Dr Darren McGuire from UT Southwestern Medical Center in Dallas, Texas, has expertise in clinical trial design and execution of large-scale cardiovascular outcomes studies, with a focus in the area of diabetes and cardiovascular disease. This places him at the forefront of an emerging treatment paradigm in cardiology where specific antihyperglycaemic agents are used for cardiovascular risk reduction rather than glucose lowering in patients with type 2 diabetes. In an interview with the limbic, he describes the approach further.
What is your background and interest in the use of type 2 antihyperglycaemic agents in cardiology?
Around 1996 as an internal medicine resident, I became interested in this area when I realised that there was little data on cardiovascular outcomes in diabetes trials. I could see that we needed a greater evidence base for treating patients with diabetes at risk of cardiovascular events, and this was an area of research I wanted to focus on.
What has been the impact of trial data on understanding the role of type 2 antihyperglycaemic agents in cardiovascular clinical care?
The global landscape changed dramatically in 2008 when the US and European regulatory authorities began requiring cardiovascular safety assessments and dedicated cardiovascular outcomes trials for all new type 2 antihyperglycaemic medications.
This necessitated the conduct of non-inferiority placebo-controlled studies, which were designed primarily to demonstrate cardiovascular safety. Secondary analyses were also conducted to investigate any potential cardiovascular benefits with the newer agents. Just over a decade later, many of these trials are now completed and provide a wealth of outcomes data.
We now have a number of completed trials with agents belonging to the SGLT2 inhibitor and GLP-1 receptor agonist classes that have demonstrated superior cardiovascular outcomes.1-8
With respect to the oral SGLT2 inhibitors, two large cardiovascular outcomes trials (one with empagliflozin1 and one with canagliflozin2) have demonstrated significant reductions in major adverse cardiovascular events (MACE) comprising the composite of cardiovascular death, myocardial infarction and stroke, in patients randomised to SGLT2 inhibitor therapy. Empagliflozin also significantly reduced the risk of cardiovascular and all-cause mortality.1 A third trial demonstrated the superiority of dapagliflozin to reduce risk of the composite of cardiovascular death and heart failure.4
Trials have also shown these therapies reduce heart failure hospitalisations and have favourable effects on kidney function in patients with type 2 diabetes.1,2,9
Is the prescribing of oral antihyperglycaemic agents with cardiovascular benefits within the scope of a cardiologist’s practice?
It’s important to note that the cardiovascular outcomes in the trials were independent of the agent’s effect on blood glucose. So when we use these medications in cardiology, it’s for cardiovascular risk mitigation and independent of any glucose-lowering effect. Glucose management can still be left to the general practitioner or the endocrinologist.
Recommendations to use these agents are now included in the European Society of Cardiology guidelines for both heart failure10 and the prevention of cardiovascular disease.11 Furthermore, they are endorsed by the consensus clinical recommendations of the ADA and EASD.12 [Recommendations are also included in The National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand: Guidelines for the prevention, detection, and management of heart failure in Australia.13]
The American College of Cardiology has also recently released a clinical decision pathway document that calls for cardiologists to embrace these therapies as part of their routine treatment in certain patients.14
Once you have prescribed an SGLT2 inhibitor, how do you work with primary care and other specialties for the ongoing management of patients with type 2 diabetes?
We routinely use these medications in our clinic. We then communicate with the GP and endocrinologists to let them know that we have initiated therapy for its cardiovascular benefits, and we leave the blood glucose management to them.
If the patient’s diabetes is very tightly controlled – particularly if they are using an insulin or a sulphonylurea – there may need to be some dose adjustments of current medications to reduce the risk of hypoglycaemia.15,16 Other than these caveats, there is little need for dose modification of the background therapy.
What are your recommendations for cardiologists with regard to prescribing SGLT2 inhibitors for cardiovascular risk mitigation – is there an ideal patient, and what are your clinical considerations?
These agents are used in patients who have type 2 diabetes and coexisting atherosclerotic vascular disease. It doesn’t necessarily limit treatment to those needing further blood glucose control. Independent of the blood glucose control, these drugs are beneficial.
The efficacy of SGLT2 inhibitors is dependent on renal function,15,16 and are therefore contraindicated in patients with significant renal dysfunction. [In Australia empagliflozin is contraindicated in patients with eGFR <30 ml/min/1.73m2 or CrCl <30 ml/min and those with eGFR persistently <45 ml/min/1.73m2 or CrCl persistently <45 ml/min; dapagliflozin is contraindicated in patients with eGFR persistently<60 ml/min/1.73m2 or CrCl persistently <60ml/min15,16].
