BJD

A year in diabetic nephropathy

Jovanna Tsoutsouki,1 Tahseen Ahmad Chowdhury2

1 Specialist Registrar in Endocrinology and Diabetes, Department of Diabetes, The Royal London Hospital, London, UK
2 Consultant in Diabetes, Department of Diabetes, The Royal London Hospital, London, UK

Address for correspondence: Dr Tahseen Ahmad Chowdhury
Consultant in Diabetes, Department of Diabetes, The Royal London Hospital, Whitechapel, London E1 1BB, UK
E-mail: Tahseen.chowdhury@nhs.net

https://doi.org/10.15277/bjd.2021.293

Abstract

Whilst 2020 was a year of unique healthcare challenges, in people with type 2 diabetes and diabetic kidney disease (DKD), it was a year of seminal progress. Randomised clinical trials have shown a significant benefit of sodium-glucose transporter-2 inhibitors in patients with DKD, and guidelines now suggest these drugs should be considered in all patients with type 2 diabetes and DKD irrespective of glucose control. Glucagon-like peptide-1 receptor agonists have shown some benefit in reducing progression of albuminuria in DKD, and should also be considered early in the therapeutic pathway. There are new guidelines on the management of post-transplant diabetes, and some new ideas in the management of diabetes in patients on haemodialysis. This article aims to review the year in diabetic nephropathy.

Br J Diabetes 2021;21:100-109

Key words: diabetes mellitus, type 2, nephropathy, post-transplant diabetes

Introduction

It is estimated that 40% of people living with type 2 diabetes (T2D) have diabetic kidney disease (DKD).1 DKD is defined as persistently reduced estimated glomerular filtration rate (eGFR) <60 mL/min/ 1.73 m2 with micro- or macro-albuminuria.2 T2D is the commonest cause of chronic kidney disease (CKD) worldwide requiring renal replacement therapy (RRT).3 CKD and albuminuria are independent predictors of cardiovascular morbidity and mortality.4

In this article we review developments in the last year in patients with T2D and DKD, with a focus on new agents, new guidance on management of post-transplant diabetes mellitus (PTDM), and possible interventions in people with T2D on haemodialysis (HD).

New agents in diabetic kidney disease (DKD)

Patients with DKD are exemplars of multi-morbidity, often living with a number of long-term conditions and frailty. Treatment of DKD involves management of hypertension with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB), improvement in glucose control individualised to the patient, management of cardiovascular risk factors, regular monitoring of renal function and screening for other complications.5 Multidisciplinary management with nephrologists is desirable when CKD is progressive. A number of interventions, such as combined ACEI/ARB,6 direct renin inhibitors,7 bardoxolone8 and endothelin-A receptor antagonists9 have been tested in DKD, with no evidence of benefit.

Cardiovascular outcomes trials (CVOTs) of newer agents in T2D have led to a wealth of cardiovascular and renal outcome data which have informed clinical practice.

Sodium-glucose transporter-2 inhibitors (SGLT2i)

Sodium-glucose transporter-2 inhibitors (SGLT2i) act on the proximal tubule to inhibit glucose reabsorption, promote glycosuria and result in improvements in glucose and body weight. As renal function declines, less glucose is filtered hence attenuating the anti-hyperglycaemic efficacy of these agents in CKD.10 Several studies, however, suggest significant benefit in DKD independent of glucose control. Table 1 outlines the studies of SGLT2i in DKD.

