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.
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.
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.
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.
In this retrospective study, investigators analyzed a group of 400 adults with hypertension due to primary hyperaldosteronism. The study found that obese patients had smaller aldosterone-producing tumors than lower BMI counterparts. It appears that obese individuals had more aggressive – higher functioning – tumors in spite of their smaller size. Adrenalectomy led to a similar clinical outcome – blood pressure improvement – in patients with or without high BMI. Although these results need to be confirmed, it would be useful for endocrinologists, radiologists, and surgeons to be aware of this phenotype.
The Endocrine Society released its guidelines on postmenopausal osteoporosis in March 2019. The treatment algorithm is primarily based on fracture risk categories. Categories include three essential ingredients; fragility fracture history, T-scores, and FRAX-scores.
Guidelines prefer bisphosphonates, specially alendronate (Fosamax) and zoledronic acid (Reclast), as the first-line therapy for women at high risk of fractures. Denosumab (Prolia) and anabolic hormones (Tymlos and Forteo) can also be used.
Adverse events from osteoporosis therapies ― osteonecrosis of the jaw (ONJ) and atypical femur fractures (AFF) ― have become a public concern in recent years. Although ONJ and AFF are real, the risk of developing fragility fractures from withholding pharmacological therapy far exceeds these potential side effects in high risk and very high-risk women. Providers need to make their patients aware of the benefit vs. harm ratio.
SGLT-2 inhibitors first came into the market in 2013. FDA approved farxiga in January 2014. SGLT-2 inhibitors, as a class, have consistently shown to reduce cardiac outcomes in patients with type 2 diabetes, who also have clinical or subclinical heart failure.
The New England Journal of Medicine published the results of DAPA-HF, a major randomized clinical trial, in September 2019. Investigators evaluated the potential heart benefits of farxiga in patients without diabetes. A group of 5000 adults with heart failure stages 2–4 and an ejection fraction of <40% were randomized to receive farxiga or placebo. Participants were followed and analyzed at 18 months.
During this relatively short interval, farxiga improved the following outcomes significantly: 25% reduction in the primary endpoint (worsening of heart failure ± cardiovascular death), 30% reduction in worsening of heart failure, 18% reduction in cardiovascular death and a 17% reduction in mortality from any cause.
Surprisingly, these benefits were similar between patients with and without diabetes, indicating that the mechanism of heart failure protection of the SGLT-2 inhibitor is independent of hyperglycemia. The rates of adverse events were similar among adults receiving farxiga or a placebo.
DAPA-HF trial adds strong evidence for the use of SGLT-2 inhibitors in heart failure management, independent of diabetes status. I anticipate more extensive use of these medications by the cardiologists. It is fascinating to see how a class of drugs designed and utilized initially for diabetes is crossing over into the cardiology world.
The Lancets, Diabetes and Endocrinology has just published the results of SUSTAIN 8 clinical trial. The study compared the efficacy and safety of semaglutide 1.0 mg/week versus canagliflozin 300 mg/day in patients with uncontrolled diabetes taking only metformin.
Investigators recruited and followed a group of 800 adults with baseline A1c 7.0-10.5% from 111 centers in 11 countries. They found that the addition of semaglutide to metformin lowered A1c and body weight more than canagliflozin by 0.5% and 2.2 lbs respectively. The trial observed that patients receiving semaglutide experienced higher rates of nausea, while those taking canagliflozin developed more urinary tract infections.
Current ADA and AACE guidelines recommend the use of a GLP-1 agonist or SGLT-2 inhibitor after metformin in uncontrolled type 2 diabetes. Although the study did not compare GLP-1 agonists and SGLT-2 inhibitors as a class, it did suggest initiation of semaglutide 1.0 mg/week over SGLT-2 inhibitors. SGLT-2 inhibitors are regarded to be clinically similar.
An SGLT-2 inhibitor, however, would be a better second-line agent after metformin in diabetes patients with clinical or subclinical heart failure but with proper kidney function (eGFR >45). I anticipate that ADA and AACE guidelines will incorporate SUSTAIN 8 results in their next published standards.
The New England Journal of Medicine first published the results of the HPS2-THRIVE randomized clinical trial in 2014. Niacin addition to statin therapy did not improve cardiovascular outcomes. Instead, the trial found an increased rate of adverse events.
Last month, Clinical Therapeutics published a detailed analysis of the trial’s adverse events. Authors found that niacin addition significantly increased the risk of new-onset diabetes, worsening of diabetes, severe bleeding, and serious infections by about 30%, 55%, 40%, and 20% respectively.
The above adverse outcomes were more pronounced in the first year after the start of niacin. The infection rate was an exception, which stayed elevated throughout the trial. Investigators followed and analyzed a group of 25,000 patients with high baseline risk for the vascular disease over four years.
Based on HPS2-THRIVE data, it is difficult to justify the clinical use of niacin from the cardiovascular standpoint.
Technology is rapidly advancing in detecting subclinical heart disease at a much earlier stage. Global heart strain, better known as Left Ventricular Global Longitudinal Strain (LV-GLS) is such an example. It utilizes speckle tracking imaging of transthoracic echocardiography.
LV-GLS identifies left ventricular dysfunction at its embryo before the ejection fraction has declined, a definition of heart failure. Investigators have tested it in a variety of heart anomalies, including ischemic, atherosclerotic, viral, hypertrophic, and dilated myopathies.
Authors applied LV-GLS technology to adults with type 2 diabetes. Retrospectively, they followed about 400 diabetes patients for six years and documented their all-cause mortality.
The article defined abnormal global heart strain when LV-GLS measurement was greater than two positive standard deviations (>-17%). All-cause mortality was significantly higher, by 2.8-fold, in adults with abnormal LV-GLS versus those with normal LV-GLS.
Prospective research would need to validate these results in outcome-driven interventional randomized clinical trials. I anticipate positive results and wide-spread use of LV-GLS technology in the future.
Fortunately, we have SGLT-2 inhibitors as a unique class of medication that could potentially treat and manage patients with diabetes and abnormal heart strain.
Obesity and its complications are common, yet on the rise. Subsequently, gastric bypass surgery is on the rise too. Severe hypoglycemia can be a long-term complication of bariatric surgery. The most common method to negate or reduce hypoglycemia is dietary modifications. Patients need to consume small meals of a low glycemic index frequently. Medical therapies with acarbose, diazoxide, and octreotide are often not useful.
Here authors describe the utility of calcium channel blockers (CCBs) in two patients. Difficult to treat hypoglycemia developed in 8 and 13 years after the bypass procedure. Standard approach did not work. Only the use of nifedipine and verapamil improved patient's resistant hypoglycemia. The proposed rationale is that CCBs reduce or delay insulin secretion by pancreatic beta cells.
Although more clinical studies are needed, it is essential to be aware of the potential benefits of CCBs. For some patients with refractory and devastating hypoglycemia, they could be the last resort. Additionally, physicians are already familiar with CCBs as they have been on the market for decades.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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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