title sub title Controlling Glucose in Patients with Renal Impairment

EXPERT MONOGRAPH ISSUE 33

Renal impairment and type 2 diabetes are common companions in everyday clinical practice. Approximately one in every four patients with type 2 diabetes seen in Australian general practice has a persistent reduction in

their estimated glomerular filtration rate (eGFR) to below 60ml/min/1.73m2. The prevalence of renal impairment is even greater in elderly patients, especially older women and those with comorbid cardiovascular disease.1

An eGFR may be considered in much the same way we might consider measures of bone density. Those individuals with a T-score of less than -2 (i.e. two standard deviations away from the mean observed in healthy 30-year olds) are said to have osteopenia (literally a deficiency of bone). Osteoporosis is defined by a T-score of -2.5 or lower. Both identify bone frailty that increases the risk of fracture in the event of a minor trauma. In exactly the same way, an eGFR below 60ml/min/1.73m2 is more than two standard deviations away from the mean observed in healthy 30-year olds, and so denotes a ‘deficiency of kidney function’ and identifies a frailty that increases the risks of adverse health outcomes in normally safe situations.

Take Home Messages

` The excess mortality associated with Type

2 diabetes is largely confined to those with CKD.

` Having CKD increases the risk of hypoglycaemia

with insulin and sulphonylurea in patients with

Type 2 diabetes.

` Intensifying glycaemic control is often more

safely achieved using DPP4-inhibitors in

patients with CKD than other agents.

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PROFESSOR MERLIN THOMAS MBChB, PhD, FRACP

Prof Merlin Thomas is a Professor of Medicine at Monash University, Melbourne. Professor Thomas is both a physician and a research scientist. He has published over 300 articles in many of the world’s leading medical journals, as well as several books including The Longevity List and Fast Living, Slow Ageing. He is internationally recognised as a speaker, opinion-leader, teacher and medical storyteller. His research focuses on discovering new ways to prevent and treat the complications of diabetes.

This article discusses common co-morbidities of type 2 diabetes and poor kidney function, and how optimal management must account for the mutual effects of one condition on the other.

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So important is this associated frailty, that excess mortality associated with type 2 diabetes is largely confined to those with chronic kidney disease (CKD).2

The consequences of ‘kidney frailty’ are readily apparent when the volume status of patients with CKD changes acutely and can rapidly swing to fluid overload or dehydration. At the same time, adverse drug reactions are also more commonly observed in patients with CKD — reflecting the pill burden, altered pharmacokinetics, interactions with abnormal physiology and other medications, as well as frequently inadequate dose-adjustments in this setting. This is particularly the case for hypoglycaemia, where renal impairment is associated with increased incidence and severity of hypoglycaemic events.3

Overall, hypoglycaemia is the most frequent complication of diabetes management, affecting up to one quarter of all patients with T2DM, at least once a year.4 It is also often an important barrier to optimal glucose control.

In patients with renal impairment, the barrier of hypoglycaemia frequently looms large. There are many different factors that conspire to increase the risk of hypoglycaemia in patients with renal impairment including inadequate compensatory gluconeogenesis and flattening of the relationship between mean glucose control and HbA1c so that the impact of intensification may be underestimated.

However, the most important factor is altered insulin and drug pharmacology in this setting.

Hypoglycaemia usually occurs when patients have too much insulin for their ambient glucose level. This may be exogenous insulin that they have injected, or endogenous insulin made in response to a sulphonylurea (SU) or a rapid-acting glinides.

Up to half of all circulating insulin is cleared by the kidneys, in patients with renal impairment insulin reaches higher peak levels and acts for longer outside meal times. At the same time, SU and their active metabolites are also partly eliminated by the kidneys, so can drive more insulin production and increase the risk of hypoglycaemia in CKD. Because of their renally cleared active metabolites, glimepiride, glyburide, glibenclamide are not recommended on patients with renal impairment. Gliclazide is metabolised by the liver to inactive metabolites, so poses a lower risk for severe hypoglycaemia. But it is still recommended to be stopped when GFR falls below 40ml/min/1.73m2.

