Ceaseless work, analysis, reflection, writing much, endless self-correction, that is my secret
Johann Sebastian Bach
I am happy to contribute to the editorial by Lisa Eramo published in Medical Economics, January 2018. The article is important as it raises physician awareness of Merit-based Incentive Payment System (MIPS) under which hypertension management falls. MIPS, part of 2015 MACRA, will go into effect in 2019.
This meta-analysis of four major clinical trials (ELIXA, LEADER, SUSTAIN 6, EXSCEL) reveals safety of GLP-1 agonists, bur more importantly their cardiovascular benefits on mortality, myocardial infarction and stroke in adults with type 2 diabetes.
The next natural step would be the quest for oral version of GLP-1 agonist given its positive profile on appetite, glucagon, insulin, glucose metabolism, proteinuria and cardiovascular system.
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.
I wish to thank Dr. Mihail "Misha" Zilbermint and Dr. Shabina R. Ahmed for inviting me to present at the 2019 Diabetes Symposium of Suburban Hospital, a member of Johns Hopkins Medicine. The symposium was a meaningful educational activity discussing the latest progress in the field of clinical diabetology. Over 100 primary care providers attended the seminar.
The topic of my presentation was "Modern lipid approach in patients with diabetes." Experts discussed in detail various important subjects, such as advanced hospital management of diabetes, recent clinical research on low carbohydrate diet, kidney protection by SGLT-2 inhibitors, diabetes devices, and cardiovascular risk reduction in patients with type 2 diabetes.
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.