13th December 2018, Dr Chee L Khoo
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the latest therapeutic strategy in the treatment of type 2 diabetes mellitus (T2DM). They feature prominently in the latest international diabetes management guidelines. They not only improve glycaemic control but recent clinical trials demonstrated cardiovascular protection, combined with a reduction in body weight and blood pressure. There used to be three SGLT2 inhibitors, dapagliflozin, empagliflozin and canagliflozin until canagliflozin withdrew from the Australian market. There is now a new SGLT2 inhibitor on the Australian market. How does this new kid on the block, Ertugliflozin, compare with the rest of the group?
If there is an SGLT2, there must be an SGLT1. Indeed, there is. SGLTs belong to a family of sodium-glucose co-transporters. SGLT1 is expressed primarily in the small intestine, the S3 segment of the proximal renal tubule and in the myocardium while SGLT2 is highly expressed in the brush border of epithelial cells in S1 and S2 segments of proximal renal tubules. In healthy humans, under normal physiological conditions, SGLT2 is responsible for 80%–90% of renal glucose reabsorption and SGLT1 for the remaining 10%–20%. Once absorbed into the tubular epithelial cells, glucose passive diffuses into the intercellular space facilitated by transmembrane glucose transporter, the GLUT2 transporter. In type 2 diabetes (T2D), hyperglycaemia can lead to increased expression of SGLT2 and GLUT2 proteins especially if there is kidney disease.
Among many actions, SGLT2 inhibitors blocked the re-absorption of glucose from the renal tubules causing glycosuria, thereby reducing hyperglycaemia in T2D. There are many other spin-offs to this mode of action – reduction in glucotoxity (potentially improving beta cell function and insulin sensitivity), reduction in blood pressure and reduction I body weight (from calorie loss in glycosuria).
So, is the new kid on the block, Ertugliflozin, any good for patients who has not achieved glucose targets? Not unexpectedly, Ertugliflozin is effective in significantly reducing HbA1c and fasting glucose whether used as monotherapy or in combination with metformin, DPP4 inhibitor or sulfonlylurea (the VERTIS series of phase 3 trials). The HbA1c reduction ranged from ~0.6% to 1.2%. It is also effective in reducing body weight by ~2.5-3.5kg after 26 weeks. BP is reduced by ~2-3mm Hg within 4 weeks of treatment. The most commonly reported side effects are genital fungal infections (GFIs) and rare urinary tract infections (UTIs) triggered by the glycosuria. Ertugliflozin represents another valid SGLT2i for the treatment of T2DM. As with other gliflozins, its insulin-independent mechanism is effective in reducing HbA1c, BP, and body weight, both as monotherapy and in combination with other glucose-lowering agents.
What about cardiovascular benefits?
Two clinical trials, EMPAREG and CANVAS, involving empagliflozin and canagliflozin respectively, demonstrated cardiovascular benefits in T2D patients with established cardiovascular disease (not just high cardiac risks). They were associated with a significant reduction in major adverse cardiovascular events (CV death, non-fatal myocardial infarction, or non-fatal stroke). In another recently published study (DECLARE), dapagliflozin was associated with similar reduction in MACE not just in patients with established CV disease but also in patients with high cardiovascular risks. We reviewed the DECLARE trial a few weeks ago. The subjects in this study is more representative of patients in general practice.
What about Ertugliflozin cardiovascular outcome trials? Well, the VERTIS-CV is looking at using Ertugliflozin in patients with established CV disease. It is not due to be completed till September 2019 (2). We will report on the trial shortly after that.
References:
- Francesca Cinti, Simona Moffa, Flavia Impronta, et al. Spotlight on ertugliflozin and its potential in the treatment of type 2 diabetes: evidence to date. Drug Design, Development and Therapy 2017:11 2905–2919
- https://clinicaltrials.gov/ct2/show/NCT01986881