New drug tirzepatide tied to superior blood sugar and weight control in diabetes: SURPASS-1 trial
USA: Tirzepatide led to superior produced strikingly positive effects in type 2 diabetes (T2D) patients, reveal results from phase 3, placebo-controlled SURPASS-1 trial. According to the results, tirzepatide, a novel subcutaneously injected drug that acts via two related but separate pathways of glucose control, led to superior A1C and body weight reductions from baseline in T2D patients after 40 weeks of treatment.
Tirzepatide is a novel investigational once-weekly dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that integrates the actions of both incretins into a single molecule, representing a new class of medicines being studied for the treatment of type 2 diabetes.
These are the topline results from Eli Lilly and Company's (NYSE: LLY) SURPASS-1 monotherapy clinical trial that evaluated the safety and efficacy of tirzepatide compared to placebo.
The objective of the study was to demonstrate that tirzepatide (5 mg, 10 mg or 15 mg) is superior in A1C reduction from baseline after 40 weeks in people with type 2 diabetes naïve to injectable therapy who haven't used any oral antidiabetic medicines within three months compared to placebo. The trial randomized 478 study participants across the U.S., Mexico, India and Japan in 1:1:1:1 ratio to receive either tirzepatide 5 mg, 10 mg or 15 mg or placebo. Study participants had a mean A1C between 7 percent and 9.5 percent and a BMI greater than or equal to 23 kg/m2. All participants in the tirzepatide treatment arms started the study at a dose of tirzepatide 2.5 mg once-weekly and then increased the dose in a step-wise approach at four-week intervals to their final randomized maintenance dose of 5 mg (via a 2.5 mg step), 10 mg (via steps at 2.5 mg, 5 mg and 7.5 mg) or 15 mg (via steps at 2.5 mg, 5 mg, 7.5 mg, 10 mg and 12.5 mg).
The primary and key secondary endpoints of SURPASS-1, the first phase 3 trial of the comprehensive SURPASS program, included superior A1C and mean body weight reductions compared to placebo. Study participants, 54.2 percent of whom were treatment-naïve, had a relatively short mean duration of diabetes of 4.7 years, a baseline A1C of 7.9 percent and a baseline weight of 85.9 kg.
Key findings of the study include:
- Using the efficacy estimandi, the highest dose of tirzepatide led to an A1C reduction of 2.07 percent and reduced body weight by 9.5 kg (11.0 percent).
- More than half (51.7 percent) of participants in this arm achieved an A1C less than 5.7 percent – the level seen in people without diabetes.
- The overall safety profile of tirzepatide was similar to the well-established GLP-1 receptor agonist class, with gastrointestinal side effects being the most commonly reported adverse events.
- Treatment discontinuation rates due to adverse events were less than 7 percent in each tirzepatide treatment arm.
- In the treatment-regimen estimand, each of the tirzepatide doses led to statistically significant A1C and body weight reductions:
- A1C reduction: -1.75% (5 mg), -1.71% (10 mg), -1.69% (15 mg), -0.09% (placebo)
- Weight reduction: -6.3 kg (5 mg), -7.0 kg (10 mg), -7.8 kg (15 mg), -1.0 kg (placebo).
- Percentage of participants achieving A1C <7%: 81.8% (5 mg), 84.5% (10 mg), 78.3% (15 mg), 23.0% (placebo)
- Percentage of participants achieving A1C <5.7%: 30.9% (5 mg), 26.8% (10 mg), 38.4% (15 mg), 1.4% (placebo)
- No events of severe hypoglycemia or hypoglycemia less than 54 mg/dL were observed in the tirzepatide treatment arms.
- The most commonly reported adverse events were gastrointestinal-related and mild to moderate in severity, usually occurring during the dose escalation period. For study participants treated with tirzepatide (5 mg, 10 mg and 15 mg, respectively), nausea (11.6 percent, 13.2 percent, 18.2 percent), diarrhea (11.6 percent, 14.0 percent, 11.6 percent), vomiting (3.3 percent, 2.5 percent, 5.8 percent) and constipation (5.8 percent, 5.0 percent, 6.6 percent) were more frequently experienced compared to placebo (6.1 percent [nausea], 7.8 percent [diarrhea], 1.7 percent [vomiting], 0.9 percent [constipation]). The overall treatment discontinuation rates were 9.1 percent (5 mg), 9.9 percent (10 mg), 21.5 percent (15 mg) and 14.8 percent (placebo).
- The majority of the discontinuations in the 15 mg and placebo arms were due to reasons other than adverse events (such as concerns due to the coronavirus pandemic and family or work reasons).
"Tirzepatide delivered impressive A1C and weight reductions for people with type 2 diabetes in this trial, confirming and building upon the phase 2 data that were released in 2018," Julio Rosenstock, Director of the Dallas Diabetes Research Center and Principal Investigator of SURPASS-1 said in the press release. "The study took a bold approach in assessing A1C targets. Not only did nearly 90 percent of all participants taking tirzepatide meet the standard A1C goal of less than 7 percent, more than half taking the highest dose also achieved an A1C less than 5.7 percent, the level seen in people without diabetes – an unprecedented finding and unique endpoint in trials evaluating glucose-lowering agents."
