Semaglutide Causes Weight Loss in Type 2 Diabetes Regardless of Baseline BMI

The SUSTAIN trials showed semaglutide causes weight loss in type 2 diabetes patients, but the true reason for the reductions in weight are still unknown.

The American Society for Metabolic and Bariatric Surgery (ASMBS), intent on improving public health and reducing obesity and obesity-related diseases, refers to type 2 diabetes and obesity as twin epidemics. According to ASMBS and the U.S. Department of Health and Human Services, obesity is a large risk factor for many diseases like hypertension, type 2 diabetes, stroke, cancer, and more. Another major concern is the fact that obesity increases all-cause and cardiovascular disease (CVD) mortality. In 2013, the WHO noted that more than 90% of people with type 2 diabetes were considered to have excess weight or obesity. Thus, getting patients to reduce their body weight is of utmost importance as it serves to alleviate diabetes-associated and CVD risks.

Weight loss can be achieved in many ways — through diet, physical activity, behavioral therapy, and even medication. Weight loss in a person with diabetes can improve glycemic control and potentially reduce the need for medications. However, some patients might benefit from both lifestyle modifications and medications with favorable side-effect profiles. One drug class well known for its weight loss is glucagon-like peptide-1 receptor (GLP-1) agonists. Current GLP-1 agonists available on the market include dulaglutide, exenatide, liraglutide, lixisenatide, and albiglutide. One of the newest agents to join this class is called semaglutide.

The SUSTAIN trials, which analyzed outcomes after semaglutide administration, were performed globally and consisted of seven separate trials studying over 8,000 people with type 2. This study found large reductions in HbA1c and body weight when compared to both placebo and other antidiabetic medications from various classes. While body weight reductions were noted, the reason for the weight loss was unknown. B. Ahren, et al aimed to analyze the impact of baseline body mass index (BMI) and nausea/vomiting incidence on weight loss in a post-hoc analysis using data from SUSTAIN trials 1-5.

Depending on the SUSTAIN trial, subjects received a range of diabetes medications. Overall, across all trials, patients were randomized to receive one of the following treatments over 30 or 56 weeks. They include semaglutide 0.5 mg, semaglutide 1.0 mg, comparator, or placebo. Comparator therapies include sitagliptin 100 mg, exenatide ER, or insulin glargine. In order to improve GI tolerability, gradual dose escalation was performed, eventually reaching the target dose of either 0.5 mg or 1.0 mg. The inclusion/exclusion criteria and trial-specific baseline medications for all trials can be found in Table 1: Inclusion/Exclusion Criteria and Trial-Specific Medications.

Table 1: Inclusion/Exclusion Criteria and Trial-Specific Medications
Trial-Specific Meds	SUSTAIN 1: Drug-naive SUSTAIN 2: Metformin and/or thiazolidinediones (TZDs) SUSTAIN 3: 1-2 drugs consisting of metformin,TZDs, or sulfonylureas SUSTAIN 4: metformin ± sulfonylurea SUSTAIN 5: basal insulin ± metformin
Inclusion Criteria	Type 2 Diabetes, ≥ 18 years old, HbA1c ≥ 7.0% – 10.0% A or HbA1c ≥ 7.0% – 10.5% B, eGFR > 30 mL/min/1.73 m2 A or eGFR > 60 mL/min/1.73 m2 B
Exclusion Criteria	History of chronic/idiopathic acute pancreatitis, known proliferative retinopathy/maculopathy needing acute treatment, calcitonin ≥ 50 ng/L, history of medullary thyroid carcinoma (persona/familial), multiple endocrine neoplasia syndrome type 2, acute coronary/cerebrovascular event within 90 days before randomization, heart failure class IV.
A: SUSTAIN 1, 4, and 5 B: SUSTAIN 2 and 3