Cases of diabetic ketoacidosis have been reported with patients treated with SGLT2 inhibitors.15,16 This has tended to occur in patients who have interrupted their normal dietary intake – due to either a gastrointestinal illness, fasting for a medical procedure, or dieting. Therefore, we encourage patients not to take these drugs if their normal dietary intake will be interrupted. Patients with diabetes are accustomed to making treatment modifications for reduced caloric intake. If ketoacidosis does occur, the medication should be discontinued and the patient needs evaluation and prompt treatment.15,16
What are your thoughts on HbA1c reduction versus cardiovascular risk reduction when it comes to managing patients with type 2 diabetes?
It’s important to acknowledge that glucose control remains an important goal for reducing microvascular disease complications of diabetes.
However, cardiologists need to embrace the antihyperglycaemic agents that have shown cardiovascular benefits – not for their benefits in managing blood glucose but for their impact on cardiovascular outcomes.
In cardiology, we use the presence of diabetes in patients with atherosclerotic vascular disease to inform our decisions around statin prescription. We should use the same paradigm for considering the introduction an SGLT2 inhibitor or GLP-1 receptor agonist in these patients – possibly even using the combination of these agents.
What is the next big thing coming in Cardiology?
In other areas of cardiology, advances in technology for mechanical interventions is very exciting. These interventions are allowing us to perform more transcutaneous cardiac interventions. For example, we are now routinely replacing aortic valves with a catheter. From an electrophysiology perspective, advanced technologies for mapping and ablating arrhythmias is also impressive. From a medical perspective, advances in the treatment of hypercholesterolaemia with the PCSK9 inhibitors have also been impressive.
- Zinman B et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Eng J Med 2015;373:2112–2128 https://www.nejm.org/doi/full/10.1056/NEJMoa1504720
- Neal et al. Canagliflozin and cardiovascular and rental events in type 2 diabetes. N Engl J Med 2017; 277:644–657 https://www.ncbi.nlm.nih.gov/pubmed/28605608
- Marso S.P, et al. Liraglutide and cardiovascular outomes in type 2 diabetes. N Engl J Med 2016;375:311–322 https://www.ncbi.nlm.nih.gov/pubmed/27295427?dopt=Abstract
- Wiviott SD et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2019;380(4):347-357. https://www.nejm.org/doi/full/10.1056/NEJMoa1812389
- Perkovic V et al Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med 2019; 380(24):2295-2306. https://www.ncbi.nlm.nih.gov/pubmed/30990260
- Marso SP et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2016;375(19):1834-1844. https://www.ncbi.nlm.nih.gov/pubmed/27633186
- Hernandez AF et al Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.” Lancet 2018;392(10157):1519-1529. https://www.ncbi.nlm.nih.gov/pubmed/30291013
- Gerstein HC et al Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019;394(10193):121-130. https://www.ncbi.nlm.nih.gov/pubmed/31189511
- Fitchett D et al. Empagliflozin reduced mortality and hospitalization for heart failure across the spectrum of cardiovascular risk in the EMPA-REG OUTCOME trial. Circulation 2019; 139:1384–1395 https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.037778
- Ponikowski P et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016;37(27):2129–2200 https://academic.oup.com/eurheartj/article/37/27/2129/1748921
- Piepoli MF et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2016;37(29):2315–2381 https://academic.oup.com/eurheartj/article/37/29/2315/1748952
- Davies MJ 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): 2669-2701. https://www.ncbi.nlm.nih.gov/pubmed/30291106
- Atherton JJ et al. National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand: Guidelines for the prevention, detection, and management of heart failure in Australia 2018. Heart Lung and Circulation 2018;27(10):1123–1208. https://www.heartlungcirc.org/article/S1443-9506(18)31777-3/fulltext
- Das SR et al. 2018 ACC Expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes and atherosclerotic cardiovascular disease. November 2018. DOI: 10. 1016/j.jacc.2018.09.020 http://www.onlinejacc.org/content/early/2018/11/29/j.jacc.2018.09.020
- Jardiance Australian Product Information https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2014-PI-01783-1&d=201907311016933
- Forxiga Australian Product Information https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2012-PI-02861-1