Safety and Tolerability of Semaglutide: Pooled Phase 3 Data

Close up of woman injecting insulin into stomach

The scope for prescribing glucagon-like peptide-1 receptor agonists (GLP-1RAs) has expanded within both specialty and primary care now that an oral formulation is available and several injectable GLP-1RAs have an indication for reducing cardiovascular risk.

Vanita R. Aroda, MD, director of Diabetes Clinical Research and an associate physician in the Division of Endocrinology, Diabetes and Hypertension at Brigham and Women’s Hospital, and colleagues saw a need for an updated understanding of the safety and tolerability profiles of these agents.

In Diabetes, Obesity and Metabolism, they report an integrated analysis of 18 randomized, controlled trials of semaglutide (17,639 patients), concluding its safety and tolerability are now well characterized—and similar for the subcutaneous and oral formulations.


The researchers created two pools of phase 3 trials and reviewed two additional phase 3 trials separately:

  • The SUSTAIN pool (excluding SUSTAIN 6) comprised nine trials (3,150 patients received once-weekly subcutaneous semaglutide and 1,657 received an active comparator or placebo)
  • The PIONEER pool (excluding PIONEER 6) comprised seven trials (4,116 patients received once-daily oral semaglutide and 2,236 received a comparator)
  • SUSTAIN 6 included patients with established cardiovascular disease or were at high risk of cardiovascular events (1,648 used subcutaneous semaglutide in addition to standard care and 1,649 received placebo)
  • PIONEER 6 had a patient population similar to that of SUSTAIN 6 but compared 1,591 patients who used oral semaglutide with 1,592 who received placebo

Here SUSTAIN 6 and PIONEER 6 are collectively termed the cardiovascular outcomes trials (CVOTs). Key exclusion criteria for all trials were a history of pancreatitis or a personal/family history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma. Patients with proliferative retinopathy were excluded from all trials except SUSTAIN 6.

Kidney Disorders

The proportions of patients with adverse events (AEs) and the rates of events of kidney disorders were comparable with semaglutide versus comparators in the SUSTAIN and PIONEER pools and the CVOTs. The rates of acute kidney injury and kidney failure were also similar for semaglutide versus comparators in the two pools. Most kidney disorder events were mild to moderate in intensity, although three serious AEs of acute kidney failure were reported secondary to dehydration.


Acute pancreatitis occurred in similar numbers and proportions of patients with semaglutide and comparators in the pools and the CVOTs.

Hepatobiliary Disorders

The cumulative incidence of gallbladder-related AEs continued to increase throughout the trials of subcutaneous semaglutide, whereas this was not seen to the same extent with comparators. The increase with subcutaneous semaglutide was driven primarily by a higher rate of cholelithiasis. A similar rate of cholelithiasis was reported with subcutaneous semaglutide in SUSTAIN 6.

In the PIONEER pool, the incidence of gallbladder-related AEs was similar with semaglutide and comparators. Cholelithiasis was the most common gallbladder-related event in all treatment groups. In PIONEER 6, the rate of cholelithiasis was similar with oral semaglutide and placebo.


The proportion of malignant neoplasms, including those of special interest, was similar between comparators and both subcutaneous and oral semaglutide. Malignant neoplasms showed no clustering within any specific organ system.

There were three malignant thyroid neoplasms with subcutaneous semaglutide in the SUSTAIN pool (none with comparators) and two events with oral semaglutide in the PIONEER pool (one with comparator). There were no cases of medullary thyroid cancer.

In PIONEER 6, there was one case of medullary thyroid cancer in a patient on oral semaglutide with pre-existing thyroid nodules and elevated calcitonin at baseline.


The proportion of patients reporting severe hypoglycemic episodes was low and similar between semaglutide and comparators. This was true for both patients who were receiving concomitant sulfonylurea or insulin and those who were not.

Diabetic Retinopathy

In the SUSTAIN and PIONEER pools, the proportion of patients reporting diabetic retinopathy events and the rate of such events were similar for semaglutide and comparators. In PIONEER 6, the cumulative incidence of diabetic retinopathy was similar with placebo and oral semaglutide.

In SUSTAIN 6 (where retinopathy was not an exclusion criterion), diabetic retinopathy was more frequent in semaglutide-treated versus placebo-treated patients throughout the trial.

Cardiovascular Events

In the SUSTAIN and PIONEER pools, the incidence of any cardiovascular events was low and similar between semaglutide and comparators. In the CVOTs, there was a decreased risk of major adverse cardiac events when subcutaneous semaglutide was added to standard care, and oral semaglutide showed non-inferiority.

Tips for Clinicians

This study suggests several ways to prevent serious complications of GLP-1RAs:

  • For patients with renal impairment who report severe gastrointestinal reactions, use caution and/or monitor renal function at initiation and when escalating the dose
  • For patients with a history of pancreatitis, consider alternative antidiabetic therapy. Any patient should discontinue GLP-1RA treatment if pancreatitis is suspected, and the drug should not be restarted if pancreatitis is confirmed
  • Patients with pre-existing diabetic retinopathy and longstanding disease treated with insulin should be monitored closely and treated in line with the standard of care

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