Studies show that an estimated 20% to 30% of patients living with diabetes develop renal impairment, a major cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD). Patients who develop CKD are at increased risk of morbidity and mortality as a result of cardiovascular (CV) disease.1,2

 

According to Thomas et al, the kidney is the most important target of microvascular damage in diabetes, which may lead to the development and progression of diabetes-related complication such as renal impairment (eg CKD). The main drivers of kidney impairment are chronic and transient hyperglycaemia, transient hypoglycaemia or increased glycaemic variability.3

Apart from the mentioned drivers, another potential cause of renal impairment include past periods of poor glucose control (even before diagnosis) – this is known as ‘metabolic memory’, ‘metabolic karma’ or the ‘legacy effect’.3

Classification of CKD

CKD is classified into six categories based on glomerular filtration rate (GFR). Staging is based on three levels of albuminuria and each stage of CKD is sub-categorised according to the urinary albumin-creatinine ratio in (mg/gm) or (mg/mmol) in an early morning ‘spot’ urine sample (see Table 1).4

In patients with an established diagnosis of diabetes, CKD is defined as a urine albumin/creatinine ratio at or above 30mg/g and/or persistently impaired renal function, defined as an estimated GFR below60 mL/1.73 m2.5

The single most important intervention to prevent CKD development and progression is strict glycaemic control in both types of diabetes. In addition, blood pressure control is essential in patients living with diabetes. All patients with CKD should also be encouraged to implement lifestyle changes and treated with a statin to address hyperlipidaemia in order to reduce CV risk.5,6

Patients with CKD should be referred to a nephrologist when estimated GFR is less than 30ml/min/1.73m2 to discuss the options of renal replacement therapy.4

Effective glucose control

As mentioned above, strict glucose control is of utmost importance in all patients with diabetes to reduce the risk of micro- and macrovascular complications and subsequent renal impairment. The 2022 American Diabetes Association (ADA) guidelines recommend an HbA1c goal of <7% for many non-pregnant adults without significant hypoglycaemia.6

Setting an HbA1c goal lower than the recommended <7% is acceptable if there is no significant risk of hypoglycaemia or other adverse effects. The decision should be based on clinical judgement and patient preference.6

Less stringent HbA1c goals (such as <8%) may be appropriate for patients with limited life expectancy or where the harms of treatment are greater than the benefits.6

First-line therapy depends on comorbidities, patient-centred treatment factors, and management needs and generally includes metformin and comprehensive lifestyle modification.6

The ADA recommends early introduction of insulin if there is evidence of ongoing catabolism (weight loss), if symptoms of hyperglycaemia are present, or when HbA1c levels (>10%) or blood glucose levels (16.7mmol/L]) are very high. The choice of medication added to initial therapy should be based on the clinical characteristics of the patient and their preferences.6

Insulin regimens typically consist of basal insulin, mealtime insulin, and correction insulin. Basal insulin includes neutral protamine Hagedorn (NPH) insulin, long-acting insulin analogues, and continuous delivery of rapid-acting insulin via an insulin pump. Basal insulin analogues have longer duration of action with flatter, more constant plasma concentrations and activity profiles than NPH insulin. Rapid acting analogues have a quicker onset and peak and shorter duration of action than regular human insulin.6

Limitations of insulin in patients with CKD

According to Harh et al, glucose control in patients with CKD is complex. It requires in-depth knowledge of which medications can be safely used and how CKD affects the metabolism of these agents.7

Kalra et al define an ideal basal insulin as: ‘a formulation which is able to deliver a steady, stable, peakless, continuous insulin concentration for at least 24 hours, in a predictable manner, with low intra-individual and inter-individual variability, without causing side effects such as weight gain or hypoglycaemia, while ensuring that mitogenicity is not induced because of excessive binding to non-insulin receptors. It should have the ability to be used as monotherapy and as part of a basal-bolus regime, as well as in combination with oral hypoglycaemic. It should be equally efficacious, safe, and well tolerated in type 1 and type 2 diabetes’.8

Impaired renal function in patients with diabetes can result in decreased clearance of insulin and, consequently, prolonged exposure. Diabetes patients with impaired renal function may therefore be at increased risk of hypoglycaemia. In addition, deterioration of renal function can lead to increased exposure to insulin therapy, potentially increasing the risk of hypoglycaemia and hampering effective diabetes management in these patients. Impairments in renal function in patients with diabetes have been shown to affect the pharmacokinetics of some insulin products, including regular human insulin.9

However, while evidence indicates that renal impairment may influence the pharmacokinetic parameters of some glucose-lowering therapies including human insulin, it seems as though long-acting insulin analogues are not affected.14

Impact of degludec on renal function

According to Thomas et al, in patients with CKD, glucose-lowering agents not associated with hypoglycaemia are preferred. Insulin degludec, an ultra-long-acting insulin analogue, is associated with a significantly lower risk of hypoglycaemia, particularly nocturnal hypoglycaemia.3,9

Furthermore, insulin degludec has unique pharmacokinetic and pharmacodynamic properties, allowing for once daily dosage. It has a half-life of more than 24 hours and a duration of action of more than 42 hours and can be injected at any time of the day, preferably at the same time of the day. These advantages suggest that insulin degludec should be the basal insulin of choice, both as a basal regime and as part of a basal-bolus regime, according to Karla et al.10

Insulin degludec is the only insulin analogue to self-associate into multi-hexamers upon subcutaneous injection. When injected, these multi-hexamers form a drug depot store from which monomers are slowly and continuously absorbed into the circulation insulin.11