715 Chowdhury Table 1a 715 Chowdhury Table 1b 715 Chowdhury Table 1c 715 Chowdhury Table 1d

In contrast to ACEI/ARBs, renoprotective effects of SGLT2i are thought to be mediated by tubuloglomerular feedback, natriuresis and glucose-induced osmotic diuresis which reduce intraglomerular pressure.11

Empagliflozin

In the EMPA-REG OUTCOME study, empagliflozin was shown to be effective and safe in patients with mild renal impairment (mean eGFR 74.1 mL/min/1.73 m²) and established cardiovascular disease (CVD).12 Empagliflozin reduced all-cause mortality by 32% (hazard ratio (HR) 0.68 [95% confidence interval (CI) 0.57 to 0.82]; p<0.001), hospitalisation for heart failure (hHF) by 35% (HR 0.65 [0.50 to 0.85]; p=0.002) and cardiovascular-related death by 38% (HR 0.62 [0.49 to 0.77]; p<0.001). In a subgroup analysis, the EMPA-REG RENAL study, a 38% reduction in macroalbuminuria onset, 44% reduction in doubling serum creatinine and 55% reduction in patients requiring RRT was seen across all CKD stages.13

The EMPEROR-Reduced trial examined participants with heart failure and mean eGFR 62 mL/min/1.73 m2, 50% of whom had T2D.14 Empagliflozin led to a significantly lower rate of eGFR decline compared with placebo (−0.55 vs −2.28 mL/min/1.73 m2; p<0.001). The risk of dialysis/transplantation or sustained reduction in eGFR was halved in the empagliflozin group (HR 0.50 [0.32 to 0.77]; p<0.001).

A specific study of empagliflozin in patients with CKD, many of whom will have T2D, (EMPA-KIDNEY) is due to report in 2022.

Canagliflozin

Cardiovascular outcomes of canagliflozin were studied in the CANVAS program, involving 10,142 participants with T2D receiving standard care with inadequate glycaemic control, established CVD or high cardiovascular risk.15 Mean eGFR was 76.5 mL/min/ 1.73 m2 and median albumin/creatinine ratio (ACR) was 12.3 mg/g. Canagliflozin led to a lower three-point major adverse cardiovascular outcomes (3p-MACE) (HR 0.86 [0.75 to 0.97]; p<0.001), with the largest benefit seen in stroke reduction in subgroups with more advanced CKD (HR 0.56 for eGFR 45–60 mL/min/1.73 m2 and 0.32 for 30–45 mL/min/1.73 m2 group).

Specific renal outcomes with canagliflozin in people with T2D were examined in the CREDENCE study.16 A total of 4,401 patients had albuminuric CKD (mean eGFR 56.2 mL/min/1.73 m2) and included patients with eGFR ≥30 mL/min/1.73 m2. Median ACR was 927 mg/g. Canagliflozin was associated with a 34% reduction (HR 0.66 [0.53 to 0.81]; p<0.001) in the renal specific composite (doubling of baseline creatinine, end stage renal disease (ESRD) or death from renal causes). Canagliflozin reduced 3p-MACE by 20% (HR 0.80 [0.67 to 0.95]; p<0.01) and hHF by 39% (HR 0.61 [0.47 to 90.8]; p<0.001). The numbers needed to treat (NNT) to prevent one case of doubling of serum creatinine, ESRD or death from renal or cardiovascular cause was 21.

Efficacy was seen across all stages of CKD, with highest efficacy in eGFR 45–60 mL/min/1.73 m2 and urinary ACR >1000 mg/g. Based on this evidence, canagliflozin is now considered an effective option for renal and cardiovascular protection in DKD and can be initiated in people with T2D and macroalbuminuria and eGFR >30 mL/min/ 1.73 m2, as an add-on to ACEI, irrespective of glucose control.

Dapagliflozin

Three large trials have studied the effects of dapagliflozin, two of which (DAPA-HF17 and DAPA-CKD18) included people with and without diabetes.17–19 Overall, dapagliflozin demonstrated a benefit in reducing cardiovascular death and hHF, irrespective of the baseline cardiovascular risk or renal function, but did not reduce 3p-MACE. Dapagliflozin reduced the number of deaths from any cause in people with impaired renal function (DAPA-CKD) (HR 0.69 [0.53 to 0.88]; p=0.004), irrespective of the baseline eGFR. In patients with eGFR 25–75 mL/min/1.73 m2 and albuminuria, dapagliflozin demonstrated a 44% reduction in the composite renal outcome (HR 0.56 [0.45 to 0.68]; p<0.001).18 The NNT to prevent doubling of serum creatinine, ESRD or death from cardiovascular or renal causes was 19.

