FIDELIO-DKD trial renders Kerendia (finerenone) the FDA approval

The study also compared the two groups for the number of patients who experienced cardiovascular death, a non-fatal heart attack, non-fatal stroke, or hospitalization for heart failure. Results showed that 367 of the 2,833 patients receiving Kerendia had at least one of the events in the composite endpoint compared to 420 of the 2,841 patients who received a placebo, with the treatment showing a reduction in the risk of cardiovascular death, non-fatal heart attack, and hospitalization for heart failure.


FDA removes boxed warning for leg amputations by Invokana

Collectively, these newly identified effects of Invokana on heart and kidney disease show significantly enhanced benefits of this medicine. Safety information from recent clinical trials also suggests that the risk of amputation, while still increased with canagliflozin, is lower than previously described, particularly when appropriately monitored. Based on these considerations, we have concluded that the Boxed Warning should be removed.


2020 ADA guidelines: blood pressure care in adults with diabetes

Here is a concise summary of the 2020 ADA guidelines on the approach of hypertension in patients with diabetes. The authors discuss lifestyle, medications, drug side-effects, and blood pressure (BP) targets. Goals are to achieve BP <130/80, <135/85, and <140/90 mmHg in adults at high risk for ASCVD, gestational diabetes, and low-ASCVD risk, respectively.

Dr. Tashko

2020 ADA Guidelines: Medications for Type 2 Diabetes

The ADA guidelines still recommend Metformin as the first drug for patients with diabetes type 2 (DM2). The advantages of Metformin are its efficacy in lowering A1c, being inexpensive, improving insulin resistance, potential weight loss, not causing hypoglycemia, and having the most extended clinical safety data – since its approval in 1957 in France and 1995 in the U.S.

If the patient has established or risk factors for cardiovascular disease, then a GLP1 agonist with proven CVD benefits is the recommended second-line medication. Examples are Ozempic, Victoza, and Trulicity. However, if a person with DM2 has heart failure or chronic kidney disease ― defined by LVEF <45%, eGFR 30-60, or urinary albuminuria >300 ― an SGLT2 inhibitor should be used. Such medications are Invokana, Jardiance, and Farxiga.

The ADA recommends the following drugs as the third line option: GLP1 agonist if already on Metformin + SGLT2 inhibitor and SGLT2 inhibitor if the patient is taking Metformin + GLP1 agonist. Any of the following agents could be fourth line therapies; sulfonylurea, basal insulin, DDP4 inhibitor, or TZD if heart failure is absent.

The above drug algorithmic guidance is general. The ultimate clinical decision is based on medication tolerability, cost, clinical setting, glucose control, comorbidities, and patient’s preference.


FDA guidance on diabetes safety clinical trials

In 2008, the Food and Drug Administration mandated the pharmaceutical industry to prove cardiovascular safety for all new anti-diabetes medications. As a consequence, we presently have critically useful safety data from clinical trials like LEADER, SUSTAIN, CANVAS, PIONEER 6, DECLARE-TIMI 58, and REWIND.

The FDA has now issued a new draft recommendation to broaden the above requirement by including safety clinical trials for nephropathy, neuropathy, retinopathy, and sleep apnea, in addition to ischemic atherosclerosis. The rationale is that the above non-ASCVD complications can also increase the mortality risk in patients with type 2 diabetes.

Although recommendations have not been specified or finalized, they will change the landscape of anti-diabetes clinical research for the next 15 years. Stay tuned.


2020 ADA guidelines: Key Revisions

Here you can find the critical modifications in 2020 ADA guidelines. Particular emphasis is placed on pharmacological therapy with GLP-1 agonists or SGLT-2 inhibitors for patients with established cardiovascular disease, heart failure, or chronic kidney disease. Guidelines are published yearly in the month of January.


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.


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.


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.


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.


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.


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.