In chronic kidney disease, diabetic patients need diligent consideration of glycaemic targets; the risks versus benefits of glucose lowering treatment need to be assessed carefully.
Chronic kidney disease (CKD) is common in elderly diabetic patients,1 causing problems with accumulation of drugs and increased risk of hypoglycaemia.2,3 Glycaemic control is a moving target as uraemia increases insulin resistance,3 but patients often lose weight and insulin accumulates in CKD stage 4-5.3,4 Hence, prescribing should anticipate worsening renal function and prefer agents accordingly that do not need dose reduction, if the patient survives. This article does not address the investigation of renal impairment.
Plasma creatinine levels are often not raised in frail older individuals due to their low muscle mass, masking renal impairment.5 Renal function is commonly assessed by the estimated Glomerular Filtration Rate (eGFR), provided by laboratories using the MDRD or CKD-EPI formulae; however, these are inaccurate in the older person. The Cockcroft-Gault formula is closest to an iohexol clearance,6 and should be used if any question regarding renal function. The eGFR should be expressed as mL/min/1.73 m2, but we assume these units in this article.
The HbA1c is variable and it is now realised that the HbA1c underestimates the level of glycaemia as early as CKD stage 33,4,7 (as well as interference from anaemia and some assays overestimating the HbA1c).4,7 Furthermore, there may be similar problems with fructosamine,3 but this falsely ‘good’ HbA1c protects the patient from overzealous guideline driven treatment. Self blood glucose monitoring is invaluable if glycaemic control is uncertain, and this is often in place because insulin treatment is common in later stages of CKD.
If the eGFR is under 15 (CKD Stage 5), poor renal hydroxylation of vitamin D requires alfacalcidol for vitamin D replacement.8 Many assays do not pick up alphacalcidol, hence one would titrate this using the calcium level.
With eGFR under 45, intravenous (eGFR under 60 for intra-arterial) radiological contrast media can worsen renal function particularly if the patient is diabetic or aged over 70 years.9 Healthcare professionals should ask whether that scan is really required? If so, optimise the renal function, ensure the patients is hydrated, review and monitor renal function as well as discussing it all with the radiologist.
Metformin and SGLT-2 inhibitors
Metformin and SGLT-2 inhibitors can not be used in significant CKD. Metformin is contraindicated if eGFR is under 30, (and use a reduced dose if eGFR under 45) due to the risk of lactic acidosis.10 SGLT-2 inhibitors have only a minor glucose lowering effect if eGFR under 50-60.11
DPP-4 inhibitors molecules have differing methods of elimination. All, except saxagliptin,12 can be used in end stage renal disease (ESRD), but most require dose reduction with decreasing eGFR.13,14,15 The exception is linagliptin16 that can be used at the standard 5mg dose for all degrees of CKD. Its biliary excretion means that cholestasis is the main contraindication. There is also a wealth of data on sitagliptin, which may become generic within a few years, if one is prepared to monitor the renal function and adjust the dose.
Pioglitazone can be used in standard 15-45mg dose in stage 5 CKD.17 It is proven to prevent secondary vascular events18 and seems to protect from dementia.19 The real problems with pioglitazone include its slow onset of action compared to other oral agents, weight gain, and fluid retention,17 which can exacerbate heart failure, and very rarely worsen diabetic macular oedema. Other less common side effects include mild anaemia, under 1% risk of a peripheral fracture per year, and 0.04% chance of bladder cancer.17 Hence, DPP-4 inhibitors are our first choice.
Sulphonylureas accumulate in renal impairment2,3,4 and subsequent hypoglycaemia is sometimes the presenting feature of new onset renal impairment. In practice, patients tend to experience hypos before breakfast.
