Glucagon-like Receptor 1 Agonists in the Treatment of Type 2 Diabetes

During the last decades, there has been a huge increase in the prevalence of type 2 diabetes mellitus (T2DM), mostly due to the Western lifestyle . T2DM and its vascular complications increase patient morbidity, hospitalisations and healthcare costs . Thus, it is beyond doubt that we need medication which can confer some improvement in the underlying pathophysiological factors leading to T2DM and its complications.

During the last decades, there has been a huge increase in the prevalence of type 2 diabetes mellitus (T2DM), mostly due to the Western lifestyle [1,2] .T2DM and its vascular complications increase patient morbidity, hospitalisations and healthcare costs [3,4] .Thus, it is beyond doubt that we need medication which can confer some improvement in the underlying pathophysiological factors leading to T2DM and its complications.
GLP-1 RAs mainly act by activating the GLP-1 receptors in pancreatic beta cells to stimulate glucose-dependent insulin secretion.Additionally, they reduce appetite and delay gastric emptying, eventually leading to reduced food intake [6,[8][9][10] .They can be used either as monotherapy or an add-on therapy to other antidiabetic agents, including insulin, in T2DM [11][12][13] .GLP-1RAs have very recently been recommended as the second antidiabetic agent after metformin in patients with established atherosclerotic cardiovascular disease and chronic kidney disease [14] .However, they should not be used together with dipeptidyl peptidase-4 inhibitors [10][11][12][13] .As regards type 1 diabetes mellitus, they have been studied but they are not currently approved [9,11,13] .
Regarding their combination with other antidiabetic agents, there are interesting results from some trials.In a study including patients treated with a GLP-1RA together with a sodium glucose transporter 2 inhibitor (SGLT2), the mean reduction of glucose was 2.2 mmol/L (39.6 mg/dL) (p < 0.0004) after 6 months [17] .This therapeutic combination achieved not only adequate glycaemic control, but also weight loss (2.1 kg; p < 0.00003) and decrease of blood pressure [17] .In addition, 34.3% of patients achieved Hb1Ac levels <7% and weight loss >5%, without hypoglycaemias [17] .These results are also supported by another real-world observational study in with patients receiving a GLP-1RA in combination with metformin and a SGLT-2 inhibitor [18] .
The main adverse effects of GLP-1RAs are gastrointestinal: nausea, vomiting, diarrhoea and abdominal complaints (see Table 2) [19] .However, these are mostly self-limited over time [19] .Another adverse effect is injection-site reactions [19] .Moreover, there are indications that incretin-based therapies may cause pancreatic diseases.Nevertheless, according to real-world evidence, the risk of pancreatic disease associated with add-on GLP-1RAs to metformin therapy appears to be no higher than that associated with other antidiabetic agents [20] .
Obviously, the need for injection may discourage some patients, but this can easily be overcome with patient education [16,19] .Moreover, the new pens and (especially) the once-weekly injection of some compounds render them more user friendly [11,16,19] .Another consideration is administration and ease of use.For example, albiglutide needs reconstruction before injection, making its use difficult for some patients, including those with visual or dexterity issues [11,16,19] .
The most important challenge for GLP-1RAs is, as indeed for all antidiabetic agents, the potential cardioprotective actions [21,22] .In this context, GLP-1RAs have demonstrated: (a) slight improvements in arterial pressure, lipid parameters and inflammation in humans; (b) improvements in heart failure and myocardial infarction in the experimental setting [21][22][23][24] .
Of particular relevance, GLP-1RAs exhibit important differences in their cardiovascular effects in large clinical trials.Indeed, liraglutide and semaglutide significantly reduce the risk of major adverse cardiac events [25,26] .By contrast, once-weekly exenatide and lixisenatide have shown a neutral cardiovascular effect: safety but no benefit [27,28] .These differences need to be appreciated in clinical practice, especially when prescribing antidiabetic treatment to patients with known cardiovascular morbidity [29,30] .
Importantly, in the most recent cardiovascular outcomes trial [31] , once-weekly albiglutide reduced the primary cardiovascular endpoint by 22%, exhibiting superiority compared with placebo (p = 0.0006).This trial further enhances the importance of GLP-1RAs, especially in patients with established cardiovascular disease [31,32] .Furthermore, there is recent evidence that that GLP-1RAs may improve the natural history of diabetic complications.A pharmacovigilance meta-analysis has demonstrated that reduced incidence of retinopathy with GLP-1RAs, as compared to other antidiabetic agents [33] .Importantly, GLP-1RAs appear to exert an additional protective role in the kidneys.According to real-world evidence, their use in patients with low estimated glomerular filtration rate (eGFR) was related to less pronounced reduction in eGFR (−0.80 vs. −1.03mL/min/1.73m 2 , p = 0.0005), as compared with other therapies, while HbA1c was significantly reduced as well [34] .Finally, it is now being increasingly appreciated that GLP-1RAs can be excellently be combined with basal insulin [32] .In this more modern combination, GLP-1RAs target post-prandial hyperglycaemia, while basal insulin targets fasting glucose.Nowadays, fixed GLP-1RAs+basal insulin combinations used as a single daily injection in the same pen are available to increase patient compliance [32] .
In conclusion, GLP-1RAs are antidiabetic agents with many advantages [5,8,14,35] .Their beneficial actions are increasingly being appreciated in the treatment of T2DM.