Effective management of T2DM with the new GLP-1 RA semaglutide
Novel approaches are needed to improve glycaemic control in patients with type 2 diabetes mellitus (T2DM). Semaglutide (Ozempic®, Novo Nordisk) is a new glucagon-like peptide 1 receptor agonist (GLP-1 RA) that has demonstrated efficacy in both HbA1c reduction and inducing weight loss in T2DM patients. At a recent webinar in Hong Kong, Professor Thomas Pieber of the Medical University of Graz, Austria, discussed some of the current research surrounding semaglutide and its benefits vs other GLP-1 RAs in T2DM management.
In recent years, GLP-1 RAs have emerged as an important treatment option for patients with T2DM. GLP-1 RAs exert a number of effects on glucose metabolism, including stimulation of glucose-dependent insulin secretion, reduction in glucagon secretion, and delay in gastric emptying. They also influence the central nervous system in a way that helps promote satiety, leading to weight loss. [Diabetes 2009;58:773-795]
Semaglutide is a new, once-weekly, human GLP-1 analogue indicated for use in patients with uncontrolled T2DM as monotherapy when metformin is considered inappropriate or in combination with other treatments. [Ozempic prescribing information] It has high homology (94 percent) to native human GLP-1, with important molecular modifications that help in achieving high affinity binding to albumin and extending its half-life to approximately 1 week, allowing for once-weekly administration. [J Med Chem 2015;58:7370-7380; Diabetologia 2017;60:1390-1399] Its small molecular size vs other GLP-1 RAs (4.11 kDa, vs 63 kDa for dulaglutide, 4.86 kDa for lixisenatide, 4.19 kDa for exenatide, and 3.75 kDa for liraglutide) suggests greater permeability of the brain-blood barrier and therefore greater ability to signal satiety. In clinical studies, 12 weeks of semaglutide treatment led to significant reductions in energy intake (24 percent relative reduction vs placebo; p<0.0001) and body weight loss (5.0 kg vs 1.0 kg with placebo) in patients with obesity. [Diabetes Obes Metab 2017;19:1242-1251]
Superior efficacy of semaglutide
The efficacy and safety of semaglutide was evaluated in the SUSTAIN clinical trial programme comprising multiple phase IIIa and IIIb randomized controlled trials comparing semaglutide with various diabetes agents in a range of uncontrolled T2DM patients.
“Results showed consistent superior efficacy with semaglutide for HbA1c control and weight loss in patients with uncontrolled T2DM compared with other GLP-1 RAs, including exenatide, dulaglutide and liraglutide,” said Pieber. “Semaglutide significantly improved HbA1c by 1.3–1.8 percent from baseline and led to mean body weight losses of 3.7–6.5 kg. The greatest effects on HbA1c and weight were seen in comparisons of semaglutide vs dulaglutide in SUSTAIN 7.” (Figure 1)
Treatment with semaglutide 1.0 mg for 40 weeks led to significantly improved HbA1c, by 1.8 percent vs 1.4 percent with dulaglutide 1.5 mg (estimated treatment difference [ETD], -0.41; 95 percent confidence interval [CI], -0.57 to -0.25; p<0.0001). Semaglutide 1.0 mg also led to a significant mean body weight loss of 6.5 kg vs 3.0 kg with dulaglutide 1.5 mg (ETD, -3.55 kg; 95 percent CI, -4.32 to -2.78; p<0.0001). Similarly, semaglutide 0.5 mg significantly improved HbA1c by 1.5 percent vs 1.1 percent with dulaglutide 0.75 mg (ETD, -0.40; 95 percent CI, -0.55 to -0.25; p<0.0001), and reduced mean body weight by 4.6 kg vs 2.3 kg with dulaglutide 0.75 mg (ETD, -2.26 kg; 95 percent CI, -3.02 to -1.51; p<0.0001). [Lancet Diabetes Endocrinol 2018;6:275-286]
“Interestingly, we saw an even greater effect on body weight loss with the lower dose of semaglutide 0.5 mg than with the higher dose of dulaglutide 1.5 mg,” highlighted Pieber. “While dulaglutide and other GLP-1 RAs may demonstrate effective glucose lowering, they do not achieve the strong reductions in weight seen with semaglutide.”
