SGLT-2 inhibitors are now recommended as first-line therapy for people with type 2 diabetes who have had a previous cardiovascular event. However, there are concerns over a few safety issues associated with these relatively new medications. A new analysis of recent clinical trials, published in a recent issue of Diabetologia, concludes that, overall, the benefits of SGLT-2 inhibitors outweigh the risks.
Around half of those with type 2 diabetes die from cardiovascular disease (CVD) but, in the last decade, there has been new hope in the form of SGLT-2 inhibitors. These drugs have been investigated in a number of cardiovascular outcome trials (CVOTs), including the CANVAS Program, CREDENCE, DECLARE-TIMI and EMPA-REG OUTCOME, in which they have been associated with reduced cardiovascular events and all-cause mortality.
These findings have led to SGLT-2 inhibitors being recommended in the latest international consensus as second-line therapy following the failure of metformin and as first-line therapy in those who have had a previous cardiovascular event. Set against this clinical benefit, however, there are the adverse effects that have been linked to the SGLT-2 inhibitors. These include genital and urinary-tract infections, volume depletion, diabetic ketoacidosis (DKA), bone fractures and cancer.
The cardiovascular efficacy of the SGLT-2 inhibitors in the CVOTs was estimated using data that are correctly powered and at a low risk of bias. Their safety, however, was estimated from observational studies, which have a higher risk of bias. There have been some meta-analyses, which have provided safety assessments, but safety and efficacy data have never been combined to show if there is actually a net clinical benefit from using SGLT-2 inhibitors in people with diabetes. Accordingly, Guillaume Grenet and colleagues, in Lyon, France, have carried out a quantitative estimation at low risk of bias of the risk/benefit ratio of the SGLT-2 inhibitors. The findings will help clinicians and people with type 2 diabetes make informed choices over whether to use these medications in the management of their condition.
Gathering evidence on SGLT-2 inhibitors
The literature was searched for randomised controlled CVOTs published between the end of 2014 and 14th September 2021. Studies that recruited only individuals with type 2 diabetes, with or without other conditions, were included. Trials comparing either placebo or active controls were included, but those comparing different SGLT-2 inhibitors were excluded. The primary outcomes looked for in the analysis were overall mortality and the risk-benefit ratio between the key efficacy outcomes and the primary safety outcomes. The efficacy outcomes were major adverse cardiovascular events (MACE) – that is, death from cardiovascular causes, non-fatal myocardial infarction and non-fatal stroke – and hospitalisation for heart failure (HHF). Cases of end-stage renal disease (ESRD) were also recorded. The primary safety outcomes were amputation, DKA and genital infection. These outcomes were chosen for their relevance to clinical practice. A number of secondary outcomes, like volume depletion, urinary infections, kidney problems, fracture and cancer were also recorded.
For each outcome, the researchers extracted the sample size, the number of events in each arm of the trial, the follow-up time and the measurement of the treatment’s effect. A total of five double-blind placebo-controlled international CVOT trials, covering 46,969 participants, was included in the primary analysis. Two of the trials tested canagliflozin (CANVAS and CREDENCE), one tested dapagliflozin (DECLARE-TIMI), one tested empagliflozin (EMPA-REG OUTCOME) and one tested ertugliflozin (VERTIS-CV). Mean follow-up ranged from 2.6 years to 4.2 years.
When it came to the participants, mean age ranged from 63.0 to 64.4 years, mean duration of type 2 diabetes was 10.5 to 15.8 years and mean HbA1c was 65 to 67 mmol/mol. Mean body mass index (BMI) was 30.6 to 32.1 kg/m2 and mean estimated glomerular filtration rate (eGFR) was 56.2 to 85.3 ml/min per 1.73m2. Participants with a history of CVD ranged from 40.6 to 99.2%, while those with a history of heart failure ranged from 10.1 to 24% and those with a history of amputation from 1.4 to 5.3%.
