Efficacy of newer agents in the glycaemic management of patients with type 2 diabetes

Type 2 diabetes mellitus (T2DM) has become a global epidemic with an estimated prevalence of 9% in the adult population¹. Both developing and developed countries are affected; for example, in the United Kingdom, it is estimated that 10% of healthcare spend is attributable to this condition and up to 20% of hospital in-patients at any one time have some form of have diabetes as a co-morbidity². This has led many healthcare systems to attempt to relocate diabetes care into the community, on the assumption that this will be cheaper than specialist hospital review. However, the management of T2DM has become more complex over the last decade with the availability of 3 additional classes of glucose-lowering agents.

Two of these drug classes impact the so-called “incretin system”. They operate via stimulation of the glucagon-like peptide 1 (GLP-1) receptor which enhances insulin secretion and reduces the production of glucagon, both in a glucose-dependent manner. The dipeptidyl peptidase-4 (DPP-4) inhibitors are oral agents, which enhance endogenous GLP-1 activity by reducing its degradation by the ubiquitous enzyme DPP-4. Their mechanism of action means that they are unlikely to cause low glucose levels (hypoglycaemia) and they do not induce any change in weight. They have also been shown to be safe in large studies examining their potential to increase cardiovascular (CV) disease related events (a mandatory regulatory requirement for new anti-diabetes therapies)^3–5. There are currently 5 licenced DDP-4 inhibitors in Europe and the United States (sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin) all dosed on a daily basis, with others including a weekly orally administered formulation (omarigliptin) being available in other parts of the world⁶.

The second class of incretin agents are the GLP-1 receptor agonists (GLP-1RAs). These are injectable peptides which are resistant to DPP-4 degradation thus providing supra-physiological stimulation of GLP-1 receptors. They are either based on the exendin-4 molecule, originally isolated from the saliva of the Gila Monster lizard (exenatide and lixisenatide) or are analogues of human GLP-1 (liraglutide, dulaglutide and semaglutide). A fourth GLP-1 analogue, albiglutide, was given marketing authorisation in the European Union in 2014 but then globally withdrawn for commercial reasons in July 2018⁷. In addition to having a low risk of hypoglycaemia, the GLP-1RAs induce weight loss in a significant proportion of patients. They are, however, less well tolerated than DPP-4 inhibitors, with gastrointestinal side-effects of nausea, vomiting and diarrhoea being common following initiation (although these diminish over time in most subjects). The CV safety studies for the subcutaneously administered GLP-1RAs have been less consistent than those for the DPP-4 inhibitors in that while the exendin-4 based molecules have shown CV safety^8,9, other GLP-1 analogues (albiglutide, dulaglutide, liraglutide and semaglutide) have demonstrated CV benefit over established glucose-lowering therapies^10–13.

The third class of anti-diabetic agent is the sodium-glucose co-transporter 2 (SGLT2) inhibitors. These have a completely different mode of action, which is independent of insulin action. Inhibition of SGLT2, a transporter which is only located in the proximal tube of the kidney, allows filtered glucose to be lost in the urine (i.e. glucosuria)¹⁴. This not only reduces plasma glucose concentrations, but the loss of calories lead to weight reduction in most patients¹⁴. These agents also lead to beneficial haemodynamic effects, reducing blood pressure without an increase in heart rate, having a diuretic effect and reducing stimulation of the sympathetic nervous system¹⁵. Since insulin secretion is unaffected¹⁴, as are the counter-regulatory responses to low plasma glucose, risk of hypoglycaemia is low unless co-administered with insulin or sulphonyurea therapy where hypoglycaemia remains a risk. There are currently 4 licenced SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin and ertugliflozin) each of which is administered orally, once daily. The side-effects of SGLT2 inhibitors include genital fungal infection (most commonly seen in women), frequency of micturition and possibly urinary tract infection. In one study canagliflozin was associated with an increased risk of lower extremity amputation and bony fracture but these safety signals were not seen in a subsequent large study investigating high-risk patients with renal disease^16,17. However, further study of this association is required¹⁸. Since 2015, 3 CV safety trials of the SGLT2 inhibitors have been published (EMPA-REG – empagliflozin, CANVAS – canagliflozin and DECLARE TIMI – dapagliflozin). Both EMPA-REG and CANVAS have confirmed superiority of empagliflozin and canagliflozin for the primary end-point of combination of CV mortality, non-fatal myocardial infarction or non-fatal stroke (termed “3-Point MACE” – major adverse CV events)^16,19. DECLARE-TIMI demonstrated a lower rate of CV death and hospitalization for heart failure in patients treated with dapagliflozin but not the co-primary end-point of the 3-Point MACE²⁰. This difference between studies probably reflects the lower CV risk cohort studied in DECLARE TIMI²⁰. A CV outcome study for ertugliflozin is pending²¹.

