New FDA approval: fish oil (vascepa) for cardiovascular risk reduction

Vascepa is a form of omega-3 fish oil named icosapent ethyl. It was first approved by the FDA in 2012 for the treatment of severe hypertriglyceridemia, as defined by blood triglyceride levels >500 mg/dL.

The FDA has now added a second indication for Vascepa. It can be utilized in patients with established cardiovascular disease or in those who have diabetes plus two or more other risk factors (e.g., hypertension, hypercholesterolemia, smoking, kidney dysfunction) for cardiovascular disorder. Before treatment, patients must also have baseline triglyceride measures >150 mg/dL.

This significant approval comes after reviewing the results of REDUCE-IT, a landmark randomized clinical trial published in NEJM, January 2019. REDUCE-IT confirmed significant cardiovascular outcome reduction of 25% in patients receiving icosapent ethyl when added to statin therapy.

I anticipate widespread use of the fish oil, icosapent ethyl, especially in patients with diabetes, who, by its nature of insulin resistance, frequently have both the increased risk of ASCVD and high triglycerides. Clinicians should be aware of possible induction or worsening of atrial fibrillation, atrial flutter, and bleeding with Vascepa, particularly in the predisposed individuals.

GT

Glucagon receptor antagonist: a diabetes drug development

Glucagon and insulin work in concert to achieve and maintain proper blood glucose levels. Glucagon, released by pancreatic alpha cells, prevents hypoglycemia, while insulin released by beta cells prevents hyperglycemia. Together they preserve a tight blood glucose concentration between 70-100 mg/dL fasting and 70-140 mg/dL after meals. In type 2 diabetes, glucagon production, release, and action are malfunctioning. Overproduction of glucagon leads to over-stimulation of gluconeogenesis and glycolysis, in turn exacerbating hyperglycemia of diabetes mellitus.

It is only natural to look for ways of lowering the synthesis, secretion, or effects of glucagon. In this phase-2 clinical trial, the researchers tested the ability of a glucagon receptor antagonist in lowering A1c in 166 patients with metformin-uncontrolled type 2 diabetes over 12 weeks. The glucagon receptor antagonist RVT-1502, at the high dose 15 mg per day, lowered A1c by 1.0% without severe hypoglycemia. Slight and mild elevation of aminotransferases and blood pressure were documented respectively.

Since study results are meaningfully positive, a follow-up phase-3 randomized clinical trial would be expected.

GT

FDA warning: biotin interferes with heart test

The FDA has now released a new warning against biotin interference with troponin, an essential heart blood test. Biotin or vitamin B7 is a water-soluble molecule found in many over-the-counter supplements such as multivitamins, prenatal, and in those that are meant to improve or protect the health of hair, skin, and nail.

Vitamin B7 is a central catalyst in many laboratory tests, especially those measuring troponin and thyroid hormone levels. When patients take high doses of biotin, especially >30 micrograms daily, it has the potential to underestimate the blood troponin concentration. Troponin measurements are critical in identifying adults with heart disease and particularly those having an acute event such as heart attack or myocardial infarction.

High doses of biotin intake, up to 300 mg daily, have been documented in patients with multiple sclerosis. These extraordinary doses may translate up to 1,200 ng/mL blood concentrations. Biotin has a short half-life of about two hours. It may be reasonable to suspend vitamin B7 intake for two to three days before undergoing any laboratory testing that incorporates biotin-analyte technology.

Patients, physicians, and laboratory personnel should be aware of possible interference of oral biotin with blood troponin and thyroid hormone testing, particularly in decisive clinical circumstances. A grave example would be a biotin user who presents clinically with a heart attack, and yet troponin measurements appear to be normal. Non-elevated troponin can lead to missed diagnosis and life-saving intervention.

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Interaction of ACAT with MTTP in making Lipoprotein B

Blood lipid particles, formally called lipoproteins, are essential for carrying and transporting triglycerides and cholesterol to various body tissues. Lipoproteins that contain B48 and B100 apoproteins are two decisive players. B48-Lipoprotein (Lp B48) is synthesized in the gastrointestinal tract, whereas B100-Lipoprotein (Lp B100) is made in the liver.

In this review article, the authors propose a feasible model of how Lp B48 and Lp B100 are created in the endoplasmic reticulum of enterocytes and hepatocytes. ACAT is responsible for converting free cholesterol into cholesteryl ester (CE), while MTTP is responsible for uploading CE and triglycerides into B48- or B100-Lipoproteins.

