean LDLc reduction with bempedoic acid was about 20 mg/dL.

These results are meaningful as it is well-established that the lower the LDLc the lower the ASCVD outcomes.  No increased adverse events were seen with the ATP Citrate lyase inhibitor compared to placebo.

GT

ACLY variants vs. cardiovascular outcomes

ACLY variants vs. cardiovascular outcomes

ATP citrate lyase is a key enzyme in cholesterol and fatty acid biosynthesis. It helps convert citrate to Acetyl CoA, the precursor to endogenous lipid genesis. Recent studies have shown that pharmacological inhibition of ATP citrate lyase causes a 30% reduction in LDLc, 50% reduction when combined with ezetimibe, and an extra 20% LDLc lowering when added to statin therapy.

This major Mendelian randomization study revealed that genetic variants in the ACLY gene led to similar clinical and biochemical outcomes as HMGCR variants. This provides a theoretical basis that medical inhibition of ATP citrate lyase could have similar cardiovascular benefits as statin therapies.

Mendelian randomization is considered nature’s randomized “clinical trial”. About 800,000 participants were included and analyzed.

GT

Aspirin is useful in diabetes but increases the risk of bleeding

Aspirin is useful in diabetes but increases the risk of bleeding

The major randomized clinical trial, ASCEND, shows that aspirin 100 mg daily lowers the rates of cardiovascular events by 12% in patients with diabetes but increases the risk of bleeding by 30%.

A group of 15,000 participants with diabetes but without baseline CVD were followed for about 7 years.

Case by case clinical judgment would be key in evaluating CVD benefits vs. bleeding risks of aspirin use in patients with diabetes.

GT

Invokana protects the heart and kidneys

Invokana protects the heart and kidneys

Patients with type 2 diabetes receiving Invokana experienced 30% and 20% lower rates of kidney disease progression and cardiovascular events respectively, when compared to the placebo group.

Results were so obvious and significant that the study was terminated early. About 4500 subjects with DM2 were followed for about 2.5 years. No increased rates of fractures or amputations were seen with Invokana.

GT

More evidence of Metformin benefits in early prediabetes

More evidence of Metformin benefits in early prediabetes

More good news for metformin. MET-REMODEL trial tested patients with known cardiovascular disease and insulin resistance, but without gross diabetes. Patients received metformin or placebo for 12 months.

Compared to the placebo group, subjects receiving metformin experienced the following improvements in 12 months: Less left ventricular mass index,  less LVM, lower systolic BP, decreased body weight and less oxidative stress.

Early start of metformin could be useful in adults with insulin resistance.  Long term side effects of metformin, however, need to be discussed thoroughly with patients.

GT

Addition of PCSK9 inhibitor Alirocumab further lowers CVD events.

Addition of PCSK9 inhibitor Alirocumab further lowers CVD events.

In ODYSSEY trial, the addition of PCSK9 inhibitor, Alirocumab to high-intensity statin further reduced cardiovascular events by 15% in patients with very-high baseline CVD risk (prior ACS) and elevated atherogenic cholesterol particles. Atherogenicity was defined by LDLc ≥70 mg/dL, non-HDLc ≥100 mg/dL, or Apo B ≥80 mg/dL.

About 19,000 patients with acute coronary syndrome 1-12 months prior to study initiation were followed for 3 years. The study target was final LDLc between 25-50 mg/dL. Similar to FOURIER 2017 results, ODYSSEY 2018 adds more evidence to the notion “the lower the LDLc, the lower ASCVD events”

GT

Risk factors control is also important in type 1 diabetes

Risk factors control is also important in type 1 diabetes


This major observational study shows that the tight control of risk factors is associated with much lower rates of cardiovascular events and total mortality in patient with type 1 diabetes. Such factors are hyperglycemia, systolic blood pressure, protein in the urine, and the “bad” cholesterol (A1c, sBP, McAlb, LDLc).

This association has already been seen in adults with type 2 diabetes. For a practitioner, this study calls for a tight control of the above risk factors in patients with type 1 diabetes as in those with type 2. A group of 30,000 DM1 individuals were followed for about 10 years

GT

Thyroid supplementation in heart failure

Thyroid supplementation in heart failure

This 5-year observational study shows that thyroid hormone supplementation increases major adverse cardiovascular events (MACE), cardiovascular death, and all-cause mortality in patients with heart failure. Indirectly, this is in accordance with the well-documented benefits of beta-adrenergic receptor blockade in persons with cardiac failure.

