Management of Diabetes in Hemodialysis Patients Ghada El-Kanishy Prof. of Internal Medicine Mansoura Faculty of Medicine

1. Management
of diabetes in
hemodialysis
patients
Ghada El-Kanishy
Prof. of Internal Medicine
Mansoura Faculty of Medicine

2. ALTHOUGH DIABETES is the most common cause of ESRD worldwide,
accounting for 44% of ESRD patients in the US Renal Data System in
2005,
data are scarce on how diabetes should best be treated
in patients in ESRD.

3. •Diabetic patients on dialysis also show a higher
morbidity and mortality than non-diabetic dialysis
patients.
•Cardiovascular disease is the main cause of mortality
in CRF diabetic patients

4. Good glycemic control
predicts better survival of
diabetic ESRD patients
starting hemodialysis
treatment
Diabetes Care 2001 May; 24(5): 909-913

5. uraemia-associated anorexia
inadequate gastrointestinal glucose absorption
insulin metabolism disorders (IR and reduced insulin
clearance)
↑ risk of hypoglycemia
ESKD and dialysis affect drug clearance
Factors influence glycaemic control in
diabetic dialysis patients:

6. Management of diabetes in
hemodialysis patients

8. oral hypoglycemic drugs

9. Challenges in use of OHD in
diabetics on HD

10. Sulfonylureas
Sulfonylureas
stimulate endogenous
insulin secretion by
pancreatic β cells

11. Sulfonylureas
Potentially cause hypoglycemia, especially in
• High doses
• Omission or reduction of carbohydrate intake
• Alcohol abuse
• Hepatic dysfunction
• Malnutrition
• Advanced age
• Interactions with certain drugs that displace SUs from
their plasma protein-binding sites salicylates, sulfonamides,
vitamin K antagonists, beta-blockers, and fibric acid derivatives

12. Sulfonylureas

13. Second generation SU
SU undergo
hepatic
metabolism with
variable
percentage of renal
excretion

14. Sulfonylureas
Glyburide & glimepiride have
relatively longer half-lives
active metabolites that are renally excreted
and so are NOT recommended for ESKD.

15. Glipizide has a short half life of 2-4 hs with
little hypoglycemic activity.

16. Meglitinides
•insulin secretagogues that stimulate
pancreatic beta cells
•Short duration of action

17. Meglitinides
• Nateglinide is hepatically metabolized,
with renal excretion of active metabolites
which might precipitate hypoglycaemic
effects.
• Repaglinide, in contrast, is almost
completely converted to inactive
metabolites in the liver, and less than 10%
is excreted by the kidneys.

18. Meglitinides
 Repaglinide is considered a safe option until the
GFR falls to <30 mL/min/1.73 m2
.
 In advanced renal disease, repaglinide should
begin cautiously, with 0.5 mg daily, to avoid
hypoglycemia.

19. Biguanides
• Metformin is not metabolized and 90% is
excreted as the active drug by the
kidneys.
• Plasma levels are thus substantially higher
in pts with ↓ GFR

20. Biguanides
• Use in non dialysis CKD

21. Biguanides in HD
Metformin
poisoning

22. Biguanides
lactic acidosis
Rare ; 5 cases per
100,000 patient-years

23. Thiazolidinediones
Pioglitazone

24. Benefits and hazards of TZDs therapy
Diabetes, Obesity and Metabolism
Volume 15, Issue 11, pages 967-977, 18 APR 2013 DOI: 10.1111/dom.12101
http://onlinelibrary.wiley.com/doi/10.1111/dom.12101/full#dom12101-fig-0001

25. Thiazolidinediones
Fluid retention
• Caution is required in patients in:
• compensated heart failure (NYHA class I
or II)
• in those at risk of heart failure, such as
 patients with previous myocardial
infarction
 Angina
 Hypertension
 LVH
 significant aortic or mitral valve
disease
 age greater than 70 years
 diabetes for more than 10 years.

26. Thiazolidinediones
• In summary
Although ESRD and dialysis do not affect the
metabolism of thiazolidinediones, these agents
are not recommended in ESRD because
of the associated risk of fluid accumulation and
precipitation of heart failure.

27. Alpha-glucosidase inhibitors
• the use of α-glucosidase inhibitors in
patients receiving dialysis is avoided
because of the lack of long-term
clinical trials of these agents in
patients with ESRD and diabetes
KDOQI Clinical Practice Guidelines and Clinical
Practice Recommendations for diabetes and chronic
kidney disease. Am. J. Kidney Dis. (2007)

28. Dipeptidyl peptidase 4 (DPP-4)
inhibitors
• Limited data suggest that these agents
are effective and relatively safe in CKD
and ESRD patients.
• Dose adjustments are needed for some
agents in this class.
.

29. Dose adjustment of DPP4i
National Kidney Foundation. KDOQI Clinical Practice Guideline
for Diabetes
and CKD: 2012 update. Am J Kidney Dis. 2012;60(5):850-886.

30. 2015

31. Safety
• meta-analysis of 59 randomized controlled
trials involving 36,620 patients treated with
DPP-4 inhibitors for at least 24 weeks also
showed a significant increase in the
occurrence of HF compared with the
placebo group
Circulation. 2014; 130(18):1579-88.

32. GLP-1 analogue
Exenatide
• exenatide undergoes minimal systemic
metabolism and is excreted in the urine.
• No dose adjustment is required if the
glomerular filtration rate (GFR) is greater
than 30 mL/min
• Exenatide is contraindicated in patients
undergoing hemodialysis or in patients
who have a GFR less than 30 mL/min

33. GLP-1 analogue
liraglutide
• In contrast to exenatide, liraglutide is not
primarily eliminated by the kidney and the
pharmacokinetics are independent of kidney
function;
–However, liraglutide is not recommended
if GFR less than 30 mL/min due to limited
experience.

