Sodium glucose cotransporter 2 inhibitors: the story continues
Evidence from the latest cardiovascular and renal outcome trials has confirmed additional benefits for this class of oral diabetes agents beyond their primary function of lowering blood glucose
The management of type 2 diabetes (T2D) is multifactorial, requiring lifestyle changes and pharmacological interventions aimed at optimising blood glucose levels, blood pressure and lipids.1 Effective management of these three risk factors has been shown to reduce cardiovascular complications, which are the cause of significant morbidity and mortality in T2D.2 In this article, we focus on the evidence for sodium glucose cotransporter 2 inhibitors (SGLT2i) in reducing blood glucose levels and evaluate how they offer additional benefits beyond glycaemic control.
By the end of this article you should be able to:
- Appreciate the mechanism of action of SGLT2i
- Recognise the different drugs within this class that are available in the UK
- Identify key cardiovascular outcomes trials (CVOT) for SGLT2i
- Evaluate the appropriate place for SGLT2i in the management of T2D
- Implement best practice for the holistic management of hyperglycaemia and beyond
It is worth stating at this point that NICE guidance for T2D is awaiting an update to reflect current evidence,3 so the recommendations made in this article are based on those from the American Diabetes Association with the European Association for the Study of Diabetes (ADA/EASD), which takes into account more recent studies.4 These recommendations are also reflected in specific guidance for primary care.5
THE MECHANISM OF ACTION OF SGLT2i
Although glucose regulation is normally associated with the pancreas and the liver, through the action of insulin and glucagon, the kidneys also have an important role to play. In healthy individuals, the body tries to avoid ‘losing’ glucose through the urine and so the filtration process in the kidneys facilitates the reuptake of glucose, mainly via the SGLT2 receptors within the proximal renal tubules.6
SGLT2 inhibitors disrupt this activity, so that glucose is excreted via the urine instead of being reabsorbed. Circulating blood glucose is therefore lowered, and the loss of calories results in weight loss. At the same time, the effect of SGLT2 inhibitors on sodium levels and the osmotic effect of raised glucose levels in the urine can help to reduce blood pressure.7 SGLT2 inhibition also has a positive impact on the endothelial layer of blood vessels and regulates sodium/hydrogen exchange within the heart and kidney, all of which leads to increased cardiovascular and renal protection.8
THE DIFFERENT DRUGS AVAILABLE WITHIN THIS CLASS
The first SGLT2i to be launched in the UK was dapagliflozin in 2012, closely followed by canagliflozin early in 2014 and empagliflozin later that year. A recent addition to the market was ertugliflozin in 2019. The mechanism of action on SGLT2 inhibition is similar for each, although canagliflozin has also been shown to target SGLT1, a receptor found primarily in the intestine.9 All four SGLT2i drugs have different molecular structures, and the trials which have been carried out with each of these drugs have a different population profile and different composite outcomes, so it is neither possible nor advisable to try to compare one SGLT2i drug or trial with another. However, it is absolutely appropriate to consider how each trial relates to a specific patient profile when applying research findings to individual patients. Trials have assessed the potential for SGLT2i to reduce cardiovascular events (CVE) in people with atherosclerotic cardiovascular disease (ASCVD), at risk of ASCVD, with or at risk of chronic kidney disease (CKD), and those with or at risk of heart failure (HF). These latter two groups have provoked a great deal of interest as T2D, CKD and HF have shared pathophysiology and current evidence suggests that treating T2D with SGLT2i can benefit all three conditions. Although diabetic kidney disease (DKD) is often recognised as a key complication of T2D, heart failure is less well recognised, and yet it is one of the most significant complications in terms of the effect it has on the individual and their family and the mortality risk it carries.10
In a systematic review and meta-analysis of cardiovascular outcome trials (CVOTs) involving SGLT2i drugs, the reduction in CVE was seen primarily in people with established ASCVD.11 Conversely, the role of SGLT2 inhibitors in reducing hospitalisation for HF (HHF) or the progression of renal disease was seen in all populations, including those with no previous history of CVD or HF. This highlights the potential role of SGLT2i as primary prevention of some of the key complications of T2D, something which has led to licence changes for some SGLT2i drugs. Furthermore, exciting benefits have been observed in some trials in people taking SGLT2i who did not have T2D.
KEY CARDIOVASCULAR OUTCOMES TRIALS FOR SGLT2I
Cardiovascular outcome trials (CVOTs) have been a feature of all newly licensed diabetes drugs since 2008, as a response to the withdrawal of rosiglitazone on the grounds of an increase in CV events observed in people taking this drug. Since then all new diabetes therapies have had to demonstrate CV safety data. Many companies have taken this further and have examined the potential CV, renal and heart failure benefits that had been observed in more detail through carefully designed trials with relevant primary outcomes. All SGLT2i trials have reported on what they term ‘3-point MACE*’, defined as a composite outcome of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death. However, as investigators realised that positive evidence regarding HF was being seen in these existing trials, more attention was paid to heart failure outcomes too, especially data on hospitalisation for heart failure.
