Cardiovascular Benefits of GLP-1 Receptor Agonists in Type 2 Diabetes Mellitus
17 May 2019
Diabetes mellitus is an important risk factor for cardiovascular (CV) disease, which caused 17.5 million deaths in 2012 worldwide, the majority from heart disease and stroke . This has intensified national diabetes screening and treatment programmes to prevent associated mortality, as well as morbidities—microvascular and macrovascular—that adversely impact quality of life and increase healthcare burden .
Recent CV outcomes trials in type 2 diabetes mellitus (T2DM) of several new anti-hyperglycaemia agents (AHA) have demonstrated their CV safety; and in the sodium-glucose cotransporter 2 (SGLT2) inhibitor  and some glucagon-like peptide 1 receptor agonist (GLP-1 RA) drugs [4,5], remarkable hitherto unrecognized CV efficacy benefits. Mechanistic understanding of these drugs’ efficacy effects is growing apace, and three main modes of action have emerged: renal protection; and in the SGLT2 inhibitor and GLP-1 RA drugs, predominant heart failure (HF) and atherosclerotic CV disease (ASCVD) protective effects, respectively [6,7]. Guidelines now emphasize the need to consider—beyond glucose control—safety, efficacy, cost-effectiveness, convenience and patient autonomy in the choice of anti-hyperglycaemic agents (AHA) in T2DM .
Metformin is cheap and widely available, and is the preferred choice for AHA initiation in most T2DM. Where glycaemic control is not at target, AHA should be added based on the presence of ASCVD, HF and chronic kidney disease (CKD). Indeed, the presence of CV disease has become a compelling indication for selecting AHA with proven CV benefits in T2DM management .
GLP-1 RAs with proven consistent beneficial effects on reducing ASCVD manifestations like nonfatal and fatal myocardial infarcts (MI) and strokes are recommended as part of glycaemic management in T2DM patients with established ASCVD . This is based on the findings of landmark trials in T2DM at elevated CV risk that demonstrated significantly reduced rates of major adverse CV events (MACE) with the GLP-1 RAs liraglutide  and semaglutide . The GLP-1 RAs comprise drugs with heterogeneous pharmacokinetic profiles and posology, and not all drugs in the class demonstrated superior CV efficacy outcomes in trials . In Singapore, liraglutide is the only available GLP-1 RA that is approved for the indication of preventing CV events in T2DM, in addition to glucose lowering and weight loss .
SGLT2 inhibitors as a class demonstrate striking benefits in terms of reduction of HF-related outcomes [3,6]. In T2DM patients where HF predilection predominates, they are strongly recommended provided the estimated glomerular filtration rate (GFR) is adequate . This is because SGLT2 inhibitors act on the renal tubules, and their glucose-lowering capacity is dependent on renal clearance of the molecules. Regardless of CV disease status, both SGLT2 inhibitors  and GLP-1 RAs like liraglutide  show promise in retarding albuminuria and GFR worsening, and should be considered in T2DM with CKD . Unlike SGLT2 inhibitors where the pharmacodynamic effect is constrained by GFR threshold, liraglutide can be administered in patients with mild, moderate or severe renal impairment.
In patients who require greater glucose lowering only possible with an injectable medication, GLP-1 RAs are preferred over and provide similar extent of HbA1c lowering as basal insulin, without hypoglycaemia and weight gain . For patients with high and symptomatic hyperglycaemia, insulin is still recommended.
The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A Long Term Evaluation (LEADER)  trial began in 2010 and followed 9,340 high CV risk adults with T2DM for 3.5 to 5 years, who were randomly assigned to receive either a subcutaneous injection of liraglutide 1.8 mg once daily or placebo along with standard treatment. The primary endpoint was time to the first occurrence of the composite outcome of MACE comprising three individual components: CV death, nonfatal MI and nonfatal stroke. Three-point MACE occurred in 13% (608 out of 4668) vs 14.9% (694 out of 4672) of subjects taking liraglutide and placebo, respectively (p=0.01 for superiority). In addition, there was a significant 22% relative risk reduction of CV death with liraglutide (4.7% vs 6.0%, p=0.007). Numerical reductions in the other two components of the 3-point MACE—nonfatal MI and nonfatal stroke—not unexpectedly did not reach statistical significance (the study was not powered for the individual MACE components) . Nonetheless, they corroborated the consistent direction of the efficacy effect across all ASCVD outcome components. These results, along with mechanistic studies of atherosclerotic plaque stabilization in animals  and human subjects , reinforce the anti-atherosclerotic mode of action of liraglutide. Of note, liraglutide did not impact HF outcomes in T2DM  and HF patients .
In the LEADER trial, exploratory analyses revealed statistically significant reduction in microvascular complications with liraglutide (7.6% vs 8.9%, p=0.02) that was driven largely by reduction in renal events (5.7% vs 7.2%, p=0.003) [4,10]. There was no observed increase in retinopathy , unlike that seen in the CV outcome trial of semaglutide . Other salutary effects of liraglutide were reduced HbA1c, body weight and rates of incident hypoglycaemia . The safety profile was similar to what had been observed in previous studies throughout the drug development programme.
Victoza® is the proprietary name for liraglutide, which is 97% structurally similar to human GLP-1, a natural incretin hormone secreted by L-cells in the distal small intestine and colon in response to food intake. The half-life is 13 hours, and it can be administered subcutaneously once daily. Victoza® stimulates pancreatic insulin and inhibits glucagon secretion in a glucose-dependent manner that minimizes hypoglycaemic episodes. Furthermore, it has been shown to improve both beta-cell sensitivity and beta cell function. A dose of up to 1.8 mg OD has been approved as an adjunct to diet, exercise and standard care therapy to reduce the risk of MACE—CV death, nonfatal MI or nonfatal stroke—in patients with T2DM and established CV disease who have inadequate glycaemic control .
Beyond focusing solely on glycaemic indicators, use of drugs that confer CV efficacy benefits like SGLT2 inhibitors and some GLP-1 RAs can potentially improve CV health and longevity of T2DM patients, and real-world evidence suggests a significant impact . The LEADER trial conclusively demonstrated superior CV outcome with liraglutide . Addition of injectable Victoza® to first-line metformin is strongly recommended to provide anti-atherosclerotic CV protection beyond glucose lowering in T2DM patients with ASCVD .