Due to the prolonged duration of action of other sulphonylureas in renal impairment, tolbutamide is probably the safest agent.20 It is metabolised via the CYP2C9 system and its largely inactive metabolites are excreted via the urine. The dosage recommendation has evolved from 500-1000mg TDS with meals to now include 500-1500mg as a single dose with breakfast. We would start with 250-500mg with breakfast and gently uptitrate this dose. The problems with tolbutamide are the large tablet size, splitting tablets for the 250mg dose, and hypoglycaemia is still a risk.
Non-sulphonylurea insulin secretogogues include repaglinide and nateglinide.
Repaglinide is metabolised by the liver and can be given in CKD.21 In practice, one starts with 0.5mg (1mg if substituting for another agent) before each meal and uptitrates gently at 1-2 week intervals up to 4mg. Matching drug intake to food intake even if taking an irregular diet can be highly advantageous eg. with Ramadan fasting, and leads to fewer (but not zero) hypos compared to a sulphonylurea.2 The disadvantage is possibly poor compliance with multiple doses.
Nateglinide is predominantly metabolised by CYP2C9 and can be used with eGFRs from 15 to 50. However, the license is only in combination with metformin,22 despite monotherapy being effective23 and prescribing off license causes many practical problems. It is taken TDS at the start of meals, and again hypoglycaemia is less frequent than on sulphonylureas, but not absent.
Both agents as monotherapy reduced the HbA1c in a comparison of repaglinide (HbA1c reduction 1.57%) and nateglinide (HbA1c reduction 1.04%),23 but repaglinide was more effective and it has been noted that repaglinide is as effective at HbA1c reduction as sulphonylureas.2,23
Guidelines suggest using repaglinide rather than sulphonylureas in dialysis patients.4
Only 1-2% of acarbose is absorbed from the gastrointestinal tract, but due to the lack of data, the manufacturers recommend avoiding it if the GFR is under 25.24 The real problem is the flatulence despite very gentle dose escalation, which leads to few patients’ spouses tolerating the drug.
For patients with type 2 diabetes needing injectable treatment there are the options of GLP-1 RAs and/or insulin.
Exenatide and lixisenatide are exendin-4 derivatives that are initially renally excreted. Their clearance is significantly reduced if creatinine clearance is under 30,25,26 and hence are contra-indicated here, although they can be used in moderate renal impairment with care (eGFR 30-50).
Liraglutide and dulaglutide are modified human GLP-127,28 and are broken down by various proteolytic pathways. Dulaglutide’s pharmaco-kinetics were similar down to an eGFR of 1528 compared to normal. Liraglutide exposure is actually decreased in decreased renal function,26 and was found to be safe in the LEADER Trial with eGFRs down to 15, as well as demonstrating vascular benefit.29 Although there is some safety data on dulaglutide in renal impairment,3 there is more data on liraglutide.
In a 26-week, double-blind trial of 279 patients with moderate renal impairment (eGFR 30-59), liraglutide decreased the HbA1c 0.66% with no deterioration in renal function compared to placebo,31 validating an earlier meta-analysis.32
A relatively small comparison of liraglutide versus placebo in patients on dialysis or with normal renal function33 showed that in ESRD trough liraglutide levels increased 49%, (although it did not appear to accumulate), and that HbA1c, glucose levels and insulin doses were reduced by liraglutide. It was associated with more transient nausea and vomiting in the ESRD arm, but no increase in creatinine level. The dose of liraglutide was escalated more slowly in the ESRD group; the investigators recommended dose reduction and prolongation of the titration period may be advisable to reduce nausea and vomiting.
All the GLP-1 RAs may cause nausea and vomiting which can worsen renal function via dehydration.27,34 In renal impairment, side effects of nausea and vomiting are more common.31,33 Renal impairment is an uncommon side effect of liraglutide (under 1% subjects in the LEADER Trial)29 and the manufacturers are very clear that one must avoid dehydration.