In DECLARE TIMI 58,19 in people with T2D with either established CVD or multiple risk factors and relatively normal renal function (mean eGFR 85.2 mL/min per 1.73 m²), dapagliflozin reduced eGFR decline >40% by 46% (HR 0.54 [0.43 to 0.67]; p<0.0001) and 59% reduced incidence of ESRD or renal death (HR 0.41 [0.20 to 0.82]; p=0.012).

Meta-analysis

Meta-analysis confirms favourable effects of SGLT2i on the renal composite of doubling of serum creatinine (eGFR 40% decline), RRT initiation or renal-related death (RR 0.63 [0.56 to 0.71]), even in the presence of CVD or multiple risk factors (RR 0.67 [0.59 to 0.76]).20 The pooled NNT for renal outcomes was 67. SGLT2i also reduce albuminuria progression (RR 0.80 [0.76 to 0.84]). The renal and cardiovascular effects of SGLT2i are present across all stages of CKD, irrespective of baseline albuminuria.21,22 Importantly, however, the effects appear to be strongest amongst those patients with albuminuria, compared with those who are normoalbuminuric. The effect is additive to ACEI or ARB use.

These benefits have been confirmed also in an observational cohort study (CVD-REAL 3),23 examining 65,231 people with T2D over 14.9 months, 35,561 of whom were newly started on an SGLT2i. SGLT2i led to a reduced eGFR decline compared with other glucose-lowering drugs (between-group difference in rate of decline 1.53 mL/min/1.73 m² per year [1.34 to 1.72]; p<0.0001). The composite end point of eGFR reduction by 50% or ESRD was also significantly lower with SGLT2i (HR 0.49 [0.35 to 0.67]; p<0.0001). Lower RRT incidence is also associated with use of SGLT2i compared with patients taking dipeptidylpeptidase-4 inhibitors (HR 0.32 [0.22 to 0.47]; p<0.0001).24

Current UK licensing suggests that empagliflozin and dapagliflozin can be initiated at eGFR ≥60 mL/min/1.73 m2.25,26 Dapagliflozin should be discontinued at eGFR <60 mL/min/1.73 m2, whilst empaglifozin should be stopped at eGFR <45 mL/min/ 1.73 m2. It is likely, however, that on the basis of new evidence, dapagliflozin will gain a licence for use at eGFR >30 mL/min/ 1.73 m2. Canagliflozin is approved for initiation in people with T2D with eGFR ≥30 mL/min/1.73 m2 and can be continued in eGFR <30 mL/min/1.73 m2 in the presence of albuminuria ≥300 mg/day unless dialysis is initiated.27 ADA-EASD consensus guidelines recommend that SGLT2i can be used in any patient with T2D with HF or CKD.28

Adverse effects

The commonest adverse event is genital mycotic infections, which commonly occur early in treatment and responds well to over-the-counter medication.29 Urinary tract infections are less frequent.

SLGT2i may cause euglycaemic ketoacidosis, and careful patient education around sick day rules is needed, including avoidance prior to surgery and avoidance of ketogenic diets.30 A reduction in bone mineral density and increased risk of fractures has been suggested, although meta-analysis has not confirmed this.31 CANVAS showed a slight increase in amputations associated with canagliflozin, which was not replicated in the CREDENCE study or with any other SGLT2i. Previous concerns regarding acute kidney injury (AKI) have been alleviated by more recent trials, and no increase in AKI has been seen in observational cohorts.32

Glucagon-like peptide-1 receptor agonists (GLP-1RA)

GLP-1RAs can be divided into incretin mimetics (exendin-4 analogues – exenatide/lixisenatide) or human GLP-1RA (albiglutide, liraglutide, dulaglutide, semaglutide). Elimination of exendin-4 analogues relies on glomerular filtration, and hence they accumulate in renal insufficiency. They have not demonstrated improved outcomes in CVOTs.33,34 In contrast, human GLP-1RA are safe in CKD.35 Studies of GLP-1RAs in DKD are shown in Table 2.

