A Scandinavian observational study has shown that sodium-glucose co-transporter 2 (SGLT2) inhibitors are associated with a significant reduction in serious renal events compared with dipeptidyl peptidase-4 (DPP-4) inhibitors.

The study used Scandinavian disease registry data to compare population outcomes in the general diabetic population rather than selected groups of high-risk patients.

Data on a cohort of patients were drawn from disease registers in Sweden, Denmark and Norway. Potentially eligible patients were included from the Swedish and Norwegian registers between April 2013 and December 2016 and from Danish registers up to December 2018. These registers provide data on diagnoses, prescribing, investigations and cause of death.

Patients aged 35-84 years who had filled their first prescription for an SGLT2 inhibitor or a DPP-4 inhibitor were eligible for the study. Initially the registers yielded 38,273 new users of SGLT2 inhibitors and 107,854 of DPP-4 inhibitors.

Patients with prior exposure to the other drug, pre-existing serious renal disease, drug misuse, severe pancreatic disease or hospital admission in the past 30 days were excluded.

The remaining patients were carefully matched one to one as closely as possible, using multiple parameters, resulting in 29,887 pairs of matched patients who were eligible for admission to the study.

The mean age of participants was 61 years, and 39% were women. Around 19% had a history of major cardiovascular disease (CVD), but only 3% had a history of chronic kidney disease (CKD). Total follow-up for the SGLT2 inhibitors was 42,632 years (mean 1.4 years) and for DPP-4 inhibitors 58,473 years (mean 1.7 years).

The primary endpoint of serious renal events was a composite of renal replacement therapy i.e. dialysis or transplant, death from renal causes and hospital admission for renal events.

After adjusting for confounding variables such as BMI, blood pressure (BP) and smoking status, the use of SGLT2 inhibitors compared with DPP-4 inhibitors was associated with a 58% reduced risk of serious renal events (2.6 events per 1,000 person years vs 6.2 events per 1,000 person years); hazard ratio 0.42 (95% CI: 0.34-0.53). The difference was mainly driven by lower rates of renal replacement therapy and hospital admissions with use of SGLT2 inhibitors. No significant differences were seen in death rates from renal causes between the groups.

The SGLT2 inhibitors are the most recent class of hypoglycaemic drugs introduced for type 2 diabetes. They work by reducing glucose/sodium exchange in the proximal tubule and increasing urinary loss of glucose. From first licensing, they have been subject to outcome studies. Not only have they been shown to result in weight reduction, BP lowering and improved HbA1c levels, but outcome studies suggest a real reduction in cardiovascular deaths on these drugs.

The study authors conclude: ‘Complementing data from clinical trials, this study provides further support for the use of SGLT2 inhibitors in a broad range of patients with type 2 diabetes.’

An accompanying editorial in the BMJ states that although there is no evidence of a protective effect against renal disease by DPP-4 inhibitors, they do not worsen renal outcomes.¹ The author of the editorial concludes that SGLT2 inhibitors seem preferable to DPP-4 inhibitors in diabetes patients who may be more at risk of renal disease.

In the UK, SGLT2 inhibitors are not recommended to be initiated in patients with an eGFR below 60 ml/min/1.73m², or continued in patients with an eGFR below 45 ml/min/1.73m².

The findings of this study are encouraging. The realisation of the role of lifestyle in preventing and treating type 2 diabetes, combined with new classes of drugs that assist weight loss and improve outcomes give grounds for cautious optimism about the future for diabetes management.

Dr Matthew Lockyer