Optimising renal risk parameters in type 2 diabetes mellitus: Perspectives from a retinal viewpoint

Abstract

Diabetic retinopathy and nephropathy share pathophysiological mechanisms and there is a defined correlation between the severity of both these microvascular complications from suboptimal glycaemic control. The reno-protective properties offered by sodium–glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists should be applicable to diabetic retinopathy as well. However, in patients with pre-existing diabetic retinopathy, sudden improvement in glycaemic control is well documented to cause early worsening of the changes in the retina that is usually transient. This paradoxical phenomenon tends to occur with longer duration of diabetes, higher HbA1c at the outset, rapid improvement of glucose levels and the magnitude of HbA1c reduction with addition of more agents to tighten metabolic control. Interestingly, this progression of pre-existing diabetic retinopathy is not quite observed with newer sodium–glucose co-transporter-2 inhibitors. This article discusses potential further areas of future research where mechanisms of renal protection can be translated to the retina.

1. Introduction

The recent evidence of sodium–glucose co-transporter-2 inhibitors (SGLT2-i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) treatment in the setting of type 2 diabetes mellitus (T2DM) have demonstrated significant improvements in optimising renal risk parameters with reduction in cardiovascular events. Diabetic patients are predisposed to loss of vision with chronic hyperglycaemia that promotes inflammation, oedema, and retinal pathological changes which if left untreated will progress to progressive changes with time. GLP-1RA therapy has been observed to be associated with early worsening of pre-existing diabetic retinopathy (DR) that is transient and improves with time, whereas SGLT2-i treatment in comparison to GLP-1RA seems to be associated with a decreased risk of sight threatening diabetic retinopathy.¹ Therefore, directing these pathways via SGLT2-i could signify further prospects to decrease progression of DR in high-risk patients. Future clinical trials investigating the potential retino-protective effects of SGLT2-i, is therefore warranted.

2. Discussion

SGLT2-i: The advancement in understanding these drugs have been very informative. Currently in the UK the three main SGLT2-i in use for patients with T2DM; are predominantly Canagliflozin, Dapagliflozin and Empagliflozin, with proven benefits demonstrated in reducing the renal risk parameters.2, 3, 4 T2DM is the leading cause of kidney failure worldwide, and the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial has assessed the effects of the SGLT2-i, Canagliflozin on renal outcomes in patients with T2DM and albuminuric chronic kidney disease.² The CREDENCE trial showed that the event rate of the primary composite outcome of end-stage renal disease (ESRD), doubling of the serum creatinine level, or renal or cardiovascular death was significantly lower in the Canagliflozin group than in the placebo group (43.2 and 61.2 per 1000 patient-years, respectively), which resulted in a 30% lower relative risk (hazard ratio, 0.70; 95% confidence interval [CI], 0.59–0.82; P=0.00001). Secondary outcome data was also similar and these results clearly indicated the benefit of the SGLT2-i Canagliflozin, in this high-risk group of patients.²

Similarly, Dapagliflozin therapy in patients with chronic kidney disease, with or without T2DM, who were randomly assigned to receive Dapagliflozin had a lower risk of the primary composite outcome of a sustained decline in the estimated glomerular filtration rate (eGFR) of at least 50%, ESRD, or death from renal or cardiovascular causes than participants who were assigned to receive placebo.³ Of note, the lower risk of hospitalisation for heart failure or death from cardiovascular causes in the Dapagliflozin group than in the placebo group were consistent with the results of two previous trials of Dapagliflozin, the DECLARE–TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58) and DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trials.

Chronic kidney disease (CKD) is often progressive, with decreased eGFR and the presence of albuminuria representing key risk factors for subsequently developing kidney failure. Therefore slowing CKD progression and avoiding the need for dialysis or a kidney transplant is highly desirable due to the impact of such procedures on quality of life, cardiovascular morbidity and mortality, and the substantial costs of kidney replacement therapy.⁴ The EMPA-KIDNEY study was an international randomised parallel group double-blind placebo-controlled clinical trial of EMPAgliflozin once daily to assess cardio-renal outcomes in patients with chronic KIDNEY disease and was designed to assess the effects of SGLT2-i therapy with Empagliflozin on kidney disease progression, cardiovascular disease and safety in a wide range of patients with CKD.

