A great prospect for type 1 diabetes

A great prospect for type 1 diabetes

Type 1 diabetes is a devastating life-long condition. It is autoimmune and frequently occurs in predisposed young adults. Chronic therapy is insulin use via multiple daily injections or insulin-pump; in addition to intensive lifestyle modifications.

The best management of type 1 diabetes is proactive prevention or elimination rather than reactive insulin usage. The current study addresses this very point. A group of 76 participants at high-risk for DM1 was randomized to receive teplizumab or placebo. The presence of autoantibodies to various entities such as GAD65, MicroIns, IA2, ICA, and ZnT8 defined the high-risk status.

Investigators followed subjects for six years. Remarkably at any point in time; teplizumab prevented the development of type 1 diabetes by about 60%. The annual rate of diagnosed diabetes was 16% vs. 39% in those treated with and without teplizumab.

Teplizumab is an immune modulator via CD3 co-receptor pathway. Treated patients experienced a higher rate of adverse events in the form of rash and temporary reduction in lymphocyte count.

I anticipate that further intense research on the subject will yield even higher rates of prevention in predisposed individuals. Family history and biochemical screening of patients would be parament. Stay tuned for similar research results as the DM1-prevention space is blossoming.

GT

A future of high triglycerides

A future of high triglycerides

Familial chylomicronemia syndrome is rare. Its prevalence is about 1 in 1 million. It is characterized by defective or deficient lipoprotein lipase (LPL) enzyme, severely high triglycerides, and recurrent pancreatitis. Apoprotein C3 antagonizes LPL activity leading to hypertriglyceridemia. Much effort has been done to target Apo C3 pharmacologically. Now we have an anti-sense inhibitor to the hepatic Apo C3 mRNA, called volanesorsen.

This phase 3, double-blind randomized clinical trial shows that volanesorsen lowers both Apo C3 and triglycerides remarkably.  Apo C3 is decreased by 25.7 mg/dL and triglycerides by about 1700 mg/dL (Δ80% reduction). Low platelet count and injection site reactions were seen more commonly with volanesorsen than placebo.  Although the study was designed to evaluate changes in triglyceride levels, clinical outcomes (pancreatitis) are also expected to improve.

Study findings are of major importance as it provides us with another tool and pathway of lowering elevated triglycerides. Hypertriglyceridemia, commonly found in patients with metabolic syndrome, is a well-established independent risk factor for cardiovascular events. I anticipate that the antisense inhibitor technology will also be tested in patients with metabolic syndrome, insulin resistance, prediabetes, and diabetes; as these conditions are far more prevalent than familial chylomicronemia syndrome.

GT

Oral "ozempic" lowers A1c and body weight in patients with type 2 diabetes

Oral "ozempic" lowers A1c and body weight in patients with type 2 diabetes

PIONEER 1 was a 26-week randomized clinical trial conducted in nine countries. It tested the efficacy and safety of oral semaglutide vs. placebo in diabetes patients with baseline A1c 8.0%. A group of 703 adults was monitored and analyzed.

At 24 weeks, the higher dose 14 mg of oral semaglutide reduced A1c and body weight by about 1.2% and 5 lbs respectively. Results were statistically significant. Gastrointestinal side effects were more common with semaglutide than placebo but similar to other GLP-1 agonists in the market.

The above results are promising for oral semaglutide to receive FDA approval.

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

Son to Father

Son to Father

If ever a composer showed polyphony in all its great strength, it was surely Bach. Nobody has shown as much as he, in works which normally seem so dry, as much imagination and original thought.

His melodies were indeed unusual, but they were always varied, rich in invention, and they are not at all like those of other composers. His serious temperament drew him primarily towards elaborate music which was grave and profound.

It was only his personal reflections which made him, right from the youth, a composer of pure and powerful fugues.

Carl Philipp Emanuel

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

Cathepsin Z, the blood test we have been waiting for osteoporosis

Cathepsin Z, the blood test we have been waiting for osteoporosis

Osteoporosis is a highly prevalent illness, especially among postmenopausal women. Left untreated, it can lead to fragility and compression fractures; in turn, associated with increased mortality and morbidity. Diagnosis of osteoporosis is currently made by bone density scan (DEXA) or when the patient experiences symptoms (fragility or compression fractures).

This scientific report published in Nature is of great significance as for the first-time its authors identify a potential blood test to diagnose osteoporosis - without having patients undergo bone scanning or present with symptoms. The test is Cathepsin Z mRNA and is measured in human peripheral blood mononuclear cells. Cathepsin Z is a protease synthesized by both bone remodeling cells - osteoclast and osteoblasts.

The test is not influenced by acute or chronic inflammation. Its diagnostic positive predictive value (PPV) is 95% with a negative predictive value (NPV) of 80%. Authors found a strong correlation of elevated levels of Cathepsin Z mRNA in patients with osteopenia in addition to those with osteoporosis.

Although study findings need to be fully validated, the results are exciting. Early diagnosis and treatment of osteoporosis are crucial to preventing fractures and its complications.

GT

Landmark NIH study: ultra-processed diet increases body weight

Landmark NIH study: ultra-processed diet increases body weight

Common sense and knowledge tell us that whole food is healthier than processed food. It is nice to now have a rigorous randomized clinical trial proving this concept.

The NIH study shows that even when food calories, energy density, macronutrients, sugar, sodium, and fiber were matched, individuals consuming ultra-processed food gained weight compared to those on unprocessed meals.

This is a landmark study as it can influence guidelines/advice at the national level.

GT

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.

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

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.

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