Articles

Colchicine may reduce inflammation in metabolic syndrome

Colchicine may reduce inflammation in metabolic syndrome

Obesity and especially metabolic syndrome are pro-inflammatory conditions, that can give rise to hypertension, dyslipidemia, insulin resistance, diabetes, and cardiovascular disease. Colchicine, an anti-inflammatory agent, is frequently used for gout, pericarditis and familial Mediterranean fever.

In this small randomized clinical trial, authors found that colchicine 0.6 mg twice daily decreased inflammatory markers CRP, ESR, WBC, and ANC in patients with obesity and metabolic syndrome. These results could provide some basis for designing outcome-driven clinical trials, such as evaluating diabetes and CVD risk reduction with colchicine.

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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.

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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.

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Vyleesi for hypoactive sexual desire disorder

Vyleesi for hypoactive sexual desire disorder

Vyleesi has been approved for generalized hypoactive sexual desire disorder (HSDD) in women younger than age 50. It is self-injected subcutaneously 45 minutes prior to the anticipated sexual intercourse. It should not be used more than 8 times per month and more than once daily. In a short-term randomized clinical trial, Vyleesi performed better than placebo. Although Vyleesi activates melanocortin receptors, its precise mechanism of action in HSDD is unknown.

Side effects include increased blood pressure, nausea, vomiting, headache, and darkening of the gums. It should be avoided in patients with uncontrolled hypertension or cardiovascular disease. This approval occurs in the context of FDA’s 2012 ruling of considering female sexual dysfunction as one of the top 20 high priority conditions. Its cost and health insurance coverage will determine its accessibility and usage.

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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.

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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.

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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.

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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.

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Thyroid hormones supplementation in pregnant women with Hashimoto’s thyroiditis

Thyroid hormones supplementation in pregnant women with Hashimoto’s thyroiditis

Thyroid hormones supplementation 50 mcg daily did not improve pregnancy outcomes in women with Hashimoto's thyroiditis in the presence of normal thyroid function.  Hashimoto’s thyroiditis was confirmed by elevated TPO antibodies at study entry. About 1,000 pregnant women were followed through full term.

This is an important study as it defies the current medical opinion of poorer pregnancy outcomes in euthyroid Hashimoto's thyroiditis.

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Bisphosphonate infusion for osteopenia

Bisphosphonate infusion for osteopenia

A group of 2,000 women with osteopenia receiving either zolendronate infusion or placebo were followed for 6 years. Zoledronate 5 mg or placebo were provided every 1.5 years. At the end of the study, the intravenous bisphosphonate reduced vertebral and nonvertebral fractions significantly by about 55% and 35% respectively.

Findings are of major significance as bisphosphonates in general and zolendronate specifically have been approved only for osteoporosis and not osteopenia. Would this expand indications for zoledronate? Should patients with osteopenia be treated or monitored?

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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.

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Metformin found to be safe during pregnancy

Metformin found to be safe during pregnancy

The study found no major adverse events of metformin during pregnancy. This is good news as metformin is an important intervention for hyperglycemia of pregnancy. The following birth outcomes were assessed: cesarean section, neonatal weight, and serious neonatal adverse events.

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New FDA Approval: hydrogel capsule for weight loss

New FDA Approval: hydrogel capsule for weight loss

About 450 overweight or obese adults with BMI 27-40 kg/m2 were randomized to receive Gelesis100 or placebo. Subjects were followed for 6 months. At the end of the trial, patients receiving Gelesis100 lost a significant amount of weight compared to placebo group: about 60% and 25% of the adults lost ≥5% (≥10 lbs) and ≥10% (≥20 lbs) body weight.

Gelesis100 comes in a capsule form. It is taken with plenty of water twice daily before meals. The capsule contains particles, that in the presence of water, have the capability of expanding massively in the stomach, thus triggering a sense of fullness and decreased appetite.

The particles are not absorbed in the bloodstream. No serious adverse events were seen. Gastrointestinal upset was the most common side effect.

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2019 Endocrine Society Guidelines: diabetes approach in older adults

2019 Endocrine Society Guidelines: diabetes approach in older adults


The Endocrine Society has just released its guidelines on how to manage the elderly with diabetes. Guidelines are overall similar to those of ADA and AACE but with greater emphasis in avoidance of adverse events such; as hypoglycemia, malnutrition, excessive weight loss, frailty, falls, and drug side effects. See below for more details.

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New FDA Approval: romosozumab for osteoporosis

New FDA Approval: romosozumab for osteoporosis

Romosozumab , brand name Evenity, has now been approved by the FDA as a viable option for patients with advanced osteoporosis.

Romosozumab is a monoclonal antibody that specifically inhibits sclerostin. The approval comes with a major black box warning as the sclerostin inhibitor elevates the risk of heart attack, stroke and cardiovascular deaths.

Prior to Evenity initiation, patients need to be screened carefully for background cardiovascular disease. As the prevalence of both CVD and osteoporosis increases with age, the most likely candidates for such a therapy would be those at the highest risk for fragility or compression fractures.

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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.

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2019 AACE Guidelines: Diabetes Type 2 principles

2019 AACE Guidelines: Diabetes Type 2 principles

AACE standards were published in January 2019. They are a continual update of the original 2013 guidelines. Unlike ADA which recommends a general A1c target ≤7.0%, AACE promotes a tighter A1c goal of ≤6.5% for most patients with type 2 diabetes.

Recommendations also address lifestyle interventions, obesity, prediabetes, hypoglycemia, hypertension and dyslipidemia. Oral and injectable medications including insulin are discussed. A key priority is the avoidance of hypoglycemia — do no harm!

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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”

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Victoza use in children with diabetes type 2

Victoza use in children with diabetes type 2

Results of ELLIPSE trial are of major significance as they show that Victoza addition to Metformin helps in further reduction of A1c and fasting plasma glucose. The efficacy and safety appear to be similar as in adults. The most common side effects are gastrointestinal in nature. Based on ELLIPSE trial outcomes, I anticipate broadening of FDA indications for Victoza, to include children and adolescents

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New FDA approval: oral testosterone

New FDA approval: oral testosterone

In March 2019 FDA approved the first oral testosterone supplementation for male patients with documented central (primary) or peripheral (secondary) hypogonadism. The medication is given twice a day orally. The recommended starting dose is about 250 mg every 12 hours. The minimum dose is about 150 mg BID with a maximum dose of 400 mg BID.

Follow up blood work needs to be done at least 7 days after initiation and 6 hours after the morning dose. Side effects may include elevated blood pressure, increased red blood cell mass, prostate enlargement, and GI upset. The approval comes with a black box warning for increased risk of hypertension and cardiovascular events.

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