Semaglutide was associated with similar rates of adverse events (AEs) vs other GLP-1 RAs. Gastrointestinal AEs, in particular nausea, was the most common AE associated with semaglutide. However, most events were mild to moderate and became less severe over time. [Lancet Diabetes Endocrinol 2018;6:275-286]
Compared with other diabetes therapies, including insulin, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors, semaglutide demonstrated significantly higher rates of glycaemic control in T2DM patients. “Up to 80 percent of patients who received semaglutide achieved HbA1c targets of <7.0 percent in the SUSTAIN trials,” noted Pieber. (Figure 1)
In the double-dummy SUSTAIN 8 trial, treatment with semaglutide significantly reduced HbA1c by 1.5 percent vs 1.0 percent with the SGLT2 inhibitor canagliflozin (ETD, -0.49 percent; 95 percent CI, -0.65 to -0.33; p<0.0001). Reduction in body weight was significantly greater with semaglutide vs canagliflozin (5.3 kg vs 4.2 kg; ETD, -1.06; 95 percent CI, -1.76 to -0.36; p=0.0029). [Lancet Diabetes Endocrinol 2019;7:834-844]
Semaglutide reduces long-term CV risk
The SUSTAIN 6 trial was a randomized, double-blind, placebo-controlled, four-armed, parallel-group cardiovascular (CV) outcome trial comparing once-weekly semaglutide (0.5 mg or 1.0 mg) vs placebo in 3,295 T2DM patients with high CV risk.
After 104 weeks of treatment, semaglutide significantly reduced the risk of major adverse CV events (MACE; first occurrence of CV death, nonfatal MI, or nonfatal stroke) by 26 percent vs placebo (rate, 6.6 percent vs 8.9 percent; hazard ratio [HR], 0.74 percent; 95 percent CI, 0.58 to 0.95; p<0.001 for noninferiority; p=0.02 for superiority). Subgroup analysis showed that the reduction in MACE was primarily driven by reductions in risk of nonfatal stroke (rate, 1.6 percent vs 2.7 percent; HR, 0.61; 95 percent CI, 0.38 to 0.99; p=0.04) and nonfatal MI (rate, 2.9 percent vs 3.9 percent; HR, 0.74; 95 percent CI, 0.51 to 1.08). [N Engl J Med 2016;375:1834-1844]
“Although the risk of nonfatal MI and rate of CV death were not significantly different between groups, this may be due to the trial design and focus on the primary endpoint of MACE,” noted Pieber. “In a post-hoc analysis of SUSTAIN 6, semaglutide showed a benefit in reducing CV risk in patients with established CV disease [HR, 0.78; 95 percent CI, 0.60 to 1.01] and those with CV risk factors [HR, 0.48; 95 percent CI, 0.23 to 0.99].” (Table) [Cardiovasc Diabetol 2019;18:73]
Semaglutide also demonstrated a 36 percent reduction in risk of new or worsening nephropathy vs placebo (HR, 0.64; 95 percent CI, 0.46 to 0.88; p=0.005), as well as an increased risk of diabetic retinopathy (DR) complications (HR, 1.76; 95 percent CI, 1.11 to 2.78; p=0.02). (Figure 2) [N Engl J Med 2016;375:1834-1844]
“The phenomenon of early worsening of DR is not a new finding. It was previously documented in the DCCT [Diabetes Control and Complications Trial] and UKPDS [UK Prospective Diabetes Study] studies, as well as in clinical studies of commonly used diabetes agents such as insulin glargine,” explained Pieber. “It is important to note that DR does not occur when there is no previous retinopathy, and that it is a phenomenon related to very abrupt improvements in HbA1c rather than to treatment differences. Moreover, both the UKPDS and the insulin glargine studies showed no differences in retinopathy between arms after long-term treatment for 3 years and 5 years, respectively. Thus, in patients with high HbA1c and DR, treatment should focus on achieving effective glycaemic control and long-term results.”
Semaglutide consistently demonstrated significantly greater improvements in glycaemic control and weight loss compared with other diabetes agents, including GLP-1 RAs, insulin, DPP-4 inhibitors and SGLT2 inhibitors, in patients with uncontrolled T2DM. The long-term benefit in reducing risk of MACE makes semaglutide a valuable treatment option for T2DM patients with high CV risk.