Gabrielle Ientile, Assistant Editor

 identified biomarkers, using a simple blood test, that are able to show in advance how a patient with diabetes will respond to treatment with metformin.

Although metformin is the first-line drug that has the ability to lower blood sugar levels in individuals with type 2 diabetes, approximately 30% of all patients do not respond well to metformin and should be administered a different drug immediately, according to the study’s investigators. Adverse effects (AEs) often consist of gastrointestinal difficulties, including nausea, stomach pain, and diarrhea. An estimated 5% of patients stop taking metformin due to severe manifestations of the drug.

Investigators assessed epigenetic modifications – DNA methylations – in the blood of patients with type 2 diabetes prior to taking metformin, and followed up 1 year later to determine clinical benefit in the way of lowered blood sugar levels, as well as whether or not the individual experienced any AEs.

The study included 363 patients of 3 different cohorts of the research and quality assurance project All New Diabetics in Skåne and Uppsala, Sweden, as well as the Optimized Program of Personalized Treatment of Type 2 Diabetes (Optimed) in Latvia.

The study marks the first time that pharmacoepigenetics have been used to study diabetes. “By compiling the responses, we have found biomarkers that can identify already at diagnosis of diabetes which patients will benefit from and tolerate metformin, which will advance personalized therapy in type 2 diabetes," said the study's first author Sonia García-Calzón, PhD.

The epigenetics-based tool may be further developed to help patients with type 2 diabetes receive optimal therapy, the investigators concluded.

Following this groundbreaking study, investigators are planning to initiate a new clinical study within a global patient cohort totaling 1000. 

García-Calzón S, Perfilyev A, Martinell M, et al. Epigenetic markers associated with metformin response and intolerance in drug-naïve patients with type 2 diabetes. 

Metformin for type 2 diabetes patients or not? Researchers now have the answer. News release. Lund University; September 17, 2020. Accessed September 18, 2020. https://www.lunduniversity.lu.se/article/metformin-type-2-diabetes-patients-or-not-researchers-now-have-answer

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The study marks the first pharmacoepigenetic study in diabetes evaluating epigenetic factors as biomarkers to predict a drug’s effects on an individual.

Study Identifies Biomarkers for Metformin Response in Patients With Diabetes

Results from a recent study showed that famotidine was associated with a reduced risk of clinical deterioration leading to intubation or death in patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes the novel coronavirus disease 2019 (COVID-19). 

However, despite the study findings, there is not enough data to support famotidine’s use in this treatment setting, as randomized, controlled trials are still needed. In late June, the Infectious Diseases Society of America recommended against the use of famotidine for the sole purpose of treating COVID-19 outside of a clinical trial.

Limitations of the study include its observational and single-center design, as well as the possibility of unmeasured confounders or hidden bias.

Famotidine, a histamine-2 receptor antagonist that functions to suppress gastric acid production, inhibits human immunodeficiency virus replication in vitro and has recently been evaluated as likely to inhibit viral replication of SARS-CoV-2. Famotidine has not been previously studied in patients for antiviral effects and relevant prior data is limited, according to investigators.

Circulated in the September publication of 

 the study evaluated famotidine through a retrospective cohort study at Columbia University Irving Medical Center or its affiliate the Allen Pavilion, which was within the epicenter of the COVID-19 pandemic in the United States. Investigators reported that, in patients who were not initially intubated, famotidine use was linked to a 2-fold reduction in clinical deterioration.

Investigators included a total of 1620 patients 18 years or older who were admitted to the medical center between February 25, 2020 and April 13, 2020 and tested positive for SARS-CoV-2 by nasopharyngeal polymerase chain reaction within 72 hours of admission due to limited testing availability amid the early phase of the pandemic. Famotidine was administered intravenously or orally at any dose or duration.

Eighty-four patients (5.1%) received famotidine within 24 hours of hospital admission; home use of famotidine was recorded on admission medication reconciliation in 15% of patients who used the drug while hospitalized compared with 1% of patients who did not. The median duration of famotidine use was 5.8 days, with a total median dose of 136 mg (63-233 mg).

Investigators reported that 142 (8.8%) of patients were intubated and 238 (15%) died. A crude analysis showed that famotidine use was significantly associated with reduced risk for the composite outcome of death or intubation.

“In patients hospitalized with COVID-19 and not initially intubated, famotidine use was associated with a 2-fold reduction in clinical deterioration leading to intubation or death,” investigators wrote. “These findings are observational and should not be interpreted to mean that famotidine has a protective effect against COVID-19. Randomized controlled trials are under way.”

Freedberg DE, Conigliaro J, Wang TC, et al. Famotidine Use Is Associated With Improved Clinical Outcomes in Hospitalized COVID-19 Patients: A Propensity Score Matched Retrospective Cohort Study. 

https://doi.org/10.1053/j.gastro.2020.05.053

The study evaluated COVID-19 patients within the epicenter of the COVID-19 pandemic in the United States.

Study Evaluates Famotidine Use in Hospitalized COVID-19

The FDA recently approved 2 additional doses of dulaglutide (Trulicity; Eli Lilly) for the treatment of type 2 diabetes.