If initiating these agents, one must warn about nausea and vomiting. One can start liraglutide at a smaller dose (1 click = 0.06 mg) and escalate the dose very gently (this is not a manufacturer’s recommendation). The ability to do this with liraglutide is a useful practical advantage of its pen. One would not start liraglutide in ESRD,4 but it could be considered if eGFR >15, but continuing it after developing ESRD would require careful weighing up of risk versus benefit and discussion with the patient; hence, one might want to use insulin if eGFR approaching the limit for liraglutide.
Despite modern oral drugs, many patients, particularly those on dialysis, will require insulin despite the increased risk of hypoglycaemia as insulin accumulates in CKD stages 4 and 5. If the eGFR drops below 10, the insulin dose is often about 50% of its original value,4 and some patients with type 2 diabetes can even reduce or stop their hypoglycaemia medication.
As a guideline, one can either use a basal bolus regime because it is so flexible, or if not feasible, a once-daily regime with long-acting basal insulin.4 On dialysis days, one might need a lower dose of insulin due to improved insulin sensitivity.3,4 Basal insulins include long-acting analogue and traditional NPH insulins. Analogue long-acting insulins tend to cause fewer hypos than traditional NPH and if hypos are troublesome, a switch from NPH to an analogue is suggested.4 Hypos often seem to occur before breakfast, so a bedtime snack is advisable. More levemir than glargine is needed for a similar glucose reduction, although otherwise they are very comparable insulins.35, 36 Hence, changes in levemir dose have a gentler effect.
Sometimes dialysis patients cannot receive their insulin daily but it is possible to give glargine thrice weekly at the end of dialysis.37 Understandably this gives worse glycaemic control than daily insulin, but it is better than nothing.37 Degludec would give more control before the next dose. Normal renal function, thrice weekly degludec gave higher HbA1c and more hypos than daily glargine,38 so thrice weekly degludec is not ideal, and has not been trialled in dialysis patients, but would be an option.
As a prandial insulin, theoretically a rapid-acting analogue would be a better choice than a short-acting insulin since it would match the food intake more closely.3
People who have been on biphasic insulin for years may be reluctant to change, and one might need to decrease their insulin 10-15% on dialysis days.4
Whatever insulin regime is used, home blood glucose monitoring is crucial in optimising the treatment safely, and one should be alert for the need to decrease insulin dose as renal function declines.
Recent guidelines recommend the use of statins in all diabetic patients with CKD stage 3 to 5.39 Most statins are contraindicated or require limited doses in ESRD, and fibrates are generally advised against in CKD 3-5.39
However, atorvastatin can be used even with ESRD,40 although the risk of rhabdomyolysis is increased. In the 4D study, atorvastatin was safe, although it did not prevent vascular events.41 Thus atorvastatin is the statin of choice, but it may not do much good. If 40mg atorvastatin does not get to target or is not tolerated, the addition of ezetmibe (which was effective in IMPROVE-IT, particularly in the diabetic sub-group) is licensed in ESRD,41,43 and safer than doubling the atorvastatin to 80mg.
Blood pressure control
Renal impairment may be exacerbated by ACE inhibitors or ARBs, and a trial without them is useful. Sometimes reintroducing a small dose of a short-acting ACE inhibitor such as ramipril 2.5mg at bedtime aids blood pressure control without biochemical upset.
Alpha blockers and calcium channel blockers are useful agents. However, indapamide, chlorthalidone and the thiazides are only fully effective only when renal function is normal or minimally impaired, and are contraindicated if eGFR under 30,44,45,46 hence one uses loop diuretics if needed. Dialysis does reduce blood pressure and peripheral oedema, so medication can be reduced with time.
Diabetes is a risk factor for type 4 renal tubular acidosis (T4RTA), due to hyporeninaemic hypoaldosteronism. It manifests as hyperkalaemia out of proportion to the CKD, and is particularly exacerbated by ACE inhibitors, ARBs and potassium sparing diuretics.47 One can perform sophisticated diagnostic tests,48,49 but pragmatically, stopping the offending medications generally succeeds. If the patient is still hyperkalaemic, adding 50-100mcg fludrocortisone daily is generally effective, and frusemide can be added if ankle oedema occurs.