Cautious prescribing, judicious dosing, patient education and vigilant monitoring in patients with renal impairment can reduce the risk of hypoglycaemia when using SUs and insulin. However, another obvious solution would be to try to entirely avoid using these agents in diabetic patients with or at risk of renal impairment.

This is easier said than done, as alternative treatment strategies also have their challenges in this setting. For example metformin also accumulates in renal impairment, meaning doses need to be reduced and eventually discontinued at low levels of renal function, chiefly because of hyperlactaemia and a perceived increased risk of lactic acidosis in this setting. However, appropriately reduced doses of metformin (≤1g/day) can be safely used in patients with stable but impaired function, including planning to discontinue therapy and seek review in the event of significant illness.5

GLP-1 receptor antagonists like exenatide are cleared by the kidneys, so renal impairment increases dose-dependent nausea and other side effects. In addition, the glucose lowering effects of SGLT2 inhibitors are negligible in patients with renal impairment, especially at low dose because of reduced glycosuria. Consequently, many practitioners reluctantly fall back on insulin therapy, despite the ever-present risks from hypoglycaemia.

Fortunately, dipeptidyl peptidase-4 (DPP-4) inhibitors still have the potential to improve and simplify glycaemic control in patients with renal impairment, with efficacy comparable to that observed in patients with normal renal function and a low incidence of adverse drug reactions including hypoglycaemia.6

Because of their differing pharmacology, differing dosing strategies may be required for all the DPP-4 inhibitors except linagliptin. This is addressed in the next article in this series and is relatively a small price to pay. DPP-4 inhibitors must also be used with metformin (or a SU) to be eligible for a PBS subsidy, even in patients with renal impairment. Using appropriately low doses of metformin5 with sick-day rule usually makes this possible. All the DPP-4 inhibitors except alogliptin are also PBS reimbursed for use with insulin.

In summary, intensive control of blood glucose levels in patients with renal impairment is often regarded as problematic in clinical practice, leading to inertia and reluctant compromise. This is despite there being a robust association between HbA1c and clinical outcomes in patients with renal impairment. When contemplating any intensification of glucose control in diabetic patients with renal impairment, our first consideration is to do least harm, prius minus nocient. The real utility of safe well-tolerated DPP-4 inhibitors is most apparent in patients with renal impairment, where other strategies have significant limitations.

References

1. Thomas MC, Weekes AJ, Broadley OJ, Cooper ME, Mathew TH. The burden of chronic kidney disease in Australian patients with type 2 diabetes (the NEFRON study). Med J Aust. 2006 Aug 7; 185(3): 140-4.

2. Afkarian M, Sachs MC, Kestenbaum B, Hirsch IB, Tuttle KR, Himmelfarb J, et al. Kidney disease and increased mortality risk in type 2 diabetes. J Am Soc Nephrol. 2013 Feb; 24(2): 302-8.

Controlling Glucose in Patients with Renal Impairment

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3. Hodge M, McArthur E, Garg AX, Tangri N, Clemens KK. Hypoglycemia Incidence in Older Adults by Estimated GFR. Am J Kidney Dis. 2017 Jul; 70(1): 59-68.

4. Amiel SA, Dixon T, Mann R, Jameson K. Hypoglycaemia in Type 2 diabetes. Diabet Med. 2008 Mar; 25(3): 245-54.

5. Lalau JD, Kajbaf F, Bennis Y, Hurtel-Lemaire AS, Belpaire F, De Broe ME. Metformin Treatment in Patients With Type 2 Diabetes and Chronic Kidney Disease Stages 3A, 3B, or 4. Diabetes Care. 2018 Mar; 41(3): 547-53.

6. Thomas MC, Paldánius PM, Ayyagari R, Ong SH, Groop PH. Systematic Literature Review of DPP-4 Inhibitors in Patients with Type 2 Diabetes Mellitus and Renal Impairment. Diabetes Ther. 2016 Sep; 7(3): 439-54.

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Controlling Glucose in Patients with Renal Impairment

Editorial TeamMedical Editors: Dr Linda Calabresi, Dr Vivienne Miller Managing Editor: Karina Lozada Editorial Assistant: Neil Harris Commissioning Editor: Dr Ramesh Manocha

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