This study aimed to include large numbers of patients without diabetes as well, patients with an eGFR less than 30 ml per minute per 1.73 m² of body-surface area, and patients with low levels of proteinuria, as measured by urinary albumin-creatinine ratio (ACR). In this population of patients with a wide range of causes of CKD, Empagliflozin safely reduced the risk of the primary outcome of kidney disease progression or death from cardiovascular causes by about 28%.⁴ In fact, treatment was effective irrespective of whether patients had T2DM or not, and across a broad range of eGFR down to around 20 ml per minute per 1.73 m². The risk of hospitalisation for any cause was also reduced by 14%.

3. SGLT2-i and diabetic retinopathy

SGLT2-i was a class of drugs initially developed as therapeutic options for patients with T2DM. Recently, randomised clinical trials have investigated their effects in cardio-renal protection through major adverse cardiovascular event reduction and reductions in diabetic nephropathy.2, 3, 4

Several mechanisms have been suggested for this protection, and micro-vascular protection is thought to be the primary component of their efficacy. While not primarily emphasised in clinical trials, evidence suggests that SGLT2-i may confer retinal protective effects via some of the same mechanisms in the above-mentioned cardio-renal trials.2, 3, 4

DR can be categorised into two separate categories, non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR). NPDR is categorised earlier in the disease course, and it is characterised by weakened blood vessels leading to microvascular leakage.

PDR is a more advanced form of DR and the hypoxic state of the retina drives the formation of fragile new blood vessels through changes in cellular genetic response.⁵ During both these stages of NPDR and PDR, diabetic macular oedema (DME) can develop, which is a pathological collection of fluid in the macula due to the breakdown of the blood–retinal barrier and is a potential for further complication as it leads to deterioration of visual acuity.

SGLT2-i blocks renal tubular reabsorption of glucose by inhibiting the SGLT2 protein, a protein expressed on the renal epithelial cells lining the proximal convoluted tubule.² This protein serves as a sodium-glucose co-transporter, and it reabsorbs glucose from the glomerular filtrate.³ This glucose returns to the systemic circulation at a propensity of up to 90% of total renally reabsorbed glucose.⁴ A reduction in SGLT2 expression promotes increased glucosuria, decreased sodium reabsorption, increased sodium and water excretion, and a reduction in blood pressure,2, 3, 4 and these parameters reduce the burden of the cardiovascular system, with implications in the retina.⁵

The physiology of SGLT2 receptors in human retinal pericytes is not completely understood. One suggestion that has been proposed is that of a Na⁺-Ca²⁺ exchanger that modulates intracellular calcium concentrations and this partially plays a role in the physiology of SGLT2. The retinal pericytes also have an SGLT2 receptor that modulates sodium and glucose entry into the cell.⁵ Nonetheless, when extracellular glucose concentrations increase; the SGLT2 receptor becomes active, causing an influx of glucose and sodium. An overabundance of sodium in the cell causes a breakdown in the receptors and leads to increased cell swelling, cell contraction, and pericyte loss. This is addressed by SGLT2-i treatment and could potentially translate to improvement in NPDR and DME by reducing endothelial damage.⁵

At a molecular level also, it has been recently revealed that Empagliflozin reduced retinal vascular lesions in both Kimba and Akimba mice and Canagliflozin reduced the development of retinal vascular lesions in Kimba mice.⁶ It is indeed very insightful to also note that a large retrospective cohort study to assess whether SGLT2-i affected progression of NPDR compared to standard of care concluded that exposure to SGLT2–i therapy was not associated with progression of NPDR compared to patients receiving other standard treatments for T2DM.⁷

The evidence from these renowned studies has been instrumental in revolutionising the use of SGLT2-i from the perspective of addressing cardiovascular risk, but in addition giving useful insights into DR, NPDR & PDR. This calls for future clinical trials looking at the retino-protective effects of individual SGLT2-i in the setting of DR.