715 Chowdhury Table 2a 715 Chowdhury Table 2b

Liraglutide,35,36 dulaglutide,37,38 and subcutaneous39 or oral40 semaglutide have demonstrated effective glycaemic control in T2D and CKD. Liraglutide has shown these effects in patients on dialysis,41 and was superior to placebo in people with T2D and moderate renal impairment.35 In patients with moderate–severe CKD, weekly dulaglutide was non-inferior to insulin glargine.42 Oral semaglutide was superior to placebo both in weight and HbA1c reduction in people with T2D and CKD, with no additional risk of adverse events.43

GLP-1RAs have shown promising results in CVOTs. Meta-analysis of the seven large GLP-1 trials of 56,004 patients showed a 12% reduction in 3p-MACE.44 Composite renal outcome was reduced by 17% for all GLP1-RAs, mainly due to a reduction in new macroalbuminuria.

These properties of GLP-1RAs have been linked to their direct actions on blood pressure, glucose and weight, but also to improving endothelial dysfunction and inflammation.45 They frequently cause an initial eGFR reduction upon administration, with subsequent plateauing. Human GLP-1RAs are approved for use at eGFR ≥15 mL/min/1.73 m2.

Liraglutide

Liraglutide has shown some renoprotective properties.36 People with T2D with established CVD or high CVD risk and mean eGFR 80 mL/min/1.73 m2 showed a 22% risk reduction (HR 0.78 [0.67 to 0.92]; p=0.003) in a pre-specified renal outcome (new onset macroalbuminuria, doubling serum creatinine, eGFR <45 mL/ min/1.73 m2, need for RRT, death from renal disease), predominantly attributed to a 26% reduction in new onset persistent macroalbuminuria (HR 0.74 [0.60 to 0.91]; p=0.004).

Semaglutide

SUSTAIN-6 involved 3,297 people with T2D and CVD, heart failure or CKD stage 3–5.39 Semaglutide decreased the incidence of non-fatal myocardial infarction by 26% and stroke by 39%, but had no effect on hHF or cardiovascular death. Semaglutide led to a 36% reduction in the renal composite of new or worsening nephropathy (persistent macroalbuminuria, persistent doubling of serum creatinine or eGFR <45 mL/min/1.73 m2) (HR 0.64 [0.46 to 0.88]; p=0.005), mainly due to reduction in new macroalbuminuria (HR 0.54 [0.34 to 0.77]; p=0.001). Post hoc analysis of SUSTAIN studies suggested favourable effects on decreasing onset of microalbuminuria.46

Renal effects of once-weekly subcutaneous semaglutide are being studied in the FLOW trial which includes people with T2D and CKD (eGFR 50–75 mL/min/1.73 m2 and ACR 300–5000 mg/g or eGFR 25–50 mL/min/1.73 m2 and ACR 100–5000 mg/g). The primary end point is persistent eGFR decline (≥50% from baseline), ESRD, renal or cardiovascular death, and will report in 2024.47

Dulaglutide

In the REWIND study, dulaglutide was associated with a 15% reduction in the composite renal outcome in patients with either established CVD or risk factors and a mean eGFR of 76.9 mL/ min/1.73 m2, driven by a 23% reduction in macroalbuminuria onset (HR 0.77 [0.68 to 0.87]; p=0.0001).37

Dulaglutide has also shown superiority over insulin glargine on attenuating eGFR decline in T2D with moderate–severe CKD (eGFR reduction by 3.3 mL/min/1.73 m2/year with glargine; eGFR reduction by 0.7 mL/min/1.73 m2/year with dulaglutide).42 Risk of progression to ESRD or >40% eGFR decline was also reduced with dulaglutide compared with glargine (5.2% vs 10.8%; p=0.038).

