Type 2 diabetes

Trulicity® (dulaglutide) for primary and secondary prevention of major adverse CV events


The glucagon-like peptide 1 receptor antagonist (GLP-1 RA) Trulicity® (dulaglutide) is indicated as an adjunct to standard of care therapy to reduce the risk of major adverse cardiovascular events (MACE) in adults with type 2 diabetes (T2D) who have multiple CV risk factors (primary prevention) OR established cardiovascular (CV) disease (secondary prevention).1 To better understand the evidence supporting this unique indication and the implications for clinical practice, the limbic spoke with Dr Richard MacIsaac, Professor and Director of Endocrinology & Diabetes at St Vincent’s Health in Melbourne.

It is well established that glycaemic control can reduce the risk of long-term complications in people with T2D.2–4 For those patients on metformin that require the greater glucose-lowering effect of an injectable medication, the American Diabetes Association (ADA) Standards of Medical Care in Diabetes 2021 recommends GLP-1 RAs, such as Trulicity, as the preferred choice to insulin (except when there is evidence of ongoing catabolism, symptoms of hyperglycaemia, HbA1c [>10%] or blood glucose levels [>16.7 mmol/L] are very high, or a diagnosis of type 1 diabetes is a possibility).4

GLP-1 RAs have been shown to have high glucose-lowering efficacy and are generally well-tolerated.3 The most common side effects are nausea, vomiting and diarrhoea, and these tend to diminish over time.3 GLP-1 RAs also have minimal risk for hypoglycaemia, except when used in combination with insulin and sulfonylureas.3 

Moving beyond glycaemic control to cardioprotection

According to Prof MacIsaac, “Every patient with diabetes is at exaggerated CV risk…CV risk is really a continuum and a person considered to be at CV risk can quickly become a person with ‘clinical disease’ in the space of a minute if an event such as a heart attack occurs.”

In light of the significant CV risks facing people with T2D, the focus of T2D management has moved beyond glycaemic control to also incorporate cardioprotection.3,5,6 In particular, according to international guidelines, GLP-1 RAs can be considered in patients with T2D and established CV disease or, in the case of Trulicity, in those without established CV disease but with multiple CV risk factors.3,4,7 The guidelines further suggest that in appropriate high-risk individuals with established T2D, the decision to treat with a GLP-1 RA to reduce MACE should be considered independently of baseline HbA1c or individualised HbA1c target.4,7

As highlighted by Prof MacIsaac, “There is now a focus away from thinking primarily about glucose lowering efficacy – although this is still important – to thinking about additional benefits, primarily cardioprotection.” He continued, “Cardioprotection is extremely important and should be one of the leading management aims in the management of T2D. Where possible, patients at CV risk or with CV disease should be offered therapies that have proven CV benefits.”  

GLP-1 RA Cardiovascular Outcomes Trials (CVOTs): the evidence

The updated international guideline recommendations are based on results from GLP-1 RA CVOTs, as shown in Table 1.4,7 Of note, prior to the Trulicity CVOT, REWIND, GLP-1 RA CVOTs consisted mainly of patients with established CV disease.8–12 As highlighted by Dr MacIsaac, “Most of the GLP-1 RA trials only included people with established CV disease and this is reflected in the indications. In contrast, REWIND included a large group of patients at CV risk.”

Table 1. An overview of GLP-1 RA CVOTs*8–12

*HARMONY (albiglutide) and PIONEER-6 (oral semaglutide) were excluded from table as they are not available in Australia.13

REWINDa8 SUSTAIN 6b9 LEADERc10 EXSCELd11 ELIXAe12
Drug tested Dulaglutide Semaglutide Liraglutide Exenatide Lixisenatide
Dose 1.5 mg/week 0.5 or 1 mg/week 1.8 mg/day 2 mg/week 20 µg/day
Median follow up, years 5.4 2.1 3.8 3.2 2.1
N 9901 3297 9340 14,752 6068
Mean age, years 66 65 64 62 60
Women, % 46 39 36 38 31
Prior CVD, % 31 83 81 73 100
Mean BMI, kg/m2 32 31 33 32 (median) 30
Mean HbA1c, % 7.3 8.7 8.7 8.0 (median) 7.7

