By Veron V. Yala MD, Advanced DOH (JLI) and MSc Diabetes (USW)
Diabetes mellitus (DM) is a complex metabolic disorder that occurs when there is a rise in glycaemia secondary to the inability of the pancreas to produce enough insulin or the inability to use it effectively (IDF, 2017).
The prevalence of diabetes is increasing worldwide - a report released by the International Diabetes Federation (IDF) in 2017 revealed that North America and the Caribbean had over 46 million people with diabetes, with this number likely to increase to 62 million by 2045 (a rise of 35%). It is expected that not only will the expected rise affect these regions, but also several other regions in the world (see IDF report).
It is widely accepted that people with diabetes are at a higher risk of cardiovascular disease compared to those without diabetes. Einarson et al. (2018) estimated the prevalence of cardiovascular morbidity in people with type 2 diabetes mellitus to be 21.2% for cardiovascular artery disease (CAD), 14.9% for heart failure (HF), 10.0% for myocardial infarction (MI), and 7.6 % for stroke.
Apropos of this, it is thus surprising that there is still a lack of detailed global estimates of diabetes related complications with the only available data from high income countries (IDF,2017).
Poorly controlled diabetes mellitus can result in microvascular complications such as nephropathy, retinopathy, and neuropathy as well as macrovascular complications like ischaemic heart disease (IHD), peripheral vascular disease, and cerebrovascular disease (Fox et al., 2004).
The UK Prospective Diabetes Study (UKPDS) demonstrated that tight glycaemic control in people with type 2 diabetes resulted in a substantial reduction in microvascular complications but it was unable to replicate that reduction in macrovascular complications (UKPDS, 1998).
In people with type 2 diabetes, there are other contributing factors that lead to complications such as hypertension, pro-inflammatory state and dyslipidaemia (Fox et al., 2004) therefore, the American Diabetes Association has recommended that healthcare professionals try to not only achieve good glycaemic control in their patients, but also effectively manage their cardiovascular risk in order to reduce the likelihood of late stage diabetic microvascular and macrovascular complications (ADA, 2018).
To conclude, as mentioned above, people with diabetes do have an increased risk of cardiovascular events compared to the general population. This risk is estimated to be fourfold greater in diabetic patients compared to those without diabetes (Buyken et al., 2007) with the most common causes of diabetic related deaths being cardiovascular and renal complications (IDF, 2017).
II. Glucagon-like peptide 1
There are two main incretin hormones released from the gut after the ingestion of food, namely:
i) Glucose-dependent Insulinotropic Polypeptide (GIP) and ii) Glucagon-like Peptide 1 (GLP-1) (Sharma et al., 2018).
Under fasting conditions, the concentration of incretin hormones is usually at a low 5-10 pmol/L range with a rise after meals that places it between 15-50 pmol/L (Sharma et al., 2018). GLP-1 exists in two active forms, GLP-1 (7-37) and GLP-1 (7-36) amide, with the most abundant form being GLP-1 (7-36) amide (Sharma et al., 2018).
When incretin hormones are produced after ingestion of food, they are rapidly degraded by the dipeptidyl peptidase 4 (DPP-4) enzyme to form GLP-1 (9-36) which is an inactivated form of GLP-1 (7-36) amide (Sharma et al., 2018).
Only 10-15% of the incretin hormones produced reach the systemic circulation and act on the pancreas (Sharma et al., 2018). The action of GLP-1 (7-36) amide on the pancreas increases insulin secretion, decreases glucagon secretion, and increases somatostatin secretion while also decreasing beta-cell mass apoptosis and increasing the growth, regeneration, and neogenesis of beta-cell masses (Sharma et al., 2018).
In addition to its action on the pancreas, GLP-1 acts on other organs which express GLP-1 receptors such as the blood vessels, gastrointestinal tract (GIT), heart, kidney, lung, breast, and central nervous system. Consequently, the discovery of these receptors revealed the additional roles of glucagon-like peptide-1 (Wei et al., 1995; Körner et al., 2007; Sharma et al., 2018).
III. GLP-1 RAs and Cardiovascular effects
GLP-1 has a half-life of only 2 minutes and has demonstrated beneficial glycaemic and extra-glycaemic properties. The biggest limitation of this endogenous incretin is its rapid degradation by the DPP-4 enzyme (Sharma et al., 2018) and to overcome this - a limitation to using native GLP-1 therapeutically - it was necessary to develop glucagon-like peptide-1 receptor agonists that are resistant to the action of DPP-4 enzymes (Gupta, 2013).
The cardiovascular safety of many anti-diabetic drugs is of greater importance when managing people with type 2 diabetes. In 2006, one of the well-known oral anti-diabetic drugs named Rosiglitazone was found to be toxic to the heart. It was discovered that it caused a 43% increase in myocardial infarction (MI) and a 64% increase in death from cardiovascular causes (Hinnen, 2017). Thereafter, in 2008, the US Food and Drug Administration (FDA) requested that any new anti-diabetic drugs should not only show reduction in glycaemia, but also demonstrate cardiovascular safety. In 2012, the European Medicines Agency (EMA) made a similar recommendation.