All in all, 3,918 participants were randomized into either semaglutide 0.5 mg, semaglutide 1.0 mg, or comparator group. Around 3,899 patients (99.5%) received semaglutide and 92.5%–95.7% completed the study. Baseline characteristics across studies and treatment were quite similar. Treatment with semaglutide showed significant reductions in body weight from baseline. Reductions were noted in all BMI groups (i.e. <25, 25 to <30, 30 to <35, ≥35 kg/m2). In those treated with semaglutide 0.5 mg, body weight reduction ranged from 2.5–5.7 kg while treatment with 1.0 mg showed reductions that ranged from 2.0–7.9 kg; weight loss with the comparator therapies was less and ranged from 1.5–3.7 kg. Patients with higher BMI at baseline were found to have greater weight loss with either semaglutide dose or comparator medication. The only medication that showed weight gain was insulin glargine a result deemed independent of baseline BMI. Investigators found that semaglutide 1.0 mg weight loss was dependent upon BMI (p = 0.0046). Weight loss was increased in those taking the higher dose of semaglutide compared to comparator therapies (p < 0.05). Similarly, weight loss with semaglutide 0.5 mg was notably higher when compared to comparators (p < 0.05). Some, albeit few, cases of non-significance were noted when comparing weight loss from semaglutide to comparator treatments.

Per most diabetes guidelines, 5%–10% weight loss is generally recommended and found to be an appropriate and achievable goal. This study sought to determine just how effective semaglutide treatment was at helping patients attain that goal. The results show that semaglutide treatment helped patients achieve ≥ 5% or ≥ 10% weight loss better than comparators. Across all BMIs, semaglutide treatment showed significantly greater attainment of ≥ 5% or ≥ 10% weight loss (p < 0.05), but the greatest reductions were noted in those receiving the higher dose. Patients with a higher baseline BMI (≥35 kg/m2) and ≥ 5% weight loss achievement, showed the following weight loss results: 30–49% (0.5 mg dose) and 47–68% (1.0 mg dose) versus 6–27% (comparator).

These results were mirrored across all BMI ranges, except for in SUSTAIN 3 and 5 trials. In trials 3 and 5, a smaller proportion of patients with lower baseline BMI achieved one or both targets, respectively. Overall, 5–10% weight loss was not dependent on BMI across all trials.

In an attempt to determine the cause of weight loss, investigators questioned if nausea or vomiting (N/V), a side effect of this class, could be the source of the weight loss. N/V was experienced in 15.2–24.0% (0.5 mg dose), 21.5–27.2% (1.0 mg dose), and 6.0–14.1% (comparator). N/V was temporary, with a median duration of 1-8 days in all treatment groups. Overall duration of nausea was higher in semaglutide (15–33 days) compared to the comparator (8 days). Weight loss was more significant in those experiencing N/V as well as those receiving semaglutide 1.0 mg dose. While this played a role in weight loss, analysis showed that N/V was minimally responsible for weight loss (0.07–0.5 kg). Even though this side effect occurred more in the semaglutide group, the medication was well-tolerated. Patients experiencing gastrointestinal side effects and/or more likely to prematurely discontinue therapy had a lower baseline BMI.

Practice Pearls:

• Semaglutide, administered as either 0.5 mg or 1.0 mg subcutaneous injection, showed greater reductions in weight from baseline when compared to comparator treatments.
• Weight loss from semaglutide use was deemed independent of baseline body mass index.
• Weight loss due to nausea and vomiting (N/V), a side effect of semaglutide, was minor. Weight loss from N/V ranged from 0.07 to 0.5 kg.
• Higher dose semaglutide (1.0 mg dose) treatment was associated with greater weight loss and more N/V.
• Semaglutide treatment helped more patients achieve ≥ 5% or ≥ 10% weight loss goal better than comparators.

References:

Ahren, B., Atkin, S., Charpentier, G., Warren, M., Wilding, J., Birch, S., Holst, A., Leiter, L. Semaglutide induces weight loss in subjects with type 2 diabetes regardless of baseline BMI or gastrointestinal adverse events in SUSTAIN 1–5 trials. Diabetes, Obesity and Metabolism. 15 May 2018. Accepted Author Manuscript. https://onlinelibrary.wiley.com/doi/abs/10.1111/dom.13353.

U.S. Department of Health and Human Services, National Institutes of Health. Managing Overweight and Obesity in Adults: Systematic Evidence Review From the Obesity Expert Panel, 2013. Available from: https://www.nhlbi.nih.gov/sites/default/files/media/docs/obesity-evidence-review.pdf.

Kaytie A. Weierstahl, Pharm.D. Candidate, LECOM School of Pharmacy