All 3 classes of anti-diabetes therapy (DPP-4 inhibitors, GLP-1RAs and SGLT2 inhibitors) have a licence for use as monotherapy for T2DM but, in reality, the first-line drug in all Western guidelines is metformin^22,23. These new classes are then an option for a second-line add-on treatment (EASD/ADA) but some guidelines, such as those from the National Institute for Health and Care Excellence (NICE, UK) relegate the GLP-1RAs to a fourth-line option, on the basis of cost (and them currently being injectable agents)^23,24. The recently updated European Society of Cardiology (ESC) guidelines recommended SGLT2 inhibitors or GLP-1RAs as first line therapy in those with T2DM and known ASCVD²⁵.

To allow for clinicians to make a rational choice between the drugs in each class requires 6-12 months duration, head-to-head studies with the primary outcome of reduction in HbA1c. To date, these studies have not been performed in either the DDP-4 inhibitor or SGLT2 inhibitor class. Generally, the DPP4-inhibitors are regarded as clinically equivalent in terms of glucose-lowering while NICE took the same view of the 3 licenced SGLT2 inhibitors when it assessed them for monotherapy use²⁴. In contrast, several head-to-head comparisons have been reported for the GLP-1RAs, with liraglutide typically being the comparator. Liraglutide, administered at a dose of 1.8 mg OD, has been found to have superior glucose-lowering ability when compared with exenatide (both short-acting and long-acting formulations), lixisenatide, and albiglutide^26–29. Only dulaglutide has been non-inferior to liraglutide, although in the same study it produced significantly less weight loss³⁰. The most recently licenced GLP-1RA, once weekly (QW) semaglutide, has been compared with the other QW GLP-1RAs (exenatide extended-release and dulaglutide) and showed superiority for both HbA1c and weight reduction^31,32.

Comparisons between the 3 classes have also been relatively uncommon, however, there are 2 studies involving sitagliptin, one versus canagliflozin and another comparing it with liraglutide, which suggests that the DPP-4 class is inferior in terms of both HbA1c and weight reduction^33,34. These findings seem to be supported by real-life studies, analysing large datasets of routine prescribing³⁵. Studies involving the use of SGLT2 inhibitors and GLP-1RAs are beginning to be reported but thus far involve the combination of drugs from the 2 classes, rather than direct comparisons. This is the knowledge gap that the study by Sharma and colleagues in this issue of Current Medical Research and Opinion seeks to address³⁶.

The authors³⁶ present a network meta-analysis (NMA) to evaluate the comparative efficacy and safety of once-weekly semaglutide versus SGLT2 inhibitors in patients with T2DM inadequately controlled with metformin. NMA is a statistical technique which allows for comparisons of distinct clinical trials and it is widely used by NICE for its technology appraisals and development of clinical guidelines. The authors³⁶ found 8 trials which were suitable for inclusion and report that semaglutide treatment was significantly better compared with SGLT-2 inhibitors in achieving adequate glycemic control. This publication offers guidance which clinicians can use along with other factors when choosing the next anti-diabetic drug after metformin is no longer keeping patients at their HbA1c target. These will include issues such as the side-effect profiles of the classes, renal status (SGLT2 inhibitors are currently not licenced in many countries for initiation in patients with stage 3 chronic kidney disease), presence of high CV risk and, of course, cost.

Transparency

Declaration of funding

This editorial received no funding.

Declaration of financial/other relationships

RC has received honoraria for presentations, attended advisory boards and received travel grants from Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, MSD, Novo Nordisk, Napp Pharmaceuticals and Takeda. SCB has received honoraria from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, Sanofi, provided expert advice for the All-Wales Medicines Strategy Group and National Institute for Health and Care Excellence UK, and is a shareholder of Glycosmedia. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Richard A. Chudleigh
Singleton Hospital, Swansea Bay University Health Board, Swansea, UK
Steve C. Bain
Diabetes Research Unit Cymru, Swansea University Medical School, Swansea, UK
[email protected]

Acknowledgements

None reported.