Utility of GLP-1 receptor agonists in T2DM patients with CV risk factors

Dr. Samantha Hocking
University of Sydney
Australia
23 Dec 2021
Utility of GLP-1 receptor agonists in T2DM patients with CV risk factors

Cardiovascular disease (CVD) is a major cause of death and disability among patients with type 2 diabetes mellitus (T2DM). Given the increasing prevalence of T2DM that will likely lead to a rising burden of CVD, concomitant management of T2DM and cardiovascular (CV) risk factors has become an important focus. At the Endocrinology, Diabetes and Metabolism Hong Kong (EDM HK) 4th Annual Meeting, Dr Samantha Hocking of the University of Sydney, Sydney, Australia, shared her expertise on the management of T2DM patients at risk of developing CVD, with an emphasis on the use of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) such as once-weekly dulaglutide, which is effective at lowering glucose levels and promoting weight loss.

The cost of suboptimal glycaemic control

“Despite the strong evidence that good glycaemic control is a key management strategy for persons with T2DM, in reality, many patients do not achieve recommended glycaemic targets,” said Hocking. Patients on 2–3 oral antidiabetic therapies with HbA1c ≥8 percent could experience a delay in intensification of treatment with insulin of approximately 6 years. [Diabetes Care 2013;36:3411-3417]

“Poor glycaemic control can result in long-term complications, including an increased risk of CV symptoms such as coronary heart disease and stroke, and microvascular complications such as retinopathy, nephropathy and neuropathy,” noted Hocking. [Diabetes Care 2015;38:140-149; Am J Med 2010;123(3 Suppl):S3-S11]

GLP-1 RAs address multiple defects in T2DM

“GLP-1 RAs have an incretin-like effect that increases insulin secretion while decreasing hepatic glucose production. They act on the intestine to delay gastric emptying, and also exert an effect on the brain to suppress appetite and increase satiety,” explained Hocking.  [Diabetes 2009;58:773-795; Gastroenterology 2007;132:2131-2157] The ability of GLP-1 RAs to address multiple defects in T2DM suggests their utility as a good treatment option for patients with increased CV risk.

“Because of the way GLP-1 RAs target many factors in T2DM, guidelines of the American Diabetes Association [ADA] and European Association for the Study of Diabetes [EASD] now suggest that GLP-1 RAs should be considered at numerous touchpoints in the management of patients with T2DM,” said Hocking. “According to the 2019 updated recommendations of ADA and EASD on management of hyperglycaemia, GLP-1 RAs are recommended for patients with T2DM and established atherosclerotic CVD [such as those with prior myocardial infarction or ischaemic stroke] and those with indicators of high atherosclerotic CVD risk [age ≥55 years plus left ventricular hypertrophy or coronary, carotid or lower extremity artery stenosis >50 percent].” [Diabetologia 2020;63:221-228]

To reduce the risk of major adverse cardiovascular events (MACE), GLP-1 RAs may also be considered in patients with T2DM without established CVD who have indicators of high risk. “In T2DM patients without established CVD, GLP-1 RAs are also recommended for those who need to minimize hypoglycaemia as well as those who need to minimize weight gain or promote weight loss,” highlighted Hocking. [Diabetologia 2020;63:221-228]

Achieving and maintaining glycaemic goals with dulaglutide

“A more potent glucose-lowering effect is more likely to enable our patients to achieve their HbA1c goals,” stressed Hocking.

In the AWARD-5 study, which compared the safety and efficacy of once-weekly dulaglutide vs sitagliptin in metformin-treated T2DM patients, dulaglutide at both 0.75 mg and 1.5 mg doses demonstrated greater potency in HbA1c lowering compared with sitagliptin. The HbA1c target of <7 percent was maintained in patients treated with dulaglutide 1.5 mg over a 2-year period. “Additionally, treatment with dulaglutide 1.5 mg resulted in greater body weight reduction vs sitagliptin,” noted Hocking. [Diabetes Obes Metab 2015;17: 849-858]

In the AWARD-2 study, which compared the efficacy and safety of once-weekly dulaglutide vs insulin glargine in T2DM patients on metformin and glimepiride, a greater proportion of patients on dulaglutide achieved the HbA1c target of <7 percent than those on insulin glargine (53 percent vs 31 percent; p<0.01). Compared with daily insulin glargine, once-weekly dulaglutide also demonstrated greater body weight loss and lower total hypoglycaemia rates. [Diabetes Care 2015;38:2241-2249]

“In patients who require the greater glucose-lowering effect of an injectable medication, the 2018 ADA and EASD consensus guidelines for management of hyperglycaemia noted that GLP-1 RAs are the preferred choice over insulin,” Hocking highlighted. “However, the 2018 guidelines also noted that insulin still remains an important treatment for catabolic patients who may have type 1 or autoimmune diabetes.” [Diabetes Care 2018;41:2669-2701]

Cardioprotective effects of dulaglutide

“While many patients with T2DM do not have existing CVDs, they may have CV risk factors. As such, a diabetes medication that is also cardioprotective should be considered for glycaemic management in patients with T2DM,” said Hocking.

The REWIND (Researching CV Events with a Weekly Incretin in Diabetes) trials assessed if the addition of dulaglutide to the existing diabetes medication regimen of middle-aged and older persons with T2DM could safely reduce the incidence of CV events compared with placebo. The trial included 9,901 patients with T2DM, recruited from 371 sites in 24 countries, who had either a previous CV event or CV risk factors. The primary outcome was the first occurrence of the composite endpoint of nonfatal myocardial infarction, nonfatal stroke or death from CV causes. [Lancet 2019;394:121-130]

At study end, the primary composite outcome occurred in 12.0 percent of participants in the dulaglutide group vs 13.4 percent in the placebo group (hazard ratio, 0.88; 95 percent confidence interval, 0.79 to 0.99; p=0.026). (Figure 1) “The CV benefit of dulaglutide vs placebo was consistent across subgroups, including in patients with multiple CV risk factors and those with established CVD,” Hocking noted.

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“The important findings of REWIND ultimately resulted in an update to the 2018 ADA and EASD recommendations on management of hyperglycaemia, which noted that the level of evidence to support the use of GLP-1 RAs for primary prevention is the strongest for dulaglutide, but lacking for other GLP-1 RAs,” said Hocking. [Diabetologia 2020;63:221-228]

Ease of dosing associated with better adherence

“In general, physicians are probably most concerned about hypoglycaemia, weight gain, and complex dosing regimens when it comes to initiating injectables in patients with T2DM. Similarly, injections can be a barrier for some patients, while some patients admit that they are fearful of insulin,” said Hocking. “Many of these barriers are overcome by dulaglutide’s simple once-weekly dosing regimen.” 

“It is important to remember that many T2DM patients are on multiple medications. As such, a once-weekly drug that is easily administered via a simple device can make a big difference,” emphasized Hocking. “This is clearly illustrated by a recent real-world study, which demonstrated that significantly more patients in the dulaglutide vs semaglutide group persisted with their medication.”  (Figure 2) [Mody R, et al, ADA 2021, abstract 654-P]

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In another study, more patients with T2DM preferred the dulaglutide device vs the semaglutide device (84.2 percent vs 12.3 percent; p<0.0001). More patients found the dulaglutide device easier to use (86.8 percent vs 6.8 percent; p<0.0001). [Diabetes Obes Metab 2020;22:355-364]

Conclusion

“GLP-1 RAs should be considered in T2DM management based on their ability to sustain HbA1c reduction, reduce the risk of MACE, and induce and maintain weight loss, as well as their low risk of hypoglycaemia and ease of use,” Hocking concluded.

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