Kiss et al (2014) investigated whether the ultra-long pharmacokinetic properties of insulin degludec observed in patients with normal renal function are preserved in those with mild, moderate, or severe renal impairment or ESRD undergoing haemodialysis (see Table 1 for classification of CKD).9

Thirty subjects (n = 6 per group) received a single subcutaneous dose of 0.4U/kg insulin degludec. Blood samples up to 120 hours post-dose and fractionated urine samples were collected.9

The ultra-long pharmacokinetic properties of insulin degludec were preserved in subjects with renal impairment, with no statistically significant differences in absorption or clearance, compared with subjects with normal renal function.9

In subjects with ESRD, pharmacokinetic parameters were similar whether the insulin degludecpharmacokinetic assessment period included haemodialysis or not, and total exposure was comparable to subjects with normal renal function. Simulated mean steady-state pharmacokinetic profiles were comparable between groups.9

While insulin dose must always be adjusted on an individual basis, this trial suggests that the pharmacokinetic properties of insulin degludec are not significantly influenced by renal function, and thus specific dose adjustment may not be required for subjects with renal impairment. Accordingly, insulin degludec represents a useful insulin treatment option in subjects with co-morbid diabetes and impaired renal function, including ESRD patients undergoing haemodialysis, concluded Kiss et al.8

De Lucas et al (2019) conducted a retrospective, observational study comparing the clinical outcomes in adults with T2DM and CKD with macroalbuminuria switching from insulin glargine 100U/mL (IGla100), insulin detemir and insulin glargine 300U/mL (IGla300) to insulin degludec.12

Endpoints were HbA1c change, hypoglycaemia and units of insulin used (mean follow-up period, 36 months) in 90 patients. Two groups of participants were identified: patients with CKD stage 2 (n=46) and patients with stage 3b (n=44).12

The CKD3b group had significantly more cardiovascular comorbidity (acute myocardial infarction, arteriopathy, hypertension, congestive heart failure) than CKD2. Initial basal insulin in both groups were insulin degludec in 22.2%, GLa100 in 60% and GLa300 in 17.8% patients.12

A statistically significant improvement were observed in HbA1c (-1.71±0.25% in CKD2 and -1.28±1.17% in CKD3b) and in basal glycaemia. Daily insulin basal dose decreased significantly in both groups at 36 months post-switch vs pre-switch. Hypoglycaemia was significantly lower (81,3% to 34,2%, all p <0.001) post-switch vs pre-switch. Renal function remained stable with a decrease in albuminuria in both groups.12

Chaudhuri et al (2020) compared the efficacy and safety of insulin degludec and IGla100 in T2DM patients with Stage 3 or 4 CKD. This was a single-centre, retrospective, observational study evaluates efficacy and safety of insulin glargine and insulin degludec in CKD with eGFR 60 and below. T2DM patients with DKD receiving IGla100 or insulin degludec for 24 weeks and beyond were included. Data relating to anthropometry, blood pressure, renal parameters, and glycaemic control were analysed.13

In advanced renal failure, insulin degludec caused statistically significant less hypoglycaemia than IGa100. Ironically, reverse occurred in CKD stage 3a which may be contributed by concomitant usage of SUs. Both drugs were found to be similarly efficacious in this population. Insulin degludec has lower rate of hypoglycaemia in advanced renal failure T2DM patients and may be a safer option to use in this scenario.13

Conclusion

Intensive management of patients with diabetes includes controlling blood glucose, blood pressure and lipid levels. These approaches will reduce the incidence of renal impairment and slow its progression.3

Table 1: Classification of chronic kidney disease4

References
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  2. Perkovic V, Badve SV and Bakris GL (2022). Treatment of diabetic kidney disease – UpToDate https://www.uptodate.com/contents/treatment-of-diabetic-kidney-disease 1/26
  3. Thomas M, Brownlee M, Susztak K et al.Diabetic kidney disease. Nat Rev Dis Primers 1
  4. Vaidya SR, Aeddula NR. Chronic Renal Failure. [Updated 2021 Oct 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK535404/
  5. Nordheim E, Geir Jenssen T. Chronic kidney disease in patients with diabetes mellitus. Endocr Connect, 2021.
  6. American Diabetes Association. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes—2022. Diabetes Care, 2022; 45(Supplement_1):S125–S143.
  7. Hahr AJ and Molitch ME. Management of diabetes mellitus in patients with chronic kidney disease. Clinical Diabetes and Endocrinology, 2015.
  8. Kalra S, Unnikrishnan AG, Baruah M, Kalra B. Degludec insulin: A novel basal insulin. Indian J Endocrinol Metab, 2011.
  9. Kiss I, Arold G, Roepstorff C, et al. Insulin Degludec: Pharmacokinetics in Patients with Renal Impairment. Clin Pharmacokinet, 2014.
  • Kalra S, Gupta Y. Clinical use of Insulin Degludec: Practical Experience and Pragmatic Suggestions. N Am J Med Sci, 2015.
  • Haahr H, Heise T. A review of the pharmacological properties of insulin degludec and their clinical relevance. Clin Pharmacokinet, 2014.
  • De Lucas MDG, Bueno BA, Olalla J, et al. 544-P: Efficacy and Safety of Insulin Degludec in Adults with T2D Macroalbuminuria and Chronic Kidney Disease Stage 2 and 3B. Diabetes
  • Chaudhuri SR, Majumder A and Sanyal D. 1045-P: Basal Insulins in Advanced Renal Failure: Time for a Paradigm Shift. Diabetes, 2020.
  • Tambascia MA and Eliaschewitz FG. Degludec: the new ultra-long insulin analogue. Diabetology & Metabolic Syndrome, 2015.