Approval of the 3.0 mg and 4.5 mg doses of dulaglutide was based on favorable results in regard to A1C and body weight reduction, stemming from the phase 3 AWARD-11 clinical trial comparing the additional doses with 1.5 mg doses in individuals with type 2 diabetes.

Diabetes affects an estimated 34 million Americans and approximately 463 million individuals around the world. Type 2 diabetes in particular accounts for between 90% to 95% of cases in the US.

Dulaglutide can be administered to adults with type 2 diabetes in order to improve blood sugar (glucose) as well as to reduce the risk of major cardiovascular events such as death, heart attack, or stroke in individuals with heart disease or multiple cardiovascular risk factors.

Lilly intends to offer dulaglutide 3.0 mg and 4.5 mg by late September. "People find the Trulicity pen simple and easy-to-use," said Leonard Glass, MD, FACE, vice president of Medical Affairs, Lilly. "Now, with the 3.0 and 4.5 doses available, people with type 2 diabetes who use Trulicity can benefit from additional A1C and weight loss as their condition progresses."

The phase 3 randomized, double-blind, parallel arm study included 1842 participants with type 2 diabetes and sought data demonstrating not only the safety and efficacy of the 2 investigational doses of dulaglutide (3.0 mg and 4.5 mg), compared with 1.5 mg, but also that a once-weekly investigational dulaglutide dose was superior to the already approved 1.5 mg dose.

According to the study, both of the investigational doses led to significant reductions in A1C and weight in participants who remained on treatment throughout the trial:

4.5 mg (A1C: -1.9%; weight: -10.4 pounds)

The phase 3 trial additionally gauged change from baseline in mean body weight and fasting serum glucose, as well as percentage of patients reaching an A1C goal of less than 7% and occurrence of hypoglycemic episodes and pharmacokinetics at steady-state through 36 and 52 weeks.

"The FDA's decision to approve the additional doses of Trulicity is a positive step forward for people living with type 2 diabetes and their care teams," said Juan Pablo Frias, MD, medical director and principal investigator, National Research Institute.

"This progressive condition can require different treatment approaches over time, and findings from AWARD-11 showed the additional doses of Trulicity can lead to further A1C and weight reductions for people with type 2 diabetes whose current treatment may no longer be meeting their needs," Frias said.

FDA approves additional doses of Trulicity (dulaglutide) for the treatment of type 2 diabetes. News release. Lilly; September 3, 2020. Accessed September 8, 2020. 

https://investor.lilly.com/news-releases/news-release-details/fda-approves-additional-doses-trulicityr-dulaglutide-treatment

Approval was based on a phase 3 clinical trial comparing the investigative doses with the approved 1.5 mg dose.

FDA Approves New Doses of Dulaglutide for the Treatment of Type 2 Diabetes

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Based on a review of latest data stemming from 3 clinical trials, the FDA has removed the boxed warning concerning amputation risk from the diabetes drug canagliflozin (Invokana, Invokamet, Invokamet XR) 

Canagliflozin is a sodium-glucose cotransporter-2 (SGLT2) inhibitor that lowers blood sugar by causing the kidneys to remove sugar from the body through the urine. The drug was initially approved for use in conjunction with diet and exercise to lower blood sugar in adults with type 2 diabetes (T2D).

The agency’s requirement of the boxed warning in 2017 was based on its assessment that the risk of amputations was substantial compared with the potential benefit of canagliflozin.

More recent clinical trials have shown significant benefits to the heart and kidneys. In 2018, canagliflozin was approved by the FDA for its potential to reduce the risk of major heart-related events, including heart attack, stroke, or deaths in patients with T2D who also have identified heart disease. In 2019, canagliflozin was approved to reduce the risk of end-stage kidney disease, worsening kidney function, heart-related death, and hospitalization due to heart failure in some patients with T2D and diabetic kidney disease.

In light of these results, as well as safety information stemming from new clinical trials that demonstrated that the risk of amputation is lower than previously described, the FDA’s review concluded that the boxed warning should be removed. Because the risk of amputation still remains elevated with the use of canagliflozin, it is described in the warning and precautions section of the drug’s prescribing information.

The FDA urges health care professionals and patients to report side effects from canagliflozin to the FDA MedWatch program by contacting the FDA at 

FDA removes Boxed Warning about risk of leg and foot amputations for the diabetes medicine canaglifozin (Invokana, Invokamet, Invokamet XR). News Release. FDA; August 26, 2020. Accessed August 27, 2020. 

https://www.fda.gov/drugs/drug-safety-and-availability/fda-removes-boxed-warning-about-risk-leg-and-foot-amputations-diabetes-medicine-canagliflozin

The removal of the boxed warning from canagliflozin was based on the FDA’s review of new data from 3 clinical trials.

Author | Gabrielle Ientile, Assistant Editor

Articles

Study Identifies Biomarkers for Metformin Response in Patients With Diabetes

Study Evaluates Famotidine Use in Hospitalized COVID-19

FDA Approves New Doses of Dulaglutide for the Treatment of Type 2 Diabetes

FDA Removes Boxed Warning for Amputation Risk From Canagliflozin