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Insulin therapy: Insulling management in renal impairment
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Diabetic kidney disease (DKD) is the single strongest predictor of cardiovascular disease (CVD) and mortality in patients with diabetes. There is a 6-fold increase in mortality rates in patients with chronic kidney disease (CKD) and diabetes. DKD is responsible for a large proportion of healthcare expenditure on diabetes care.

ESRD: end-stage renal disease

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Renal impairment patients are at high risk of both hyperglycaemia and hypoglycaemia, both of which are associated with increased mortality.2,6

Factors predisposing to hyperglycaemia: reduced glucose filtration and excretion, inflammation-induced insulin resistance.

Factors associated with hypoglycaemia: decreased renal gluconeogenesis, deranged metabolic pathways (including altered metabolism of medications), reduced insulin clearance.

The alert value for hypoglycaemia has been set by the American Diabetes Association (ADA) and the Endocrine Society at <3.8mmol/L.7,8

Many of these patients also have a history of poor adherence to treatment and co-morbidities that further hamper their ability to adhere to treatment.
Our ability to interpret data can be altered in the setting of CKD.

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The CKD workgroup Kidney Disease Improving Global Outcomes (KDIGO) has defined CKD as abnormalities of kidney structure or function present for more than three months. The group classifies CKD based on cause, estimated glomerular filtration rate (eGFR) and albuminuria.9

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This slide shows the relative risk of CVD in CKD according to pooled data from more than 1 million participants from general, high-risk and kidney disease populations. This shows declining eGFR and increasing albuminuria reaching (red) levels of high incidence rates, as adjusted for covariates.10

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It is important to note that some 80% of exogenous insulin may be metabolised by the kidney. In CKD, insulin and other commonly used medicines require dose reduction.

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These commonly used medications require dose reduction in CKD.

EPS: extrapyramidal symptoms

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Endogenous insulin has a half-life of 6 minutes and is almost cleared from the circulation within 10-15 minutes. It is mainly degraded in the liver, to a lesser extent in the kidneys and muscles, and only slightly in other tissues. About 40-50% is metabolised by the liver in its first pass.

Exogenous insulin does not undergo a first-pass effect in the liver, with up to 80% being metabolised in the kidney. The kidney therefore plays an important role in the metabolism and clearance of circulating insulin.

As GFR decreases, there is reduced clearance of insulin. This reduction is initially compensated for by an increase in insulin uptake by the proximal tubular cells. When GFR falls below 20ml/min, insulin clearance is markedly reduced. A restricted diet (prescribed or uraemia-induced) and decreased hepatic gluconeogenesis will further contribute to risk of hypoglycaemia.2,11,12

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CKD is also associated with alterations in endogenous insulin secretion. Uraemia influences calcium and phosphate metabolism. Secondary hyperparathyroidism and vitamin D deficiency associated with CKD decrease the secretory capacity of beta cells. Experimental studies have shown that parathyroidectomy or treatment with verapamil can improve insulin secretion.

Uraemia-induced insulin resistance has been shown to be due to reduced glucose uptake in the peripheral tissues. The insulin resistance is related to accumulation of uraemic toxins, markers of inflammation, increased visceral fat, oxidative stress and vitamin D deficiency.2,6,11-15

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Important to note that dialysis improves insulin resistance.

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The overall incidence of lactic acidosis in metformin users varies across studies from approximately 3 per 100 000 person-years to 10 per 100 000 person-years and is generally indistinguishable from the background rate in the overall population with diabetes.16

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There is a move to reduce the eGFR level at which non-use of metformin is recommended to 15 or lower.

Future guidelines may reflect this.

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This study showed a significant reduction in almost all of the renal parameters and is indicative of the potential value of this SGLT-2 inhibitor in diabetic patients exposed to renal risk.18

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This renal risk reduction is of great interest and points to the use of this medication earlier in type 2 diabetes patients.20

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There is conflicting evidence on the role of HbA1c as a marker of glycaemic control in CKD and it may often be unreliable in ESRD. In fact, glycaemic control may be static or worsening without a concomitant increase in HbA1c.1,2,4

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Target HbA1c levels associated with the best outcomes in pre-dialysis or dialysis CKD patients have not been established.