Clinician’s knowledge of Lp B48 and Lp B100 physiology is vital as both lipoproteins are – directly or indirectly – involved in all forms of dyslipidemias (Fredrickson classifications I – V)

GT

New: Transoral Endocrine Surgery

About 250,000 thyroidectomies and parathyroidectomies are conducted yearly in the United States. The typical thyroid or parathyroid surgery is performed via the front of the neck. These operations are done mainly for thyroid enlargement, nodules, cancer, and parathyroid masses. Although conventional surgeries are effective and safe, they have one disadvantage in common: they leave an undesirable visible scar for many patients.

To avoid the neck scar, surgeons introduced the concept of transoral endocrine surgery (TES) in 2011. The first operation was performed in the United States, Apr 2016. Since then, more than 300 transoral operations have been conducted in the U.S. alone. The main surgical route was achieved via the upper lip, otherwise called the “endoscopic vestibular approach.”

To date, the reported experience has shown that the safety of TES is similar to the traditional operations for the following outcomes: recurrent laryngeal nerve injury, hypoparathyroidism, and rate of infections. Based on standard inclusion and exclusion criteria, authors have found that 56% of all patients undergoing thyroidectomy or parathyroidectomy are eligible for TES. 

The two most common conditions qualified for transoral endocrine surgery were thyroid nodules (76%) and parathyroid adenomas (58%). TES has the potential to be performed in the 100,000s of individuals annually. However, the authors’ findings need to be formally tested and validated before the mass application of the operation.

GT

Islet cell transplantation in type 1 diabetes

Allogenic transplantation refers to the method of removing and processing stem cells from a donor individual, and subsequently inserting them into a patient in need of replacing his or her diseased cells or tissue. In type 1 diabetes, beta cells or islet cells are gradually destroyed by autoimmunity over six months to four years. Proper regeneration or replacement of islet cells is the ultimate treatment of type 1 diabetes.

Allogenic islet cell transplantation (ICT) research started in 2000. After 20 years of investigative experience, we now have the current essential prospective study. A group of 28 subjects with end-stage type 1 diabetes, as documented by severe hypoglycemia of unawareness, was followed for ten years after allogenic ICT. Study participants received two to three intraportal infusions of islet cells within 60 days. Immunosuppression was induced with IL-2 receptor antibody and then maintained with sirolimus or tacrolimus.

The goal of the study was to reach A1c <6.5% without external insulin therapy or injections. Impressively, 39% and 28% of participants achieved an A1c <6.5% in 5 and 10 years. Moreover, 50% of subjects obtained and maintained A1c <7% without significant side effects. Outcomes were similar whether or not patients underwent a kidney transplant. The authors found that allogenic ICT was associated with a lower risk of adverse events compared to the traditional pancreas transplantation.

The current study marks a significant step forward in healing patients with end-stage type 1 diabetes suffering from severe hypoglycemia of unawareness. It is central for physicians to identify such high-risk persons and refer them appropriately to academic centers involved in allogenic islet cell transplant technology.

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From obesity and triglycerides to pancreatitis

Obesity rates are rising worldwide. Acute pancreatitis is also on the rise. The authors of the current study followed prospectively about 120,000 individuals. As expected, they found a high correlation between BMI and acute pancreatitis events. Investigators also observed that hypertriglyceridemia could explain about 22-30% of the relationship between obesity and pancreatitis.

The results of the study, although not new, confirm prior research and knowledge that obesity leads to insulin resistance, which in turn elevates blood triglyceride concentration. Hypertriglyceridemia is a well-known specific cause of acute pancreatitis, especially when triglyceride measurements are above 500 mg/dL.

Clinically, it is essential to screen obesity patients for hypertriglyceridemia. A fasting lipid panel is a simple and inexpensive laboratory test that can provide significant insights into the patient’s risk of insulin resistance and pancreatitis.

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Diabetic Gastroparesis

Diabetic gastroparesis is a late complication of long-standing uncontrolled diabetes. Pathogenesis is complex as it involves hyperglycemia, vagus neuropathy, and inflammation. Gastroparesis leads to gastric outlet obstruction, delayed gastric emptying, and gastroesophageal reflux. Symptoms are nausea, vomiting, reflux, bloating, weight loss, and improper gastrointestinal absorption.

In this article, the authors provide an in-depth analysis and review of the literature on diabetic gastroparesis. They discuss in detail the pathogenesis, structural anomalies, the role of hyperglycemia, neuropathy, inflammation, and symptoms. They also discuss thoroughly various diagnostic testing, current medications available, and potential future drugs.