Clinically, in patients with concomitants hypothyroidism and heart failure, thyroid hormone supplementation should be started at a low dose, increased slowly, and aiming a higher TSH target than in general population.

GT

Vascepa (fish oil) reduces ischemic cardiovascular events in high risk patients

Vascepa (fish oil) reduces ischemic cardiovascular events in high risk patients

The current study is of a major clinical significance as it shows that EPA lowers ischemic cardiovascular events by 25% in high rick CVD patients who are already receiving statin therapy. The EPA treated patients, however, experienced more hospitalizations for atrial fibrillation and a higher propensity for serious bleeding than placebo. Findings are remarkable as they come from a major randomized clinical trial (REDUCE IT). About 8,000 patients were followed for 5 years.

This outcome data is in accordance with established observation and notion that hypertriglyceridemia is an independent risk factor for cardiovascular disease, mainly via increased inflammation and concentration of the non-HDL cholesterol. Prior clinical studies have also shown that EPA lowers non-HDL cholesterol more than DHA.

Omega-3s, EPA and DHA, are two key ingredients of fish oil. A stable and pure form of EPA has been FDA approved for very high serum triglyceride >500 mg/dL since 2012. It is marketed under the brand-name vascepa. Lovaza, a mixture of EPA and DHA, has also been approved by FDA since 2004 for severe hypertriglyceridemia.

I anticipate that in the future NLA, ACC/AHA, AACE and ADA guidelines will reflect and incorporate the current findings of REDUCE IT.

GT

Lipoprotein(a), Familial Hypercholesterolemia and CVD

Lipoprotein(a), Familial Hypercholesterolemia and CVD

Familial hypercholesterolemia (FH) has a high prevalence of cardiovascular morbidity and mortality, due to the lifelong cumulative exposure of high serum cholesterol levels.

The study finds that only a minority of patients are capable of achieving LDLc targets set by the European guidelines. About 25% of FH patients reach LDLc ≤100 mg/dL and only 8% of very high-risk CVD patients reach LDLc ≤70 mg/dL.

Importantly, those with high Lp(a) experienced twice as much CHD events than those with low Lp(a) levels. Specific drug development toward Lp(a) would be a breakthrough in helping patients with familial hypercholesterolemia.

A group of 714 FH adults were followed for about 11 years.

GT

Newer diabetes medications also help prevent heart and kidney disease

Newer diabetes medications also help prevent heart and kidney disease

About 80,000 diabetes patients were analyzed from 8 clinical trials.

Authors found that GLP1 agonists and SGLT2 inhibitors prevented cardiovascular events (MACE) equally by 14% in those with established CVD. However, both classes of medications did not appear to be effective in reducing MACE in adults with diabetes but without established CVD.

SGLT2 inhibitors showed superior results compared to GLP1 agonists in regard to preventing hospitalizations for heart failure or severe kidney disease progression, such as end-stage-renal disease or death.

If cost, side effects, drug interactions and contraindications allow, diabetes patients would greatly benefit from these therapies on three fronts; glucose control, heart and kidney disease prevention.

GT

Second line diabetes medication on the risk of CVD

Second line diabetes medication on the risk of CVD

Among patients with type 2 diabetes initiating second-line diabetes therapy, the short-term cardiovascular outcomes of GLP-1 receptor agonists, SGLT-2 inhibitors, and DPP-4 inhibitors were similar.

Higher cardiovascular risk was associated with use of sulfonylureas or basal insulin compared with newer drug classes.

Clinicians may consider prescribing GLP-1 receptor agonists, SGLT-2 inhibitors, or DPP-4 inhibitors more routinely after metformin rather than sulfonylureas or basal insulin.

JAMA

Familial Hypercholesterolemia and CVD risk factors

Familial Hypercholesterolemia and CVD risk factors

Genetic inability to clear LDL-particles leads to familial hypercholesterolemia. Persistent high serum LDLc and total-cholesterol are major cumulative risk factors for premature cardiovascular disease.

The article identifies other independent risk factors contributing to CVD in these patients. Such factors are male sex, smoking, hypertension, diabetes, elevated Lp(a), and family history of CVD.

Obviously, the modifiable contributors; hypertension, smoking and diabetes need to be managed aggressively.

GT