Overall, the GLP-1RA data suggest a favourable effect in DKD, predominantly due to a reduction in the rate of appearance or progression of macroalbuminuria.

Aldosterone receptor antagonist

A recent study of the aldosterone receptor antagonist finerenone in 5,734 people with T2D and CKD showed some positive benefits.48 Patients included had eGFR 25–60 mL/min/1.73 m2 and urine ACR 30–300 mg/g, and maximum tolerated ARB or ACEI therapy. The primary composite outcome of kidney failure, a sustained decrease of at least 40% in the eGFR from baseline or death from renal causes was reduced by 18% in the finerenone group (HR 0.82 [0.73 to 0.93]; p=0.001). Hyperkalaemia necessitating cessation of finerenone occurred in 2.3% of patients treated.

New guidance on post-transplant diabetes (PTDM)

Solid organ transplantation (SOT) is a life changing therapy for hundreds of thousands of people worldwide. Advances in immunosuppression have led to dramatic improvements in graft and patient survival, but morbidity and mortality from CVD is high, with PTDM being an important contributor. PTDM is a distinct clinical entity that affects between 10% and 40% of SOT recipients,49 and confers a higher risk of graft failure and mortality.50 Recent guidance on the diagnosis, management and prevention of PTDM have been developed by the Association of British Clinical Diabetologists (ABCD) and Renal Association (RA) diabetic nephropathy clinical specialty group.51 These guidelines do not include the management of patients undergoing pancreas transplantation.

Pathogenesis

Weight gain (due to glucocorticoids and fewer dietary restrictions) is common in patients post SOT.52 Risk factors for the development of PTDM are similar to T2D, but specific transplant-related risks also contribute, including immunosuppression and infection (eg, hepatitis C).

Calcineurin is an important factor in β-cell function and growth, and calcineurin inhibitors have adverse effects on β-cell function leading to reduction in insulin secretion.53 Whilst tacrolimus is a highly effective immunosuppressant, it has a more potent adverse effect on β-cell function, leading more frequently to significant hyperglycaemia compared with ciclosporin.54

Diagnosis

Early hyperglycaemia is common in SOT recipients due to stress hyperglycaemia, infection, pain, immunosuppression and parenteral/enteral feeding.55 In the immediate post-transplant period where doses of immunosuppression are high, screening for post-transplant hyperglycaemia should involve frequent capillary blood glucose (CBG) testing, predominantly later in the day (post lunch or evening meal). International consensus suggests a clear method of diagnosis of PTDM based on the oral glucose tolerance test or glycated haemoglobin (HbA1c).56 Interpretation of HbA1c can, however, be problematic postoperatively and in patients with renal disease. It is therefore recommended that HbA1c only be used at least three months post-transplant, and prior to this, glucose tests should be undertaken.

Management

Early post-transplant hyperglycaemia requires active monitoring and management (Figure 1). Persistent hyperglycaemia (≥2 CBGs >11 mmol/L) should prompt treatment. CBGs <14 mmol/L may respond to oral hypoglycaemic agents. Higher levels should be treated with intravenous or subcutaneous insulin, with once daily NPH insulin as a suggested starting regimen.

715 Chowdhury Figure 1a 715 Chowdhury Figure 1b

As immunosuppression doses reduce, hyperglycaemia may improve or resolve. Insulin doses must be reduced accordingly, and the patient must be taught to self-test glucose levels and adjust insulin doses. Input from the diabetes specialist team is important.