Risk-benefit ratio of SGLT-2 inhibitors
There were 3303 deaths during the trials, with an overall mortality rate of 21 per 1000 person-years. Taking SGLT-2 inhibitors is associated with a 14% decreased risk of overall mortality compared with controls. Put another way, for 1000 individuals treated over 3.5 years, SGLT-2 inhibitors will decrease the number of deaths, on average, from 70 to 61.
A total of 4798 participants had a MACE, and SGLT-2 inhibitors reduced the risk by 9%, which means that if 1000 participants are treated for 3.5 years, the number of MACE will be reduced from 37 to 26.
Finally, 310 participants developed ESRD, and SGLT-2 inhibitors reduced this risk by 33%. So, if 1000 participants are treated for 3.5 years, the number of cases of ESRD will be reduced from 8 to 6.
The mean spontaneous rate of amputation was four per 1000 person-years. This means that SGLT-2 inhibitors are not associated with a significant increase in the risk of amputation, compared with controls. However, they were associated with a significant increase in DKA and in genital infections. This means that if 1000 participants were treated over 3.5 years, the number of cases of DKA would increase from 1 to 3 and the number of genital infections from 15 to 51.
In summary, the findings of the CVOT trials suggest that if 1000 individuals are treated for 3.5 years, on average 22 of them will benefit, with nine MACE, 11 HHF and two cases of ESRD prevented. However, 38 will be harmed by SGLT-2 inhibitors – namely, two cases of DKA and 36 genital infections. This means, according to the analysis, that 778 people will not experience any of the following outcomes: MACE, HHF, ESRD, amputation, DKA or genital infection. The authors conclude that the balance between MACE and DKA and MACE and amputation remains in favour of SGLT-2 inhibitors being of benefit (by reducing MACE more than they increase DKA or amputation). For HHF, the benefit again outweighs the risk of DKA or amputation. However, the number of genital infections exceeded the number of MACE and HHF.
When it came to secondary outcomes, there were no significant differences in the risk of bladder, breast or kidney cancer, or fracture with SGLT-2 inhibitors compared with controls. There was, however, an increase in the risk of volume depletion.
In a large population of individuals with type 2 diabetes and a high risk of CVD, the cardiovascular and renal benefits of SGLT-2 inhibitors were substantial, despite the risk of DKA and the hypothetical risk of amputation. This study puts actual numbers on the benefits in terms of MACE, HHF and ESRD versus the risks in terms of DKA and genital infections (see above). It should also be noted that this new analysis finds that SGLT-2 inhibitors reduce mortality by around 14% compared with controls, which is comparable to the 16% reduction over five years found in a 2021 study by Palmer et al.
To expand a little on the safety issues, the study did confirm an increased risk of DKA, genital infections, urinary tract infections and volume depletion for people on SGLT-2 inhibitors. This is consistent with the findings of a recent meta-analysis. Genital infections generally occur in the first months of treatment and are usually benign or mild and easy to treat. Of more concern is the potential increased risk of amputation, which was seen in the CANVAS trial. This might be related to canagliflozin, although the CREDENCE trial did not find this increased risk. Or it might even be a false positive. In conclusion, this new analysis, which covers several CVOT trials, does not find an increased risk of amputation, which is reassuring.
The authors go on to say that it’s important that the clinical relevance of the benefits of SGLT-2 inhibitors should be set against those of the risks. Most genital infections can be easily treated, whereas with stroke, myocardial infarction and heart failure there is a high risk of sequelae or even death. Their analysis also did not capture the risk of other microvascular complications, like retinopathy, which might occur with SGLT-2 treatment – this could, of course, be investigated in future studies.
Overall, though, this is a valuable analysis, showing that for individuals with type 2 diabetes and a high CVD risk, the cardiovascular and renal benefits seem to outweigh the risks. It is to be hoped that these results will help inform both clinicians and people with type 2 diabetes when discussing what to expect when starting on an SGLT-2 inhibitor.
To read this paper, go to: Marilly E, Cottin J, Cabrera N, Cornu C, Boussageon R, Moulin P, Lega JC, Gueyffier F, Cucherat M, Grenet G. SGLT-2 inhibitors in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials balancing their risks and benefits. Diabetologia 4 August 2022.
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Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.