Diabetic gastroparesis requires a multidisciplinary approach, including a nutritionist, primary care physician, endocrinologist, gastroenterologist, and surgeon. Tight control of hyperglycemia is paramount in preventing gastroparesis in the first place as well as halting its progression.

GT

Intensive weight loss eliminates type 2 diabetes

Type 2 diabetes has traditionally been perceived as a non-reversible, progressive condition that eventually requires insulin therapy. Recent evidence, however, has been mounting in showing that type 2 diabetes, if diagnosed early, can be fully reversed with intense lifestyle modifications in a subset of patients.

In the current study published in Diabetic Medicine in September 2019, investigators followed prospectively about 900 adult diabetes patients age 40-70 over five years. Individuals who lost more than 10% of body weight within the first few years of the study, had the best chance of eliminating diabetes, as documented by A1c <6.5%.

At the study conclusion, 30% of adults achieved diabetes remission. Important to note that remission or reversal was accomplished independently of any specific lifestyle modifications, except the >10% weight loss.

More clinical trials are needed to confirm the above results. Nonetheless, intensive weight loss at the onset of diabetes diagnosis could be reasonable general advice for people who are overweight or obese.

GT

New FDA approval: glucagon nasal powder for severe hypoglycemia

Although uncommon, severe hypoglycemia can be devastating. It can occur in patients with type 1 diabetes or those with type 2 diabetes receiving insulin or sulfonylurea. If a patient experiences loss of consciousness or seizure from profound low sugars, glucagon needs to be administered immediately by a friend, family member, or caregiver.

The FDA has now approved a glucagon nasal powder as the second form of glucagon delivery for patients with severe hypoglycemia. In clinical trials, glucagon nasal spray has demonstrated similar efficacy as the injectable counterpart in increasing blood glucose concentrations.

The glucagon nasal powder is an excellent additional tool to combat severely low sugars in individuals with type 1 or type 2 diabetes. It has been approved for patients age four or older.

GT

New FDA approval: semaglutide, the first oral GLP-1 agonist for type 2 diabetes

The FDA has now approved the first oral semaglutide, Rybelsus, for the treatment of type 2 diabetes. This approval marks a breakthrough advancement in the field of clinical diabetology. Rybelsus is the first “protein” based molecule to be administered orally and not subcutaneously via an injection.

Oral administration of semaglutide is made possible through the use of SNAC compound. SNAC helps escort and transport the semaglutide intact across the gastrointestinal epithelial cells. It assists in bypassing the harsh acidic environment of the stomach.

Various clinical trials, under the name PIONEER, have consistently shown A1c improvements and weight loss benefits with Rybelsus – thus leading to this landmark FDA acceptance.

Rybelsus comes at three doses; 3, 7, and 14 milligrams. Patients should start at 3 mg per day for one month before advancing to the 7 mg, and if needed, to the 14 mg daily dosage. Rybelsus should be taken in an empty stomach, with no more than 4 ounces of plain water, and at least 30 minutes before breakfast.

Similar to other GLP-1 agonists, oral semaglutide can cause gastrointestinal side effects like nausea and diarrhea. Providers should be cautious when prescribing Rybelsus in those with a predisposed risk for pancreatitis, diabetic retinopathy, or kidney injury. It should not be prescribed in people with a personal or family history of medullary thyroid carcinoma.

GT

Levoketoconazole therapy for Cushing’s syndrome

Cushing’s syndrome is defined by a persistent or cyclical increase in blood cortisol concentrations. The professional diagnosis is based on two or more positive tests: low dose dexamethasone suppression, late-night salivary cortisol, or 24-hour urinary free cortisol.

Surgery is the treatment of choice, which often leads to a permanent cure. However, not infrequently, the source of hypercortisolism cannot be identified, or surgical intervention is not sufficient. In such circumstances, medical therapy is preferred over watchful waiting.

SONICS was a phase 3, open-label, non-randomized clinical trial. Its investigators tested the utility of levoketoconazole in normalizing urinary cortisol levels in 94 adults with uncontrolled Cushing’s syndrome.

After full dose titration and 6-month maintenance therapy, about 30% of patients achieved the desired outcome, as defined by normalized urinary cortisol concentrations. The rate of adverse events was not insignificant: nausea 32%, headaches 28%, study discontinuation 13%, and increased liver enzyme in 11% of participants.

Although the study results are not stupendous, they are meaningful and provide additional options for patients with refractory or uncontrolled Cushing’s syndrome.

GT