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SUSTAIN 7: Semaglutide superior to dulaglutide for lowering HbA1c
Adults with type 2 diabetes assigned semaglutide 0.5 mg or 1 mg had greater reductions in HbA1c and body weight compared with those assigned to dulaglutide 0.75 mg or 1.5 mg, according to an analysis of data from the SUSTAIN 7 clinical trial published in The Lancet Diabetes & Endocrinology.
Richard E. Pratley, MD, Samuel E. Crockett Chair in Diabetes Research, director of research and education at Florida Hospital Diabetes Institute and senior investigator and diabetes program head at the Translational Research Institute for Metabolism and Diabetes in Orlando, Florida, and colleagues evaluated data on adults with type 2 diabetes to determine the effects of semaglutide (Ozempic, Novo Nordisk) at two doses and dulaglutide (Trulicity, Lilly) at two doses on HbA1c and body weight over 40 weeks.
Participants were randomly assigned to subcutaneous semaglutide 0.5 mg (n = 301; mean age, 56 years; 56% men; 77% white; mean HbA1c, 8.3%; mean diabetes duration, 7.7 years), dulaglutide 0.75 mg (n = 299; mean age, 55 years; 54% men; 78% white; mean HbA1c, 7%; mean diabetes duration, 7 years), semaglutide 1 mg (n = 300; mean age, 55 years; 54% men; 81% white; mean HbA1c, 8.2%; mean diabetes duration, 7.3 years) or dulaglutide 1.5 mg (n = 299; mean age, 56 years; 57% men; 74% white; mean HbA1c, 8.2%; mean diabetes duration, 7.6 years) between Jan. 6 and June 22, 2016.
At week 40, the reduction in HbA1c was greater in the semaglutide 0.5-mg group compared with the dulaglutide 0.75-mg group (1.5 percentage points vs. 1.1 percentage points) as well as the semaglutide 1-mg group compared with the dulaglutide 1.5-mg group (1.8 percentage points vs. 1.4 percentage points; P < .0001 for both for noninferiority and superiority). The reduction in mean body weight was also greater in the semaglutide 0.5-mg group compared with the dulaglutide 0.75-mg group (4.6 kg vs. 2.3 kg; P < .0001) as well as the semaglutide 1-mg group compared with the dulaglutide 1.5-mg group (6.5 kg vs. 3 kg; P < .0001).
Participants in both semaglutide groups compared with the dulaglutide groups were more likely to achieve HbA1c less than 7% or HbA1c 6.5% or less at week 40 (P < .0001 for the low-dose comparison; P = .0021 for the high-dose comparison) and achieve weight loss of at least 5% or at least 10% (P < .0001 for all).
Adverse events occurred in 68% of the semaglutide 0.5-mg group, 62% of the dulaglutide 0.75-mg group, 69% of the semaglutide 1-mg group and 74% of the dulaglutide 1.5-mg group. Gastrointestinal disorders were the most frequent adverse events reported.
“This study illustrates that there are important differences within the class of GLP-1 agonists with respect to both glycemic efficacy and weight loss,” Pratley told Endocrine Today. “We now have better treatment options for helping our patients achieve their goals. In a shared decision-making interaction with patients, we can offer a treatment that will more than likely get them an HbA1c goal of less than 7% and at the same time promote significant weight loss. And importantly, these benefits are available with a simple to use, well-tolerated once-weekly injection.”
“While a pre-approved study (SUSTAIN 6) indicated that semaglutide may have a significant cardiovascular benefit, this needs to be confirmed in a robust cardiovascular outcome study,” he said. “The potential benefits of semaglutide in patients with obesity and prediabetes also need to be elucidated.”
In an accompanying commentary, Abd A. Tahrani, MD, MRCP, PhD, a National Institute for Health Research clinician scientist at the University of Birmingham in the United Kingdom, and colleagues wrote that multiple factors in addition to glycemic efficacy should be considered by health care practitioners when choosing glucose-lowering drugs for individual patients with type 2 diabetes.
“Such factors might include the effect on weight, hypoglycemia, cardiovascular risk, diabetes-related complications, tolerability, ease of use, durability of effects, interactions with other drugs, a patient’s age, and renal or hepatic impairment,” they wrote. “Although two head-to-head trials of other weekly GLP-1 agonists have shown glycemia and weight advantages with semaglutide, treatment decisions should allow for differences in trial designs and the generalizability of the findings in a real-life setting.” – by Amber Cox
For more information:
Richard E. Pratley, MD, can be reached at richard.pratley@flhosp.org.