Caution should be used when comparing GLP-1 RA CVOT trials due to differences in study design, population and key inclusion/exclusion criteria

aREWIND: History of MI, ischaemic stroke, revascularisation, hospitalisation for unstable angina with concordant new ischaemic electrocardiogram changes, or a positive stress test with concordant imaging; bSUSTAIN-6: Established CVD, including CKD of stage 3 or higher; cLEADER: The majority (81.3%) had established CVD (72.4%), CKD of stage ≥ 3 (24.7%), or both (15.8%); dEXSCEL: The majority (73%) have ≥1 prior CV event, defined as history of major clinical manifestation of CAD, ischaemic cerebrovascular disease, or atherosclerotic PAD; eELIXA: Acute coronary event within 180 days before screening; BMI, body mass index; CAD, coronary artery disease; CKD, chronic kidney disease; CVD, cardiovascular disease; CVOT, cardiovascular outcomes trial; GLP-1, glucagon-like peptide-1; MI, myocardial infarction; PAD, peripheral artery disease; RA, receptor agonist; UA, unstable angina.

REWIND: a CVOT assessing Trulicity

REWIND was a double-blind, randomised, placebo-controlled trial assessing CV outcomes with Trulicity in adults with T2D aged ≥50 years, who were considered to be at CV risk.8 Overall, 9901 patients were randomised to Trulicity 1.5 mg once weekly (n=4949) or placebo (n=4952), in addition to standard of care treatments including oral antidiabetic treatments, insulin, anti-hypertensives, anti-platelets and lipid-lowering therapies.8 The REWIND study design was representative of the general T2D population in that most participants did not have established CVD (68.5%), nearly half of participants were female (46%) and it was the longest GLP-1 RA CVOT to date (median follow-up 5.4 years).8,14,15 Furthermore, patients in REWIND had relatively well-controlled glucose levels at baseline (mean HbA1c 7.3%).8

Results showed that Trulicity provided a significant 12% relative risk reduction in the primary composite outcome (major adverse cardiovascular events or MACE) in patients with and without established CV disease (absolute risk reduction 1.4%; HR 0.88; 95% CI 0.79–0.99; p=0.026).8 CV benefit was consistent across subgroups, including patients with multiple CV risk factors or established CVD.8

Trulicity: a GLP-1 RA with a unique CV indication

Based on the REWIND study, Trulicity is the only weekly GLP-1 RA to be indicated as an adjunct to standard of care therapy to reduce the risk of MACE in adults with T2D who have established CV disease (secondary prevention) OR multiple CV risk factors (primary prevention).1 CV risk factors include smoking, overweight, hypertension, dyslipidaemia and impaired kidney function.16 

†Composite of CV death, non-fatal myocardial infarction (MI), non-fatal stroke.

Prof MacIsaac explained, “Trulicity is the only weekly GLP-1 RA to be indicated for the reduction of MACE in both patients with established CVD and in those with multiple CV risk factors… so we should be thinking about recommending Trulicity to our patients who haven’t had an event and telling them that it may protect them from having an event in the future.”

Practical considerations when prescribing Trulicity

Trulicity is a once-weekly GLP-1 RA that can be taken at any time of day, with or without food, and comes with a pre-attached hidden needle and a preset dose with no need for titration.1 However, while Trulicity is simple to use, patients may have preconceived ideas about injectable therapies that create a barrier to initiation.17 In particular, they may have a fear of needles or have concerns about the complexities of administration.17 

Prof MacIsaac highlighted the importance of explaining to patients who are moving to a GLP-1 RA like Trulicity that “it is not insulin, it is a once-weekly injection that comes in a very convenient and easy-to-use pre-filled injection pen.” He continued, “Even just showing a patient what the injection pen looks like is a good way of helping to overcome the barriers surrounding injectable therapy, because I still think that people have the idea that it involves a syringe and drawing something up from a vial.” 