Intensive glycaemic control has been shown in large RCTs to delay the onset and progression of DKD.

Even when CKD is already established, glycaemic control remains a major therapeutic weapon to combat progression of CKD. However, the benefit of tight glycaemic control in advanced CKD has not been established (ACCORD study).

NKF-KDOQI guideline recommendations of an HbA1c target of 7% (same as for non-CKD patients) refer mainly to patients in the initial stages of CKD.
For diabetic patients with more advanced CKD, a more relaxed target would be appropriate.

Most diabetic patients with CKD broadly fit ADA criteria for patients at high risk of hypoglycaemia.2,9-11

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It is important to note that the balance between altered insulin resistance and insulin clearance is difficult to predict in any given patient, so insulin adjustment is largely empiric.2,11

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The American College of Physicians recommend a 25% dose reduction when GFR is between 10-50ml/min, and a 50% dose reduction when the GFR is <10ml/min.

It is suggested that these dose adjustments be applied regardless of type of insulin used. All insulin preparations can be used. Insulin analogues have been shown to maintain their pharmacokinetic and pharmacodynamic properties in patients with CKD.

 

An in-patient study of patients with GFR <45ml/min compared basal-bolus regimes based on either 0.5u/kg or 0.25u/kg body weight. The two regimes showed similar glycaemic control, but less hypos in the lower dose group.

 

Treatment with analogues glargine and lispro were associated with better renal function compared to human insulin.21 These beneficial effects were rarely seen with insulin aspartate and detemir.

Both long-acting and short-acting human insulins did not show any relationship to eGFR across a wide range of eGFR.

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NOTE: This article was made possible by an unrestricted educational grant from Sanofi, which had no control over content.

References

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  2. Pecoits-Filho R, Abensur H, Betonico CCR, et al. Interactions between kidney disease and diabetes: dangerous liaisons. Diabetol Metab Syndr 2016; 8: 50.
  3. Toth-Manikowski S and Atta MG. Diabetic Kidney Disease: Pathophysiology and Therapeutic Targets. J Diabetes Res 2015; 2015: Article ID 697010. doi:10.1155/2015/697010.
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  7. Alsahli M and Gerich JE. Hypoglycemia in Patients with Diabetes and Renal Disease. J Clin Med 2015; 4(5): 948-964.
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  10. Levey AS, de Jong PE, Coresh J, et al. The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int 2011; 80(1): 17-28. doi: 10.1038/ki.2010.483.
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  12. Mak RH. Insulin resistance in uremia: effect of dialysis modality. Pediatric Res 1996; 40(2): 304-8.
  13. Sampanis CH. Management of hyperglycemia in patients with diabetes mellitus and chronic renal failure. Hippokratia 2008; 12(1): 22-27.
  14. Mak RH. Impact of end-stage renal disease and dialysis on glycemic control. Semin Dial 2000; 13(1): 4-8.
  15. Mak RH and DeFronzo RA. Glucose and insulin metabolism in uremia. Nephron 1992; 61(4): 377-82.
  16. Inzucchi S, Lipska JA, Mayo H, et al. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA 2014; 312(24): 2668-2675.
  17. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015; 373(22): 2117-28. doi: 10.1056/NEJMoa1504720.
  18. Wanner C, Inzucchi SE, Lachin JM, et al. Epagliflozin and progression of Kidney Desease in Type 2 Diabetes. N Engl J Med 2016; 375(18): 1800-1.
  19. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016; 375(4): 311-22.
  20. Mann JF. ADA 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA.
  21. Hasslacher C, Kulozik F and Bermejo JL. Treatment with insulin analogs, especially Glargine and Lispro, associates with better renal function and higher hemoglobin levels in Type 1 diabetic patients with impaired kidney function. Ther Adv Endocrinol Metab 2016; 7(4): 166-177.

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