There is, however, a controversial debate surrounding the safety of some of these drugs; for instance, incretin-based drugs which include Dipeptidyl Peptidase-4 inhibitors and Glucagon-like Peptide-1 receptor agonists (Filion et al., 2016).
One of the new classes of anti-diabetic drugs named Dipeptidyl Peptidase-4 (DDP-4) Inhibitors raised concerns regarding the risk of hospitalization for heart failure. In three large randomized trials - SAVOR-TIMI 53 (compared Saxagliptin versus placebo), EXAMINE (compared Alogliptin versus placebo), and TECOS (compared Sitagliptin versus placebo) - these new drug classes did not increase the risk of major adverse cardiovascular events, cardiovascular mortality or all causes of mortality (Scirica et al., 2013; White et al., 2013; Green et al., 2015) but it was found that Saxagliptin unexpectedly raised the rates of heart failure hospitalization. This increased rate of heart failure hospitalization led the US FDA in 2014 to request further investigation for a possible association between the use of Saxagliptin and heart failure (Scirica et al., 2014).
However, in two large randomized controlled trials using SGLT2- inhibitors - EMPA- REG OUTCOME (compared empagliflozin against placebo) and CANVAS (compared Canagliflozin versus placebo) - they demonstrated a reduction in CV events and hospitalizations for heart failure (Zinman et al., 2015; Neal et al., 2017).
IV. Do GLP-1 RAs reduce the risk of major adverse cardiovascular events (MACE)? Or do they increase the risk for heart failure hospitalization?
This review looked at:
1.Primary outcomes: the three components of Major Adverse Cardiovascular Event (MACE) outcomes which included cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke.
2.Secondary outcomes: hospitalization for heart failure was evaluated as the secondary endpoint. Six large major clinical trials of GLP-1 RAs have demonstrated cardiovascular safety compared to a placebo. There are six GLP-1 RAs approved by the US FDA and EMA namely Liraglutide, Exenatide, Semaglutide, Albiglutide, Dulaglutide, and Lixisenatide. However, there are some investigational GLP-1 RAs such as Semaglutide oral tablet (3-14 mg) and ITCA 650 - an implantable subdermal osmotic titanium minipump, designed to provide continuous injection-free delivery of Exenatide, 20 to 60 microgram per day for up to six months, which are not yet US FDA or EMA approved drugs (Lovshin, 2017).
Details of each major trial cannot be fully discussed in this article, however clinicians should be aware that only four out of six GLP-1 RAs demonstrated cardiovascular safety when compared to the placebo in terms of reducing the MACEs:
i). The LEADER Trial (Marso et al., 2016a): Liraglutide demonstrated the most reduction in cardiovascular death.
ii). The SUSTAIN-6 Trial (Marso et al., 2016b): Semaglutide was most associated with the reduction of non-fatal stroke and non-fatal myocardial infarction.
iii). The HARMONY Trial (Hernandez et al., 2018): Albiglutide exerted the most reduction in nonfatal myocardial infarction.
iv). The REWIND Trial (Gerstein et al., 2019): Dulaglutide reduced the risk of non-fatal stroke.
The reduction of major adverse cardiovascular events has been demonstrated by four GLP- 1 RAs namely Liraglutide, Semaglutide, Albiglutide and Dulaglutide but none of these GLP-1 RAs were superior to the placebo with regards to the risk of heart failure hospitalization. The discrepancies observed in the trials might be due to differences in the trial design, the study population, the duration of action of GLP-1 receptor agonists, differences in HbA1c between the groups, background medications used and the molecular structure of GLP-1 receptor agonists.
V. Implications for clinicians
The result of these different trials can prompt some clinicians to have a selective choice of one GLP-1 RA over another. However, none of them have demonstrated beneficial effects in terms of reducing the risk for heart failure hospitalization. Therefore, for a cardiologist prescribing in a patient with type 2 diabetes mellitus at high risk of heart failure, this novel class of medication may not be the drug of choice.
On the contrary, SGLT-2 inhibitors such as Empagliflozin in the EMPA-REG OUTCOME trial have demonstrated reduction in death from cardiovascular causes, heart failure hospitalization, and all-cause mortality (RR reductions of 30 to 40%) (Zinman et al., 2015).
Furthermore, a recent study by McMurray et al. (2019) evaluated the effect of dapagliflozin in patients with chronic heart failure both with and without diabetes and it was found that dapagliflozin reduced the incidence of heart failure hospitalization by 25% in patients with diabetes and 27% in those without diabetes. These results from the DAPA-HF trial provide clinicians with a possible new approach to the treatment of heart failure with reduced ejection fraction and mean that dapagliflozin, which is an antidiabetic drug, may have a role as a heart failure medication and subsequently change our guidelines.
To conclude, GLP-1 RAs and SGLT-2is have tremendously helped clinicians in cardiovascular medicine but a few differences may be highlighted; GLP-1 receptor agonists exert a greater benefit in atherosclerotic outcomes whereas SGLT-2 inhibitors exert increased benefits for heart failure outcomes. Be that as it may, these novel drugs are not readily accessible to all patients and clinical settings due to their high costs, particularly in low-income countries and some middle-income countries.