Treatments Extend Options to Individualize Care For & Beyond Diabetes

Insights on FDA approvals, side effects of pain meds, and key study findings presented at the European Association for the Study of Diabetes annual meeting,

Dual Benefits Likely with Dapagliflozin—Heart Failure and CKD

Dapagliflozin (Farxiga) has been granted fast track status by the Food and Drug Administration to prevent cardiovascular-related renal failure and to slow progression of chronic kidney disease (CKD) in individuals both with and without type 2 diabetes,1 according to a company announcement.

This timing is aimed at addressing the prevalence of CKD, which affects about 14% of adults in the  United States, nearly half of whom have also been diagnosed with type 2 diabetes and/or cardiovascular disease.

As new meds address diabetes complications, better care is possible. Photo: 123rf

Given an estimated 37 million people in the United States require treatment for renal impairment, and who are also at increased risk for cardiovascular disease and stroke, dapagliflozin appears to meet the need for an effective overall therapy for a significant number of patients.

While sulfonylureas appear to have weathered long-held concerns about cardiovascular safety, this antidiabetic class does not confer any benefit regarding improvement in heart failure among patients with type 2 diabetes, and still promotes undesirable weight gain.3

While cost should be a consideration when discussing pharmacotherapy with the patient, these findings should be compared to the advantages conferred by the newer agents, which demonstrate more comprehensive therapeutic benefits with regard to renal dysfunction, heart failure, and weight gain—even in at-risk individuals who do not have diabetes.

As such, results from the long anticipated CAROLINA (Cardiovascular Outcomes Study of Linagliptin versus Glimepiride in Type 2 Diabetes) randomized trial, presented at the European Association for the Study of Diabetes (EASD) 2019 annual meeting in Barcelona, Spain, and simultaneously published in the Journal of the American Medical Association,3 demonstrated similar rates of major adverse cardiovascular events (3-point MACE) for the dipeptidyl peptidase 4 (DPP-4) inhibitors, or gliptins, and the sulfonylureas (11.8% and 12%, respectively).

The trial assessed the effects among 6,000 patients with type 2 diabetes who were followed for a median of 6.3 years,3 reported the lead author, Julio Rosenstock, MD, director of the Dallas Diabetes Research Center, and clinical professor of medicine at the University of Texas Southwestern Medical Center in Dallas.

As has already been demonstrated in earlier trials, hypoglycemic events occurred more frequently in the group taking the sulfonylurea.3

Building on results of the EMPA-REG trial,4 empagliflozin appears to reduce progression of renal failure as well as the rates of hospitalization for heart failure and cardiovascular mortality in patients with type 2 diabetes. Even more compelling, the benefits regarding heart failure persisted in patients with chronic renal disease. These findings were confirmed with similar reports of benefit with dapagliflozin from the DECLARE-TIMI 58 trial,5 and with canagliflozin based on results of the CANVAS trial.6

One of the most compelling findings is the consistent reduction in heart failure events even among individuals who have not been diagnosed with diabetes,3 according to the investigators.

The most recent findings from the DAPA-HF trial,7 also presented at the EASD annual meeting, indicate that in patients receiving dapagliflozin, there was a 26% lower rate of worsening heart failure (the primary composite outcome) in comparison to placebo (P < 0.001).  Secondary cardiovascular outcomes, including fewer first and recurrent hospitalizations for heart failure, decreased all-cause mortality, and improved quality of life scores, were also reported.

Maybe most compelling, there was an addictive effect to background heart failure therapies, and the magnitude of benefit remained consistent whether or not the patient had diabetes. However, the population in this trial had moderate heart failure so the findings may not be the same for those with more severe disease.8

Tramadol Carries a Significant Risk of Hypoglycemia  

Investigators from the University of California at San Diego in La Jolla, California, report that tramadol, a commonly used analgesic, and methadone, appear to induce hypoglycemic events. This observation stems from a review of more than 12 million reports for reactions to 20 drugs in the US Food and Drug Administration Adverse Event Reporting System,as part of retrospective analysis published in Scientific Reports.