This is a nightmare in ESRD; after optimising glycaemic control and vitamin D status, oral agents such as opiates, anti-depressants and anti-epileptics are all significantly renally excreted, although one could try lidocaine patches.
In CKD, one needs a careful consideration of glycaemic targets and risks versus benefits of glucose lowering treatment in particular. Oral agents such as linagliptin and pioglitazone which do not per se cause hypoglycaemia are strongly worth considering, and if an insulin secretogogue is required, then tolbutamide or repaglinide seem the safest options. Regarding injectable medication, liraglutide can be used down to an eGFR of 15, but insulin is often required.
CKD 4-5 and dialysis treatment are associated with foot ulceration;4 when attention is focused on the kidneys, do not neglect the feet.
We are grateful to the delegate at the 2017 GM conference who asked this question. This article is dedicated to Brian Page who put up with all the above cheerfully.
Simon Croxson, Consultant Physician
Poppy Mackay, Foundation Program Doctor, Chelsea and Westminster Hospital, London
Hippolyte Fraser, IP & Lead Elderly Care Pharmacist, Bristol Royal Infirmary.
Conflict of interest: Simon Croxson has received consultancy fees or lecture fees or trips from almost all diabetes pharma companies.
Poppy Mackay and Hippolyte Fraser have no conflict of interest.
4. Joint British Societies for Diabetes Inpatient Care. Management of adults with diabetes on the haemodialysis unit. JBDS Document 11; 2016 April (a). http://www.diabetologists-abcd.org.uk/JBDS/JBDS_RenalGuide_2016.pdf
9. Stacul F, van der Molen AJ, Reimer P, et al; Contrast Media Safety Committee of European Society of Urogenital Radiology (ESUR). Contrast induced nephropathy: updated ESUR Contrast Media Safety Committee guidelines. Eur Radiol 2011; 21(12): 2527–41
10. NICE. Type 2 diabetes in adults: management. NICE guideline 28. Published: 2 December 2015. https://www.nice.org.uk/guidance/ng28
12. AstraZeneca UK Limited. Onglyza 2.5mg & 5mg film-coated tablets. eMC 17 Oct 2017 www.medicines.org.uk/emc/product/6675/smpc Accessed 7/3/2018
13. Takeda UK Ltd. Vipidia 12.5mg film-coated tablets. eMC 29 Jan 2015. www.medicines.org.uk/emc/product/7572 Accessed 8/3/2018
14. Merck Sharp & Dohme Limited. JANUVIA 25mg film-coated tablets. eMC 2 Jan 2018. www.medicines.org.uk/emc/product/321/smpc Accessed 7/3/2018
15. Novartis Pharmaceuticals UK Ltd. Galvus 50 mg Tablets. eMC 12 June 2017. www.medicines.org.uk/emc/product/6225/smpc Accessed 7/3/2018
16. Boehringer Ingelheim Limited. Trajenta 5 mg film-coated tablets. eMC 1 Aug 2017. https://www.medicines.org.uk/emc/product/4762. Accessed 8/3/2018
17. Takeda UK Ltd. Actos Tablets SmPC. eMC 9 June 2016. https://www.medicines.org.uk/emc/product/1287/smpc Accessed 4/3/2018
18. Dormandy JA et al. Secondary prevention of macrovascular events in patients with T2DM in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a RCT. Lancet 2005; 366: 1279–89
20. Actavis UK Ltd. Tolbutamide 500 mg BP tablets. eMC 20 Sep 2017. https://www.medicines.org.uk/emc/product/5968. Accessed 4/3/2018
21. Novo Nordisk Ltd. Prandin 0.5mg tablets SmPC. eMC 10 June 2016. https://www.medicines.org.uk/emc/product/258/smpc Accessed 4/3/2018