Prof MacIsaac also highlighted that it can be helpful to explain to patients being initiated on Trulicity that it may help them control their weight.1 This is in contrast to insulin which can lead to weight gain.3 Furthermore he explained, “We always tell patients upfront about the potential for nausea, but that it will settle down over time.”

‡Trulicity is not indicated for weight loss; weight change was a secondary endpoint in clinical trials.1

Prof MacIsaac concluded that, “Usually patients are very satisfied with Trulicity.” He also emphasised that in light of the range of therapies available for the management of T2D, “We really need to be thinking more about individualising therapy for our patients based on comorbidities such as CV risk, but also other factors such as glucose-lowering potential, weight, risk of hypoglycaemia and patient centric considerations such as ease of use and frequency of administration.”

Disclaimer: This article was sponsored by Eli Lilly Australia Pty Ltd. While the expert received an honorarium for their input into this article, all views are their own and independent of the sponsor.

References:

  1. Eli Lilly Pty Limited. Trulicity® (dulaglutide) Approved Product Information, approved 14 July 2020 [cited 2021 March]. 
  2. Stratton IM. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405–12. 
  3. Davies MJ, D’Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, et al. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669–701. 
  4. American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2021. Diabetes Care. 2021;44(Supplement 1):S111–24. 
  5. International Diabetes Federation. IDF Diabetes Atlas, 9th edn. Brussels, Belgium: 2019. Available at: https://www.diabetesatlas.org. Accessed September 2020. 
  6. Taylor KS, Heneghan CJ, Farmer AJ, Fuller AM, Adler AI, Aronson JK, et al. All-Cause and Cardiovascular Mortality in Middle-Aged People With Type 2 Diabetes Compared With People Without Diabetes in a Large U.K. Primary Care Database. Diabetes Care. 2013 Aug 1;36(8):2366–71. 
  7. Buse JB, Wexler DJ, Tsapas A, Rossing P, Mingrone G, Mathieu C, et al. 2019 Update to: Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2020;43(2):487–93. 
  8. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394(10193):121–30. 
  9. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375(19):1834–44. 
  10. Holman RR, Bethel MA, Mentz RJ, Thompson VP, Lokhnygina Y, Buse JB, et al. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2017;377(13):1228–39. 
  11. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JFE, Nauck MA, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311–22. 
  12. Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Køber LV, et al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med. 2015;373(23):2247–57. 
  13. Therapeutic Goods Administration, Product and Consumer Medicine Information [cited 2021 March 06]. Available from: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/PICMI?OpenForm&t=PI&q=eltromopag&r=https://www.ebs.tga.gov.au/. 
  14. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Design and baseline characteristics of participants in the Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial on the cardiovascular effects of dulaglutide. Diabetes Obes Metab. 2018;20(1):42–9. 
  15. Boye KS, Riddle MC, Gerstein HC, Mody R, GarciaPerez L, Karanikas CA, et al. Generalizability of glucagonlike peptide1 receptor agonist cardiovascular outcome trials to the overall type 2 diabetes population in the United States. Diabetes Obes Metab. 2019;21(6):1299–304. 
  16. Giorgino F, Vora J, Fenici P, Solini A. Cardiovascular protection with sodiumglucose cotransporter2 inhibitors in type 2 diabetes: Does it apply to all patients? Diabetes Obes Metab. 2020;22(9):1481–95. 
  17. Davida Kruger, LaRue S, Estepa P. Recognition of and steps to mitigate anxiety and fear of pain in injectable diabetes treatment. Diabetes Metab Syndr Obes. 2015;(8):49–56. 

Already a member?

Login to keep reading.

OR
Email me a login link
logo

© 2022 the limbic