Semaglutide and Empagliflozin Shine at EASD 2019: New Clinical Insights Highlight Superior Glycemic Control, Weight Loss, and Renal Benefits

Diabetes is one of the major factors threatening human health worldwide. According to estimates by the International Diabetes Federation (IDF), more than 425 million people globally are living with diabetes. Consequently, it has become a key focus of research and development in the pharmaceutical industry. Recently, the 55th Annual Meeting of the European Association for the Study of Diabetes (EASD 2019) opened in Barcelona, Spain, where several pharmaceutical companies presented the latest clinical trial results of their diabetes therapies. Today, WuXi AppTec’s content team will share with readers the most recent developments in new drug research and development for diabetes.

Semaglutide Demonstrates Superior Efficacy in Glycemic Control and Weight Loss Compared to Two Common Therapies

Semaglutide (brand name Ozempic), developed by Novo Nordisk, is a long-acting human glucagon-like peptide-1 (GLP-1) analog. It received FDA approval in 2017 to help patients with type 2 diabetes control blood glucose levels when combined with diet and exercise. GLP-1 is a hormone secreted by the small intestine that promotes insulin secretion and inhibits glucagon secretion after meals, thereby accelerating glucose metabolism. GLP-1 analogs also delay gastric emptying and suppress appetite, leading to weight loss.

At EASD 2019, Novo Nordisk presented data from two Phase 3 clinical trials. In the Phase 3 trial named SUSTAIN 8, patients received either semaglutide or the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin. SGLT2 is primarily responsible for glucose reabsorption in the kidneys; SGLT2 inhibitors lower blood glucose levels by blocking SGLT2 function, thereby promoting the excretion of excess glucose in the urine. Currently, clinical trials directly comparing the efficacy of GLP-1 analogs and SGLT2 inhibitors remain very limited.

The trial results demonstrated that after 52 weeks of treatment, semaglutide reduced the mean glycated hemoglobin (HbA1c) level by 1.5% from a baseline of 8.3%, outperforming the active control group (1.0%). Furthermore, 66.1% of patients in the semaglutide group achieved the target HbA1c level of <7%, compared to 45.1% in the control group.

In terms of weight reduction, patients in the semaglutide group experienced a mean weight loss of 5.3 kg, compared with 4.2 kg in the control group; the baseline body weight was 90.2 kg. Furthermore, 22.3% of patients in the semaglutide group achieved a weight loss of >10%, versus 8.9% in the control group.

Dr. Ildiko Lingvay of UT Southwestern Medical Center, the lead investigator of the study, stated, “The SUSTAIN 8 trial data support semaglutide as an effective treatment option for reducing blood glucose and body weight in patients with type 2 diabetes after metformin.”

Meanwhile, Novo Nordisk also compared the efficacy of semaglutide with another GLP-1 analog from the company, liraglutide (brand name Victoza). Like semaglutide, liraglutide is a long-acting GLP-1 analog, and semaglutide is an optimized product based on liraglutide.

▲ Structures of liraglutide and semaglutide (Image source: Reference [5])

Data from the Phase 3 SUSTAIN 10 clinical trial demonstrated that after 30 weeks of treatment, semaglutide reduced HbA1c levels by an average of 1.7%, outperforming liraglutide (1.0%), in patients with a baseline HbA1c of 8.2%. Furthermore, 80% of patients in the semaglutide group achieved HbA1c levels <7%, compared to 46% in the liraglutide group. Semaglutide also demonstrated superior efficacy to liraglutide in terms of weight reduction.

Oral Semaglutide Improves Glycemic Control in Patients with Type 2 Diabetes

In addition to its injectable semaglutide, Novo Nordisk has developed an oral formulation of semaglutide. This new oral medication offers greater convenience for patients, and its regulatory application has been accepted by the FDA, with approval expected in the near future. If approved, it will become the first and currently only oral GLP-1 analog.

▲Oral semaglutide is absorbed in the stomach (Image source: Reference [5])

At EASD 2019, the company presented pooled analysis results of data from multiple Phase 3 trials of oral semaglutide. Researchers stratified data from 5,657 patients enrolled in the PIONEER 1–5, 7, and 8 clinical trials into three groups based on baseline HbA1c levels: HbA1c <8.0%, ≥8.0% to <9.0%, and ≥9.0%. Analysis of these subgroups demonstrated that oral semaglutide (at doses of 7 mg and 14 mg) was superior to control treatments in reducing HbA1c levels, regardless of baseline HbA1c, with a greater proportion of patients receiving oral semaglutide achieving the target HbA1c level of <7%. Control groups included placebo, sitagliptin (100 mg), liraglutide (1.8 mg), and empagliflozin (25 mg).