22. Novartis Pharmaceuticals UK Ltd. Starlix 60mg film coated tablets. eMC 30 June 2015. https://www.medicines.org.uk/emc/medicine/4622 Accessed 3/3/2018
23. Rosenstock J, Hassman DR, Madder RD, et al; Repaglinide Versus Nateglinide Comparison Study Group. Repaglinide versus nateglinide monotherapy: a randomized, multicenter study. Diabetes Care 2004; 27(6): 1265–70
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28. Eli Lilly and Company Limited. Trulicity 1.5 mg solution for injection in pre-filled pen. eMC 5 March 2018 www.medicines.org.uk/emc/product/3634/smpc Accessed 8/3/2018
30. Tuttle KR, McKinney TD, Davidson JA, et al. Effects of once‐weekly dulaglutide on kidney function in patients with type 2 diabetes in phase II and III clinical trials. Diabetes, Obesity & Metabolism 2017; 19(3): 436–41
31. Davies MJ, Bain SC, Atkin SL, et al. Efficacy and Safety of Liraglutide Versus Placebo as Add-on to Glucose-Lowering Therapy in Patients With Type 2 Diabetes and Moderate Renal Impairment (LIRA-RENAL): A Randomized Clinical Trial. Diabetes Care 2016; 39(2): 222–30
33. Idorn T, Knop FK, Jørgensen MB, et al. Safety and Efficacy of Liraglutide in Patients With Type 2 Diabetes and End-Stage Renal Disease: An Investigator-Initiated, Placebo-Controlled, Double-Blind, Parallel-Group, Randomized Trial. Diabetes Care 2016; 39(2): 206-213;
35. J. Rosenstock, Davies M, Home PD, et al. A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetologia 2008; 51(3): 408–16
37. Bouchi R, Babazono T, Onuki T, et al. Administration of insulin glargine thrice weekly by medical staff at a dialysis unit: A new insulin regimen for diabetic management in physically impaired patients undergoing hemodialysis. Diabetology Int 2011; 2: 197–201
38. Zinman B, et al. Efficacy and safety of insulin degludec three times a week versus insulin glargine once a day in insulin-naive patients with type 2 diabetes: results of two phase 3, 26 week, randomised, open-label, treat-to-target, non-inferiority trials. The Lancet Diabetes & Endocrinology 2013; 1(2): 123–31
39. Mark PB, Winocour P on behalf of the ABCD -RA Diabetes CKD guidelines writing group. Association of British Clinical Diabetologists -Renal Association (ABCD-RA) Clinical Practice Guidelines for Management of Lipidsin Adults with Diabetes Mellitus and Nephropathy and/or Chronic Kidney Disease (on-line guidelines). https://renal.org/wp-content/uploads/2017/07/management-of-lipids-in-adults-with-diabetes-mellitus-and-nephropathy-and-or-chronic-kidney-disease.pdf. Accessed 1/3/2018
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42. Giugliano RP, Cannon CP, Blazing MA, et al; IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) Investigators. Benefit of Adding Ezetimibe to Statin Therapy on Cardiovascular Outcomes and Safety in Patients With vs. Without Diabetes: Results from IMPROVE-IT. Circulation 2017
43. Merck Sharp & Dohme Limited. Ezetrol 10mg Tablets. eMC 27 Feb 2018. https://www.medicines.org.uk/emc/product/6792 Accessed 8/3/2018
44. Servier Laboratories Limited. Natrilix 2.5mg. eMC 2 June 2017. https://www.medicines.org.uk/emc/product/1151 Accessed 17/3/2018
45. Alliance Pharmaceuticals. Hygroton Tablets 50mg. eMC 3 Oct 2014. https://www.medicines.org.uk/emc/product/863 Accessed 17/3/2018
46. Actavis UK Ltd. Bendroflumethiazide Tablets BP 2.5mg. eMC 19 May 2015 https://www.medicines.org.uk/emc/product/5727 Accessed 17/3/2018