The first CVOT to report involved 7,020 patients with T2D and CVD who received either empagliflozin or placebo on randomisation. The Empagliflozin, Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG) reported a significant reduction in 3-point MACE in the empagliflozin-treated group versus placebo (10.5% vs 12.1%) and also a significant reduction in all-cause mortality (5.7% vs 8.3%), CVD mortality (3.7% vs 5.9%) and HHF (2.7% vs 4.1%).12 The reduction in CVD mortality (38%) was thought to be driven primarily by a reduction in HHF (35%) as rates of myocardial infarction and stroke remained unchanged with therapy.13 In addition, all-cause mortality was reduced by 32%.13
The Canagliflozin Cardiovascular Assessment Study (CANVAS) followed soon afterwards.14 This study had a larger study population (10,142) and the participants, who all had T2D, were a mixture of those with established CVD and those with risk factors for CVD. The results from CANVAS were consistent with EMPA-REG with respect to HHF (although it should be noted that this finding fell outside the study’s pre-specified hypothesis-testing sequence) and also demonstrated a significant reduction in CVE in people with T2D and high CV risk. Both EMPA-REG and CANVAS demonstrated renal benefits in people with T2D, alerting investigators to the potential renoprotective effects of these drugs, which at the time were only licensed to use in people with normal renal function.
The third CVOT to report was the biggest. The Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes trial (DECLARE-TIMI-58), enrolled 17,276 participants with T2D and either established CVD or risk factors for CVD.15 Although treatment with dapagliflozin in this study group did not impact on MACE, it did result in a lower rate of cardiovascular death mainly due to a 27% reduction in HHF.15
Latterly, ertugliflozin’s CVOT, eValuation of ERTugliflozin effIcacy and Safety (VERTIS-CV) confirmed the safety profile of SGLT2i although no specific CV benefits were identified.16 However, it was noted that ertugliflozin produced a 30% drop in HHF, although it should be noted that this finding fell outside the study’s primary and key secondary end points.
The results in these trials, particularly with respect to renal events and hospitalisation for heart failure, led to further trials to explore these areas in more detail and in trials that were specifically set up with these outcomes in mind.
RENAL OUTCOMES
Diabetic kidney disease can impact on people’s physical and psychological wellbeing, especially at end-stage, when dialysis and blood and bone complications significantly affect quality of life. Diabetes, and in particular, hyperglycaemia, leads to afferent arteriolar dilatation, raised intraglomerular pressure and hyperfiltration.17 SGLT2 inhibitors offer renoprotection by activating renal tubuloglomerular feedback as a result of increased delivery of sodium to the macula densa, restoring adenosine production and resulting vasoconstriction in the afferent renal arterioles, lowering intraglomerular pressure, reducing hyperfiltration and albuminuria.18
The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial examined the use of canagliflozin 100mg in 4,401 patients with T2D and CKD (eGFR 30 to>90ml/min/1.73m2) and albuminuria.19 CREDENCE was stopped early as the results were so convincing. The primary composite outcome of doubling of serum creatinine from baseline or death from renal or CV cause was achieved, with a rate of 43.2 in the canagliflozin treated group versus 61.2 in the placebo group. The p number was an astonishing 0.00001, indicating that this effect was highly significant. In CANVAS, a statistical anomaly was thought to be responsible for a perceived increase in lower limb amputations; there was no signal for amputation risk in CREDENCE.19
On the basis of the CREDENCE results, canagliflozin 100mg has been licensed to initiate in renal impairment down to an eGFR of 45ml/min/1.73m2. It can also be initiated down to an eGFR of 30ml/min in people who also have an ACR of 3mg/mmol or more. In people already taking canagliflozin 100mg, this can be continued, even if the eGFR drops below 30ml/min but canagliflozin should not be initiated in people with an eGFR of less than 30ml/min.
HEART FAILURE
DAPA-HF reported in 2019 and demonstrated benefits for HF patients with reduced ejection fraction (HFrEF) beyond a good standard of currently recommended heart failure therapy.20 DAPA-HF reported a 26% reduction in CV death or the worsening of heart failure status among patients with HFrEF, and excitingly, this was regardless of diabetes status, as those without diabetes seemed to benefit as much as those with. Further results are anticipated for people with HF with preserved ejection fraction (HFpEF). Additionally, DAPA-HF data suggest that dapagliflozin may prevent the onset of T2D among at-risk patients with prediabetes.
Dapagliflozin has recently been licensed in the USA to reduce the risk of CV death and HHF in adults with HFrEF, with and without T2D, based on DAPA-HF. In 2019 dapagliflozin was licensed for reducing HHF in people with T2D and established CVD or risk factors for CVD, based on the findings from DECLARE-TIMI-58. A similar change to dapagliflozin's licence in the UK is anticipated.
