Hypoglycemia (when combined) on Ozempic (semaglutide 0.5-2 mg): Incidence, Severity, and Realistic Expectations

What Ozempic does on its own

Semaglutide is a GLP-1 receptor agonist, and the Ozempic label describes its effect on insulin as occurring in the presence of elevated blood glucose concentrations [1].

In the label's placebo-controlled trials, the monotherapy study ran 30 weeks with 129 patients on placebo, 127 on Ozempic 0.5 mg and 130 on 1 mg [1]. Severe hypoglycemia, which the label defines as an episode requiring the assistance of another person, occurred in 0% of all three arms [1]. Documented symptomatic hypoglycemia at a threshold of 70 mg/dL or below occurred in 0% on placebo, 1.6% on 0.5 mg and 3.8% on 1 mg [1]. The label's stricter combined category, severe or blood glucose-confirmed symptomatic at 56 mg/dL or below, was 1.6% on placebo, 0% on 0.5 mg and 0% on 1 mg [1].

When a sulfonylurea is in the mix

The label's warning states that patients receiving Ozempic with an insulin secretagogue such as a sulfonylurea, or with insulin, may have an increased risk of hypoglycemia, including severe hypoglycemia, and that hypoglycemia was more frequent when Ozempic was used in combination with a sulfonylurea [1]. It also says the risk may be lowered by reducing the sulfonylurea dose [1].

When basal insulin is in the mix

The label's hypoglycemia table also covers Ozempic added to basal insulin with or without metformin over 30 weeks: 132 patients on placebo, 132 on Ozempic 0.5 mg and 131 on Ozempic 1 mg [1].

• Severe hypoglycemia: 0% on placebo, 0% on 0.5 mg, 1.5% on 1 mg [1].
• Documented symptomatic at 70 mg/dL or below: 15.2% on placebo, 16.7% on 0.5 mg, 29.8% on 1 mg [1].
• Severe or blood glucose-confirmed symptomatic at 56 mg/dL or below: 5.3% on placebo, 8.3% on 0.5 mg, 10.7% on 1 mg [1].

In all three categories the 1 mg column was the highest. The placebo arm, which was also taking basal insulin, recorded lows too [1].

On injecting the two drugs, the label says Ozempic and insulin are given as separate injections and are not mixed together; injections may go in the same body region, but not at adjacent sites [1].

Does the 2 mg dose change anything

The label's hypoglycemia table gives rates for 0.5 mg and 1 mg, but not a separate rate for 2 mg [1]. For 2 mg, the label describes a 40-week trial of 959 patients given 1 mg or 2 mg as add-on to metformin with or without a sulfonylurea, and reports that no new safety signals were identified [1].

Other semaglutide products report their own numbers

For the tablets, the Rybelsus label reports an add-on-to-insulin trial of 52 weeks in which glucose below 54 mg/dL occurred in 32% on placebo, 26% on 7 mg and 30% on 14 mg [2]. Ozempic tablets draw their safety data from the Rybelsus trials, and the two oral products are not substitutable mg for mg [2].

What the label tells patients and prescribers

• At initiation: When Ozempic is started, its label says to consider reducing the dose of the insulin or sulfonylurea to lower hypoglycemia risk [1].
• Education: The label says people taking insulin or a sulfonylurea should be informed of the hypoglycemia risk and taught the signs and symptoms of low blood sugar [1].
• Definitions: The label defines severe hypoglycemia as an episode requiring another person's assistance, and its two glucose thresholds are 70 mg/dL or below for documented symptomatic hypoglycemia and 56 mg/dL or below for blood glucose-confirmed symptomatic hypoglycemia [1].