“Patients with type 2 diabetes have individualized glycemic control targets,” said Dr. Juris Meier, Professor of Medicine at Ruhr University Bochum. “The findings of this analysis are highly significant, as they demonstrate that oral semaglutide improves glycemic control across a diverse population of patients with type 2 diabetes.”

Empagliflozin Delays the Progression of Diabetic Nephropathy in Patients with Diabetes

Eli Lilly and Boehringer Ingelheim presented data analyses at EASD 2019 demonstrating that the SGLT2 inhibitor empagliflozin (brand name Jardiance) delays the progression of kidney disease in patients with diabetes. In June this year, Janssen announced that its SGLT2 inhibitor canagliflozin effectively delayed the progression of chronic kidney disease (CKD) in patients with diabetes in the Phase 3 CREDENCE clinical trial. Recent meta-analyses have indicated that other SGLT2 inhibitors also play a role in slowing the progression of chronic kidney disease.

The data for this post-hoc analysis were derived from the EMPA-REG clinical trial. The results of this trial demonstrated that empagliflozin reduces cardiovascular risk in patients with type 2 diabetes. In this instance, researchers analyzed a subgroup of patients exhibiting symptoms of chronic kidney disease. These patients had elevated proteinuria levels, and their characteristics were similar to those of participants in Janssen’s CREDENCE trial.

The analysis results indicate that empagliflozin can also improve cardiovascular outcomes and slow the progression of kidney disease in this patient population. Furthermore, the analysis shows that empagliflozin improves cardiovascular outcomes and slows kidney disease progression regardless of whether patients exhibit symptoms of chronic kidney disease.

Eli Lilly and Boehringer Ingelheim have launched a Phase 3 trial to evaluate the efficacy of empagliflozin in slowing disease progression in patients with chronic kidney disease. If the trial is successful, empagliflozin could be used to treat non-diabetic patients with chronic kidney disease.

Sanofi’s Soliqua Improves Glycemic Control in Patients with Inadequate Response to GLP-1 Analogs

Soliqua, developed by Sanofi, is a fixed-dose combination therapy comprising insulin glargine (a long-acting insulin) and the GLP-1 receptor agonist lixisenatide. At EASD 2019, the company presented long-term efficacy results in patients who switched to Soliqua after their blood glucose levels remained inadequately controlled despite treatment with GLP-1 analogs.

Trial results demonstrated that 52 weeks after switching from a GLP-1 analog to Soliqua, 64% of patients achieved the target HbA1c level of <7%. Previous study results indicated that among patients who continued treatment with a GLP-1 analog, only 26% achieved the target HbA1c level after 26 weeks of therapy.

“For progressive diseases such as type 2 diabetes, patients may experience situations where glycemic levels cannot be effectively controlled with GLP-1 therapy alone,” said Mr. David Werner, Global Head of Insulin at Sanofi. “Choosing the next step in therapy in such cases is a critical issue.”

The study also demonstrated that regardless of the duration of diabetes, patients switching to Soliqua therapy achieved comparable benefits. Mr. Werner pointed out that this means “for patients receiving GLP-1 therapy who require intensified glycemic control, it is never too late to switch to Soliqua.”

References:

[1] Ozempic® Offers Superior Reductions in HbA1c and Body Weight Compared to Both Victoza® and Canagliflozin in People With Type 2 Diabetes. Retrieved September 17, 2019, from https://www.prnewswire.com/in/news-releases/ozempic-r-offers-superior-reductions-in-hba1c-and-body-weight-compared-to-both-victoza-r-and-canagliflozin-in-people-with-type-2-diabetes-812932851.html

[2] Oral semaglutide improves glycaemic control in people with type 2 diabetes across baseline blood sugar levels. Retrieved September 17, 2019, from https://finance.yahoo.com/news/oral-semaglutide-improves-glycaemic-control-130000467.html

[3] EASD: Lilly, BI tout new Jardiance kidney analysis as rival J&J nears FDA nod. Retrieved September 17, 2019, from https://www.fiercepharma.com/pharma/easd-lilly-bi-tout-new-jardiance-kidney-analysis-as-rival-j-j-nears-fda-nod

[4] EASD: Sanofi trumpets sustained Soliqua benefits for GLP-1 switchers. Retrieved September 17, 2019, from https://www.fiercepharma.com/pharma/easd-sanofi-touts-sustained-soliqua-benefits-for-glp-1-switchers

[5] Knudsen and Lau. (2019). The Discovery and Development of Liraglutide and Semaglutide. Front. Endocrinol., https://doi.org/10.3389/fendo.2019.00155

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