For healthcare professionals only. This article has been initiated and founded by Sanofi, written by UK Diabetes Inpatient forum and finally reviewed by Sanofi for compliance with ABPI code of practice.
Guidelines for the management of hyperglycemia in adults with diabetic kidney disease have been reviewed and updated.
Dr Steve Bain from Swansea University served as lead author of the 2021 update, which builds on the guidelines published in 2018.
It is now thought that the current version of the Clinical Practice Guidelines for Management of Hyperglycemia in Adults with Diabetic Kidney Disease now include the most up-to-date recommendations since the KDIGO 2020 guidelines which were published in November 2020.
Endorsed by the Royal College of Physicians, Dr Bain recently took part in a joint symposium on diabetes and CKD in partnership with Diabetes UK, Association of British Clinical Diabetologists (ABCD), the Renal Association, and Kidney Research UK.
The newly updated document is now organised by pharmacological therapy, spanning insulin, sulphonylureas, biguanides (i.e., metformin), alpha-glucosidase inhibitors, thiazolidinediones, DPP-4 inhibitors, SGLT-2 inhibitors, and GLP-1 receptor agonists.
Key revisions from 2018 are highlighted in yellow on the document. Dr Bain specified that while new data has emerged across almost every therapeutic class, significant additions for patients with type 2 diabetes and CKD have only been made to insulin, biguanides, and most dramatically, GLP-1s and SGLT-2 inhibitors.
SGLT-2 inhibitors have seen the largest shifts for patients with DKD since 2018, spurred by positive data from dedicated renal outcomes trials.
From visuals alone, the SGLT-2 inhibitor section is almost entirely highlighted in yellow, signaling a complete overhaul. Broadly, the guidelines now read: “We therefore recommend the consideration of SGLT-2 inhibitors in all individuals with type 2 diabetes with an eGFR ≥30 mL/min/1.73 m2, irrespective of glycemic control, recognising that this is currently off-license practice.”
As a reminder, J&J’s canagliflozin was the first SGLT-2 inhibitor to demonstrate a hard renal benefit in individuals with DKD, followed by AZ’s dapagliflozin in the DAPA-CKD trial.
Overall, Dr Bain emphasised his belief that SGLT-2 inhibitors will become “very complicated” in terms of their various indications with variable eGFR cut-offs between glucose lowering, kidney disease, and heart failure, though there is undoubtedly diverse benefits for a broad patient population.
In particular, we imagine that dapagliflozin for CKD, which is now under Priority Review at FDA, may see its eGFR cut-off drop down to ≥25 mL/min/1.73 m2 vs. canagliflozin, which is indicated to ≥30 mL/min/1.73 m2 for DKD. We also point out that the baseline groups for each trial are not identical (this would be impossible) so we are not sure the degree to which the outcomes can or should be compared – of course, there are natural comparisons that will always be made, and we’d love to get more definitive opinions on this.
While definitive data on GLP-1s in DKD will have to wait until results from Novo Nordisk’s phase 3 FLOW trial (n=3,508) for semaglutide 1.0 mg, Dr Bain pointed to several promising findings that have emerged from recent CVOTs. Although there is some evidence from CVOTs (i.e, LEADER for liraglutide, REWIND for dulaglutide, etc.), that GLP-1s slow the progression of DKD, this benefit has largely been driven by reductions in albuminuria (a surrogate rather than “hard” renal endpoint).
That being said, post-hoc analyses of several trials have also suggested a reduction in eGFR: for example, while dulaglutide did not confer a statistically significant reduction in eGFR ≥30%, subsequent sensitivity analyses showed that dulaglutide was significantly associated with eGFR declines of both ≥40% (HR=0.70; 95% CI: 0.57 to 0.85, p=0.0004) and ≥50% (HR=0.56; 95% CI: 0.41 to 0.76, p=0.0002). Dr. Bain also touched on the continued controversy surrounding GLP-1s and diabetic retinopathy (which emerged from SUSTAIN-6); to this.
Dr Bain said: “I personally believe that’s down to rapid glucose lowering on a background of established, existing significant retinopathy, and in the setting of poor control.”
Nevertheless, DR is being further studied in Novo Nordisk’s FOCUS study, slated to complete in July 2026.
Improving glycaemic control while reducing the risk of hypoglycemia
At present, there is no direct evidence that insulin reduces the progression of kidney disease, therefore the clinical rationale behind insulin usage should be improving glycemic control/quality of life.
As many oral anti-hyperglycemic agents are contraindicated with CKD or may be ineffective in people with a longer duration of disease, insulin remains an important cornerstone of therapy. On top of existing data from 2018, two new post-hoc analyses have now been incorporated into the 2021 guidelines: (i) a meta-analysis of six-month pooled data from EDITION 1, 2, and 3, which showed a 24% relative risk reduction in nocturnal or severe hypoglycemia (95% CI: 0.62 to 0.94) in people with CKD taking insulin glargine U300 (Toujeo) vs. U100 (Lantus); and (ii) a post-hoc analysis from the BRIGHT trial, which suggested greater reductions in A1c at lower eGFR rates in individuals on insulin glargine U300 (Toujeo) vs. insulin degludec U100 (Tresiba). Dr. Bain was quick to point out that both studies were retrospective and exploratory in nature, however, necessitating further investigation of the findings to draw conclusive recommendations.
New data on metformin in patients with diabetic kidney disease was mixed. A 2017 systematic review published in the Annals of Internal Medicine found that metformin conferred a mortality benefit of 22% (95% CI: 0.63 to 0.96) in those with moderate CKD (60≥eGFR≥30 mL/min/1.73 m2).
Conversely, a post-hoc analysis from the SAVOR-TIMI 53 cohort showed that while metformin was associated with lower rates of all-cause mortality, this benefit was less pronounced in individuals with CKD. Regardless of these discrepancies, Dr Bain emphasised that metformin is widely underutilized by those who might benefit from the medication: a survey of >35,000 individuals with DKD found that ~1/3 of patients who were eligible for metformin were not receiving the medication, which Dr Bain stated could potentially be due to the FDA’s now outdated 1976 restrictions on metformin in individuals with CKD due to lactic acidosis. Dr Bain was quick to point out that both studies were retrospective and the renal sub-analysis was exploratory in nature.
Prescribing Information: Lantus® (insulin glargine) 100 units/ml solution for injection
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