In the absence of randomised controlled trials, the management of PTDM should follow that of T2D. There is currently no evidence that tight glycaemic control will improve graft or patient outcomes in PTDM, so glycaemic targets should be individualised according to age, co-morbidity, ability to self-manage and patient preference.28 Safe options for oral hypoglycaemics include metformin (if renal function allows), dipeptidylpeptidase-4 inhibitors (of which linagliptin can be used in any level of renal function), glitazones and meglitinides/sulfonylureas (although hypoglycaemic risk and weight gain must be considered).57 GLP-1RAs may be useful if weight gain is a concern.58 The potential for increased risk of genitourinary infection has led to concern over the use of SGLT-2i in the post-transplant setting, but a small trial of 44 patients with PTDM randomised to empagliflozin or placebo showed a modest glucose benefit, but with significant weight loss, and no increase in risk of infections.59

Change in immunosuppression regimen may aid the management of hyperglycaemia. If feasible, consideration may be given for conversion of tacrolimus to ciclosporin or mycophenolate mofetil plus azathioprine in patients with difficult to control hyperglycaemia.60

All patients with established PTDM must be put on to a primary care diabetes register and undergo structured diabetes care, including referral to structured diabetes education and regular screening for complications (eyes, feet and kidneys). In addition, they require control of cardiovascular risk factors such as smoking cessation, statin therapy and anti-hypertensive therapy aiming for blood pressure <130/80 mmHg.

Patients with PTDM may be most effectively managed in a multidisciplinary setting with diabetes and transplant specialists co-managing the patient.

Managing people with diabetes on haemodialysis (HD)

Diabetes is common in people on HD, and may occur prior to or during dialysis therapy. Managing glycaemia in people with diabetes on HD is uniquely challenging. Glycaemic variability is exacerbated in people with diabetes on HD, as HD clears glucose and glucoregulatory hormones (insulin and glucagon); dialysis-related improvement in uraemia, acidosis and hyperphosphataemia can lead to periodic changes in insulin secretion, and symptoms of hypoglycaemia can often be confused with hypotension.61,62 Assessment of glycaemia may be difficult due to problems in interpreting HbA1c in renal anaemia.63 Therefore, glycaemic management may be reliant on self-monitoring of blood glucose, an additional burden on patients undergoing already burdensome therapy.

Guidance on the management of diabetes in patients on HD has been published by the Joint British Diabetes Societies in 2016,64 and is due to be updated in 2021. There is growing evidence that asymptomatic hypoglycaemia is common in people undergoing HD, and that this may contribute to adverse outcomes.65 With a significant improvement in glucose monitoring technology available for managing people with diabetes, it may be appropriate to consider intermittent ‘diagnostic’ use of flash or continuous glucose monitoring in high-risk patients on HD, especially those on insulin or sulfonylurea. Indeed, NHS guidance on the use of FreeStyle Libre includes people with any form of diabetes on haemodialysis and on insulin treatment.66

Conclusions

A paradigm shift in the management of early DKD using SGLT2i irrespective of glycaemic control is now established and needs to be implemented safely. Most international guidelines now recommend these agents as at least second-line treatment following metformin in people with T2D and, in addition, GLP-RAs are high in the therapeutic pathway. European Society of Cardiology guidelines suggest use of SGLT2i in renal disease even in metformin-naïve patients.67

Recent guidance on PTDM suggests that the condition is an important risk marker for early and late graft failure and mortality. Immediate post-transplant hyperglycaemia requires active monitoring and management. Once PTDM is established, treatment targets and pathways should be as for T2D.

People with diabetes on HD have a significant risk of adverse effects from anti-hyperglycaemic therapy, and newer technologies may enable their care to be made safer.

The year 2020 will be remembered for its unique healthcare challenges related to the COVID-19 pandemic. In DKD, however, it has been an important year, with a number of seminal publications enabling people living with this condition, and their physicians, to hope for better outcomes in the future.

715 Chowdhury Key Messages

Author contributorship JT and TAC contributed equally to this article.

Conflict of interest None.

Funding None.

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