GLP-1RA: The effects of Semaglutide in SUSTAIN 6 and Liraglutide in LEADER, compared with placebo, on clinically important kidney outcomes, including change in albuminuria from baseline to the 2-year visit between treatment and placebo groups; Semaglutide 0.5 mg lowered albuminuria by 20% compared with placebo (95% CI, 10–28%; P<0.001) and the 1.0 mg dose lowered albuminuria by 33% compared with placebo (95% CI, 24–40%; P<0.001).⁸ Albuminuria was 23% lower in Liraglutide-treated patients compared with placebo (95% CI, 18–27%; P<0.001), and the effect of the Semaglutide1.0 mg dose was statistically greater than that of Liraglutide (P=0.024) at 2 years after randomisation.

4. GLP-1RA and diabetic retinopathy

DR is a leading cause of vision loss globally and develops in response to prolonged exposure to poor metabolic control in the setting of T2DM. Despite clear evidence that near-normalisation of blood glucose levels reduces the long-term risk of DR, transient worsening of pre-existing DR has also been demonstrated when glucose control is intensified.⁹

The GLP-1RA class of medications are effective glucose-lowering agents that reach steady state quickly to produce significant glycaemic optimisation, but the effect of glucose lowering by these agents on DR has been of renewed interest.

Cardiovascular outcome trials (CVOTs) provide the longest available randomised, placebo-controlled follow-up for the GLP-1RA drugs. Some CVOTs have shown a point estimate suggestive of increased risk of DR related to treatment; however, none of these trials were designed or powered to provide robust estimates of GLP-1RA effects on DR.⁹

Nonetheless, early detection and treatment of DR remains the standard of care. Screening for DR in patients with T2DM is recommended from the time of diagnosis and typically annually thereafter, depending on the level of glycaemic control and DR status. Those with severe PDR should undergo treatment before or in conjunction with the initiation of intensive glucose lowering therapy. Progression of DR due to intensified glycaemic control is typically transient and reversible over a longer period of time.⁹

Even with the potential for initial progression of DR, it is prudent to remember that intensive glucose management and treatment reduces risk for the onset and progression of DR over time compared with conventional treatment. The current recommendations suggests that GLP-1RA be used early in the treatment of T2DM acknowledging their effective glucose lowering effects and associated potential for weight loss and low risk of hypoglycaemia.

As with any potent glucose lowering agent, clinicians should consider DR status at the time of treatment initiation and follow guidelines for monitoring in patients with established DR, and should try to achieve tight glycaemic control, as persistent hyperglycaemia has more deleterious effects on DR than this temporary paradoxical phenomenon.

The legacy effect of tight glycaemic control on risk reduction (UK Prospective Diabetes Study) has been demonstrated,¹¹ and similar impact of metabolic memory on the prolonged influence of glycaemia during the Diabetes Control and Complications Trial (DCCT) on Future Risks of Complications During the Study of the Epidemiology of Diabetes Interventions and Complications (EDIC) has indeed already been established.¹²

Semaglutide is a GLP-1RA used for treating T2DM and in the CVOT SUSTAIN 6,⁸ it was associated with a significant increase in the risk of DR related complications vs placebo. There is also a paucity of GLP-1 receptors in the human retina, and antibodies used to detect expression have been documented to fail to detect the GLP‐1R using immunohistochemistry, making a direct drug effect less likely.¹⁰ This is further reiterated by the sparse expression of GLP‐1 receptors in the normal human eye and being undetectable in advanced stages of PDR.

The strongest relationship between GLP-1RA treatment and early worsening of DR after drug initiation is thought to be via their impact on HbA1c with the magnitude of rapid improvement in glycaemic control, more so seen in patients with longer duration of diabetes and higher HbA1c at the outset.¹³ It is therefore prudent to collaborate with the retinal specialist and local diabetic eye screening programme in such situations where challenging clinical scenarios warrant close observation and a more watchful approach.¹⁴

5. Conclusion

The rationale for initiation, continuation and discontinuation of these medications would have to be individualised for at-risk patients with diabetes mellitus. Therefore, while the hugely beneficial effects on cardiovascular risk reduction enhancement is well recognised, the variable effects on retinopathy and associated pleiotrophic effects of SGLT2-i and GLP-1RA are less commonly perceived in routine clinical practice. This certainly warrants further studies in the future to evaluate the precise reasons for variability seen in retinal changes in the context of treating renal disease.

Declaration of competing interest

SJ is a Consultant Ophthalmologist leading a regional retinopathy screening service and treating patients with diabetic retinopathy & GIV is a Consultant Physician managing patients with diabetes mellitus related complications.