Disclosures: Pratley reports he receives research grants (to his institution) from Novo Nordisk; speaker and consultancy fees (to his institution) from AstraZeneca and Takeda; consultancy fees (to his institution) from Boehringer Ingelheim, Eisai, Eli Lilly, GlaxoSmithKline, Hanmi Pharmaceutical Co., Janssen, Ligand Pharmaceuticals, Merck, Novo Nordisk and Pfizer; and research grants from Eli Lilly, Gilead Sciences, Lexicon Pharmaceutical, Ligand Pharmaceuticals, Merck, Novo Nordisk, Sanofi-Aventis U.S. and Takeda. Tahrani reports he receives grants from the National Institute for Health Research U.K.; personal fees and nonfinancial support from AstraZeneca and Boehringer Ingelheim; non-financial support from Eli Lilly; and grants from Novo Nordisk and Sanofi Aventis outside the submitted work. Please see the study and comment for all other authors’ relevant financial disclosures.
Perspective
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The first GLP-1 receptor agonist (exenatide twice daily, Byetta, AstraZeneca) for the treatment of type 2 diabetes was approved by the FDA in 2005. Since then multiple once-daily and once-weekly GLP-1 receptor agonists have been introduced into the U.S. and worldwide markets, and we anticipate approval of a 6-month subcutaneous implantable osmotic mini-pump (ITCA 650, Intarcia) that delivers exenatide continuously. Within 2 to 3 years, oral GLP-1 receptor agonists are likely to become available, and combined GLP-1 hybrid molecules with glucagon and other peptides currently are under investigation.
Not surprisingly, this has become a highly competitive market with monthly publications comparing the efficacy of one agent vs. another, as exemplified by SUSTAIN 7, in which semaglutide was compared with dulaglutide.
GLP-1 receptor agonists have many metabolic and cardiovascular benefits that make them ideal first-line agents for the treatment of patients with type 2 diabetes, including a large and durable reduction in HbA1c; normalization of beta-cell function that can be observed within 8 hours, continues unabated at 12 weeks and persists for up to 3 years; sizeable (up to 5% to 7%) reduction in body weight; minimal hypoglycemia unless used with an insulin secretagogue or insulin; good overall safety profile; once-weekly administration; and reduced CV events in high-risk patients with type 2 diabetes. The American Association of Clinical Endocrinologists has elevated GLP-1 receptor agonists to first-line therapy in patients with newly diagnosed type 2 diabetes, and the American Diabetes Association has recommended that liraglutide (Victoza, Novo Nordisk) be considered as first-line add-on therapy to metformin-treated patients with type 2 diabetes and established atherosclerotic CVD.
Nonetheless, the GLP-1 receptor agonist class represents only 10% of the U.S. market share and, of this, about 85% of the prescriptions are written by endocrinologists and only about 15% by primary care physicians. More disturbingly, a small percentage of the endocrinologists write the majority of the prescriptions.
The recent publication of SUSTAIN 7 by Pratley and colleagues clearly documents the potent effects of the GLP-1 receptor agonists to decrease HbA1c and reduce body weight in patients with type 2 diabetes and demonstrates that there are significant differences with respect to efficacy between individual GLP-1 receptor agonists. Patients with type 2 diabetes (n = 1,201) inadequately controlled on metformin monotherapy were randomly assigned to receive low-dose semaglutide 0.5 mg vs. low-dose dulaglutide 0.75 mg, or high-dose semaglutide 1.0 mg vs. high-dose dulaglutide 1.5 mg. For both the low-dose semaglutide and high-dose semaglutide, the reductions in HbA1c were significantly greater than with dulaglutide. Similarly, the reductions in body weight with both doses of semaglutide were significantly greater than with dulaglutide. Both drugs were well tolerated, with gastrointestinal side effects (primarily nausea and to a lesser extent diarrhea and vomiting) being the most frequent adverse events and occurring with similar incidence with both GLP-1 receptor agonists. The discontinuation rates were similar between the low and high doses of the two GLP-1 receptor agonists.
Although the results of SUTAIN 7 demonstrate superiority of semaglutide over dulaglutide, the effect of both GLP-1 receptor agonists on HbA1c reduction and weight loss are impressive, and the safety profile of both drugs is very good. In addition, SUSTAIN-6 (semaglutide) has demonstrated CV benefit and we await the results of REWIND (dulaglutide) in 2018. Although I believe that GLP-1 receptor agonists should be first-line therapy for all patients with type 2 diabetes, cost often presents a challenge, and most insurance formularies carry only one GLP-1 receptor agonist. However, it is reassuring from the results of SUSTAIN 7, as well as from SUTAIN-6 and EXSCEL, that all three long-acting GLP-1 receptor agonists (semaglutide, dulaglutide and exenatide XR) exert highly beneficial effects on glycemic control, promote weight loss and have a good safety profile.
Our real goal should be to encourage the large number of primary care physicians and endocrinologists who use GLP-1 receptor agonists sparingly, or not at all, to prescribe them as first-line agents or, at least, to introduce them early in the natural history of type 2 diabetes, for their potent effects to preserve beta-cell function, reduce HbA1c, decrease body weight and reduce CV events, although the latter remains to be proven in patients with type 2 diabetes with lesser degree of CV risk.