Given the growing reliance on tramadol to supplant oxycodone for pain relief—with prescriptions for tramadol and other synthetic opioids increasing 88% between 2008 to 2013,10  the authors sought to confirm this association. The rates of low blood sugar occurred at a much greater rate when compared to other pain-relieving medications, including other opioids, serotonin-norepinephrine reuptake inhibitors, and drugs affecting NMDAR activity.9

As such, senior author Ruben Abagyan, PhD, a professor at the Skaggs School of Pharmacy and Pharmaceutical Sciences, of the University of California San Diego, and colleagues, concluded that “it may be beneficial to monitor glucose levels when initiating tramadol or methadone in both diabetic and non-diabetic patients. Alternative…pain medications may be safer to use in patients at risk of hypoglycemia or any complications associated with [low blood sugar].9

Easy-to-Administer Liquid Glucagon Approved for Severe Hypoglycemia

Following up on reporting from a year ago, the Food and Drug Administration (FDA) has granted approval to Xeris Pharmaceutical to market, Gvoke (G-Pen), a ready-to-use liquid stable form of glucagon for severe hypoglycemia in individuals ages 2 years and older who have type 1 diabetes.11

Approval was granted following review of data submitted from three phase 3 clinical trials aimed to evaluate the efficacy and safety of Gvoke (1mg injection) against standard glucagon.12-14 The first two randomized single-blind trials, reported here a year ago, comparing this injectable glucagon to the standard formulation, in adults with type 1 diabetes.

Data from this phase 3, open label sequential study in 31 pediatric patients (2 to 17 years) with type 1 diabetes demonstrated satisfaction with the Gvoke glucagon injection pen at two dosing levels: 0.5 mg mg (for the younger cohort, 2-11 years) and 1 mg (for patients 12-17 years).14 Patients were administered insulin to induce a plasma glucose of < 80 mg/dL, followed by an age-appropriate injection dose of Gvoke glucagon. Study results confirmed that all but one patient met the primary endpoint—reaching a target glucose increase of ≥ 25mg/dL.

“We believe that all patients on insulin would benefit by having a ready-to-use option like our Gvoke versus the standard 9-step assembly process of the glucagon rescue kit,” Ken Johnson, PharmD, senior vice president of clinical development and medical affairs at Xeris Pharmacueticals told EndocrineWeb.

“As you may know, Lilly recently launched a nasal dry powder of 3.0 mg of glucagon. As such, we believe people will make their decision based on two factors:

  1. Usefulness of Gvoke’s premixed, prefilled, premeasured liquid stable glucagon; and
  2. Route of administration and the associated certainty of the dose.

People who prefer Gvoke may like that it is a route of administration they are familiar with. Our market research has shown people associate Gvoke with the fact that it is easy to tell if the full dose has been administered. In addition, caregivers of children also like the premeasured dosing option for kids that 0.5mg, which is half the dose of the adult devices,” he added.

Regarding safety, the most common adverse reactions in adults were nausea, vomiting, injection site edema, and headache;13,14 and among the children, the most common adverse reactions were nausea, hypoglycemia, vomiting, headache, abdominal pain, hyperglycemia, injection site reactions and discomfort, and urticaria.15

This stable liquid glucagon is administered by prefilled syringe (Gvoke PFS) or autoinjector (Gvoke HypoPen) into the lower abdomen, outer thigh, or outer upper arm.

Xeris plans on making the pre-filled syringe available by mid-November and the autoinjector next year, said Dr. Johnson. The cost of the prefilled syringe and the autoinjection of Gvoke will similar to currently marketed glucagon formulations. For example, the glucagon therapy, Baqsimi (Eli Lilly), has a list price of $280.80 for a one-pack and $561.60 for a two-pack.

 

The CAROLINA trial was underwritten by Boehringer Ingelheim and Eli Lilly and Company

Continue Reading:
Diabetes and Heart Failure: What Endocrinologists Need To Know
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