DAPA-CKD is due to report later this year,21 and the empagliflozin EMPEROR trial, which is examining the effect of empagliflozin on HFrEF has reported positive outcomes, with further results expected for HFpEF.22
NON- ALCOHOLIC FATTY LIVER DISEASE
Non-alcoholic fatty liver disease (NAFLD) is more prevalent in people who have T2D and the presence of NAFLD is associated with an increased risk of CVE and liver-related mortality. Initial data suggest that SGLT2i drugs can have a beneficial effect on NAFLD related to improvements in liver function tests, body mass index and fatty liver index.23,24 There has also been some evidence that glucagon-like peptide-1 receptor agonists (GLP-1 RA) may also have a positive effect on NAFLD.25
IMPLICATIONS FOR PRACTICE
The American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) guidelines recommend profiling people with T2D according to their specific needs or preferred outcomes.4 For example, if the individual has established ASCVD or is high risk for ASCVD, the recommended approach to management, along with lifestyle interventions and metformin, is a GLP1-RA with proven cardiac benefits (e.g. liraglutide, semaglutide and dulaglutide) or an SGLT2i with proven CV benefits.
For people with renal disease or heart failure, the recommendation is to use an appropriate SGLT2i after metformin and along with lifestyle changes. The consensus statement from ADA/EASD specifically highlights the evidence for canagliflozin in CKD and dapagliflozin in heart failure. If treating with an SGLT2i is not possible, a GLP-1 RA can be considered, as above. For people whose main concern is weight management, again the key recommendations are an SGLT2i or a GLP-1 RA and for those where avoidance of hypoglycaemia is important (which presumably should be everyone) an SGLT2i or GLP-1 RA is recommended, along with DPP4 inhibitors (the -gliptins) or pioglitazone, as none of these drugs is associated with a significant risk of hypoglycaemia. Of interest, an oral version of semaglutide has recently been launched, providing a GLP-1 RA for people who would prefer to avoid injectable treatment. See the summary of product characteristics at https://www.medicines.org.uk/emc/product/11507/smpc
In essence, the choice of the most appropriate therapy after metformin should be tailored to the individual, reflecting the optimal risk: benefit ratio. For nurses, the personalised approach to diabetes care taken by the ADA/EASD authors chimes with the four Ps of the NMC code of conduct: prioritise people, practise effectively, preserve safety and promote professionalism and trust. However, real life experience tells us that the economics of health care are also a priority, especially for primary care organisations that need to balance the books. Ertugliflozin is considerably cheaper than other SGLT2i drugs, and it may well be that your local guidelines recommend using it. This would be appropriate for someone who falls outside of the risk categories mentioned in this article, as it has evidence of benefit when it comes to improving glycaemic control, which would be the main objective in these individuals. However, many people living with T2D will either have, or be at risk of developing, CVD, DKD or HF, and in those situations, the ethical dilemma of failing to offer the most evidence-based and appropriate SGLT2i should be recognised.26
SGLT2i IN TYPE 1 DIABETES
Dapagliflozin is also licensed to use in type 1 diabetes (T1D) in the UK and has been shown to lead to an average 5mmol/mol reduction in HbA1c along with weight loss and associated reductions in insulin doses.27 There does not appear to be a significantly increased risk of hypoglycaemia when using dapagliflozin in T1D but, as has been seen in T2D, there is an increased risk of diabetic ketoacidosis (DKA) and genitourinary symptoms.
DIABETIC KETOACIDOSIS
All patients starting on an SGLT2i should be aware of the significant benefits of these drugs beyond glycaemic control as this may help with adherence. However, they also need to have access to any information that may impact on their health so they can measure risks versus benefits and make an informed decision, in line with the Montgomery ruling.26 A recent Medscape commentary acts as a reminder about the potential risk of DKA in people taking SGLT2i but reading the whole article rather than just the title helps to put this risk into perspective.28 Overall, the risk of SGLT2 inhibitor-induced DKA in T2D was said to be in the region of one episode per 1,000 patient-years but DKA is more likely in people who are unable to eat or drink normally. In those situations (e.g. in acute illness, where the sick day rules would be implemented) use of the SGLT2i should be paused until 24-48 hours post-recovery, when it can be restarted. The use of SGLT2i should be discontinued in people with a history of DKA.
CONCLUSION
In conclusion, SGLT2i therapy appears to offer a strong benefit to risk ratio for most people with T2D, with cardiac and renal benefits. This is achieved through the unique action of SGLT2i drugs, and their benefits are reflected in a range of CVOTs. Furthermore, there is evidence that these drugs have benefits in people who do not have diabetes. This highlights the importance of these medicines in the broader arena of promoting good health and underpins the importance of considering cost-effectiveness, not just drug acquisition costs, when treating people. Prescribers should therefore recognise that they are responsible and accountable for their own prescribing decisions and act accordingly.
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