2023 In Review: Major Developments In The Field Of Endocrinology

Let us take a glimpse into the notable progress and accomplishments within the field of endocrinology for the year 2023. This overview showcases some of the latest developments, groundbreaking research, and significant milestones that have shaped our understanding and treatment of endocrine disorders.

Diabetes

1. Once weekly insulin

Insulin icodec is a once weekly basal insulin analogue for the management of diabetes. In the ONWARDS 1 trial in type 2 diabetes, a study comparing once weekly insulin icodec to once daily insulin glargine, HbA1c reduction at 52 weeks and was greater with insulin icodec compared to insulin glargine.

Hypoglycemia rates were similar. ONWARDS 2-5 trials with insulin icodec in type 2 diabetes patients, involving insulin naïve and non-naïve patients have shown promising results and is expected to reach the patients by 2025. It mainly offers the advantage of reduction in the number of insulin injections and comparable or superior glycemic control with no increase in the hypoglycemia risk.

Insulin icodec was also studied in adult type 1 diabetes patients in the ONWARDS 6 trial. The trial compared insulin icodec with insulin degludec. HbA1c reduction was comparable, but hypoglycemia risk was almost double insulin icodec. More studies are needed in type 1 diabetes patients to determine whether risk of hypoglycemia will limit the use in this group.

2. New oral drug for kids with type 2 diabetes

The U.S. Food and Drug Administration (FDA) has approved tablet empagliflozin 10 mg and 25 mg in children 10 years and older with type 2 diabetes.

FDA approval is based on the results from the DINAMO phase III trial, in which empagliflozin use in participants aged 10-17 years with type 2 diabetes, was associated with a significant reduction in HbA1c at 26 weeks compared to placebo.

The safety characteristics in children receiving empagliflozin were comparable to those seen in adults with type 2 diabetes, except for an increased risk of hypoglycemia in pediatric patients treated with empagliflozin, irrespective of concurrent insulin use.

3. Baricitinib to preserve β-cell function in early type 1 diabetes

Teplizumab, a monoclonal antibody, is the only therapy approved for delaying the onset of clinical type 1 diabetes in individuals with preclinical disease.

In a phase 2 trial in patients with type 1 diabetes of recent onset, daily treatment with baricitinib (a janus kinase inhibitor) over 48 weeks appeared to preserve β-cell function as evidenced by higher C-peptide level in those who received baricitinib compared to placebo.

4. Triple agonist therapy (retatrutide) for the treatment of type 2 diabetes

Retatrutide is a triple glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon receptor agonist in development for the treatment of type 2 diabetes. In a phase 2 trial, retatrutide showed clinically meaningful improvements in glycemic control and significant reduction in body weight, maintaining a safety profile consistent with GLP-1 receptor agonists and combinations of GIP and GLP-1 receptor agonists.

5. Oral GLP-1 receptor agonist (orforglipron) for the treatment of type 2 diabetes

Orforglipron is an oral non-peptide glucagon-like peptide-1 (GLP-1) receptor agonist, in development for type 2 diabetes and obesity. In a phase 2 trial, orforglipron showed significant reductions in HbA1c and bodyweight compared with placebo or dulaglutide, with a safety profile similar to other GLP-1 agonists.

Obesity

1. Dual GLP-1 and GIP agonist (Tirzepatide) for obesity management

Tirzepatide is a novel GLP-1 and GIP agonist, already approved for the treatment of type 2 diabetes. On November 8, 2023, US FDA approved it for chronic weight management in adults with a body mass index of 27 kg/m2 or greater who also have a weight-related medical condition, such as hypertension, dyslipidemia, type 2 diabetes, obstructive sleep apnea, or cardiovascular disease.

The approval was based on the phase 3 SURMOUNT-1 and SURMOUNT-2 trials. In the SURMOUNT-1 trial, adults with obesity had average weight reductions of 19.5% with 10-mg dose and 20.9% with 15-mg dose by week 72, compared with around 3% weight reduction with placebo.(4) In SURMOUNT-2 trial, participants had weight reduction of up to 14.7% by week 72.

2. Semaglutide reduces cardiovascular events in obese patients without diabetes

In the SELECT trial, individuals with preexisting cardiovascular disease, overweight, or obesity, and without diabetes experienced a superior reduction in the occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke with a weekly subcutaneous injection of 2.4 mg semaglutide compared to a placebo, over an average follow-up period of 39.8 months.

3. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity

In STEP-HFpEF trial, treatment with semaglutide (2.4 mg) in patients with heart failure with preserved ejection fraction and obesity, led to larger reductions in symptoms and physical limitations, greater improvements in exercise function, and greater weight loss than placebo.

The positive results of this trial offer a potentially early intervention option for patients with heart failure with preserved ejection fraction and obesity.

Thyroid

Selpercatinib in Advanced RET-Mutant Medullary Thyroid Cancer

In an open-label, randomized trial comparing selpercatinib (a selective RET inhibitor) with either cabozantinib or vandetanib (less selective antiangiogenic kinase inhibitors with some RET inhibition), selpercatinib resulted in superior progression-free survival and treatment failure–free survival as compared with cabozantinib or vandetanib in patients with RET-mutant medullary thyroid cancer.

The trial confirmed that selpercatinib was a more effective treatment than the multikinase inhibitors cabozantinib and vandetanib in advanced RET-mutant medullary thyroid cancer. The trial also highlights the importance of implementing timely biomarker testing to detect actionable RET mutations to inform first-line therapy for all patients with advanced medullary thyroid cancer.

Menopause

Fezolinetant, a neurokinin 3 receptor antagonist for hot flashes

While hormone therapy remains the most effective approach for treating hot flashes, a new category of nonhormonal medications known as neurokinin 3 receptor (NK3R) antagonists presents as a viable option for those unable to undergo hormone therapy.

The initial NK3R antagonist to receive approval for clinical use is fezolinetant. In a trial involving over 500 postmenopausal women experiencing moderate-to-severe hot flashes, fezolinetant demonstrated a significant reduction in both the frequency and intensity of hot flashes compared to a placebo.