34. Sodium-glucose cotransporter-2
(SGLT-2) inhibitors
• This therapeutic class has
been approved for the
treatment of patients with
T2DM with an eGFR of ≥45
mL/min/1.73 m2
.
• Canagliflozin has been
evaluated, showing safety and
efficacy in a subset of patients
with stage 3 CKD
Am J Nephrol.2014;40((1)):64–74

35. Because of its urine-dependent mechanism of action, these
medications are NOT EFFECTIVE in pts with severe renal
impairment
SGLT-
2

36. Oral antihyperglycemic drugs
– Glipizide
– Repaglinide
– linagliptin

37. Insulin

38. Hemodialysis
• use insulin rather than oral agents
• Insulin doses may change substantially
during the transition from earlier stages of
CKD to dialysis.
• 2005

39. Insulin dosing in CKD

40.  ↓ initial dose of insulin
by approximately 50 %,
as for nondialysis CKD
patients with GFR
<10 mL/min.
The dose should be
titrated upward, as
indicated by blood
glucose monitoring

41. Which isulin is preferred ?

42. • .
Intensive insulin analogue treatment provided better
glycaemic control without long-term hypoglycaemia
risk.
Although the cost is a disadvantage, insulin
analogues can be preferred in selected haemodialysis
patients with diabetes mellitus
Nephrol. Dial. Transplant.(February 2006)

43. Dose adjustments due to impaired renal function should NOT be
required for insulin degludec.

44. Problems with control of DM
in patients on HD

45. • Goals ofglycemic control
• Monitoring ofglycemic control
• Fluctuation of blood glucose levels
due to various and opposing effects
of ESRD and dialysis.

46. GOALS OF THERAPY

47. GOALS OF THERAPY
7 - 8%
based upon
the risk of hypoglycemia
presence of comorbid
conditions.

48. HbA1c target
relatively young (<50
years) and without
significant comorbid
conditions
older patients with
multiple comorbid
conditions
7 - 7.5 7.5 - 8

49. 2014
high levels (≥8.5%)
are associated with
increased mortality
risk.
Very low
HbA1c levels (≤5.4%)
also may be
associated with
increased mortality
risk.

50. MONITORING
GLYCEMIC
CONTROL

51. HbA1c
Glycated
Albumin
(GA)

52. HbA1c
• Not as accurate among ESRD patients
as in the general population due to:
AJKD 2008; 52: 766–777.

53. Glycated Albumin (GA)
Reflects glycemic control over a much
shorter interval (7 to 14 days, compared
with 60 to 120 days for HbA1c)
GA measurements may not be reliable in
patients with proteinuria or in those on
peritoneal dialysis
.

54. Glycated Albumin (GA
There are no long-term clinical trials
evaluating the relationship between GA
and risk of chronic complications of
diabetes
.

55. •HbA1c in these patients might lead to underestimation likely as a
result of the increasing proportion of young erythrocyte by the use of
erythropoietin.
•GA provides a significantly better measure to estimate glycemic
control in HD patients with diabetes
•In patients on dialysis with anaemia and Hb levels <10 g/l, GA
and daily fasting blood glucose levels more accurately reflect
glycaemic control than haemoglobin A1c levels
2007

56. 2013
Conclusions
HbA1c (compared with GA and other markers of glycemic
control) was most closely associated with mean blood
glucose

57. WHAT IS BETTER AS
GLYCEMIC MARKER?

58. limited data
absence of interventional outcome
studies based on GA
expensive and laborious
methodology
•It seems premature to abandon HbA1c in favour of glycated albumin
•HbA1C still remains the cornerstone as follow-up of longer term glycaemic control,
GA

59. For these reasons, HbA1c is preferred
in monitoring glycemic control

60. Reasonable glycemic control
in diabetics on HD is:
• FBG ≤ 140md/dl
• PPBG ≤ 200mg/dl
• HbA1c () 7-8%

61. Glucose monitoring

62. Fluctuation of blood
glucose levels

64. Hyoglycemia

65. Hypoglycemia
• 24-h mean glucose values and 24-h CGM
area under the glucose curve in
hemodialysis patients on the day of their
treatment is lower relative to nondialysis
days, with frequent episodes of
asymptomatic hypoglycemia.
Ardebili S et al. Assessing glycemic control in maintenance hemodialysis
patients with type 2 diabetes. Diabetes Care2009

66. When a glucose-free
dialysate is used
asymptomatic hypoglycaemia
(occurs in approximately
40% of patients with or
without diabetes.
Jackson, M. A. et al. Clin. Nephrol. (2000)

68. Hyperglycemia

69. Hyperglycemia
• causes
– Inadequate insulin dose
– noncompliance (with diet or
the insulin regimen)
– microvascular disease can
cause erratic absorption of
insulin from the
subcutaneous tissue,
particularly if the patient
does not rotate injection
sites

70. Hyperglycemia and
ketoacidosis

71. ketoacidosis
• In ESRD
– minimal symptoms, even among those with extreme
hyperglycemia
– glucosuria is absent in anuric individuals
→hypovolemia and marked hypernatremia do not
occur
– marked hyperkalemia which could reach life-
threatening severity

72. ketoacidosis
• management
– Insulin infusion is the only
treatment required in
majority of the patients.
– Emergency hemodialyis
may be considered in
severe pulmonary edema,
profound metabolic
acidosis and severe
hyperkalemia

73. Alternating hypoglycemia
and hyperglycemia

74. Mechanisms of haemodialysis-induced hypoglycaemia and
haemodialysis-associated hyperglycaemia in patients with diabetes.

75. • Insulin-treated diabetes patients on
hemodialysis showed different glucose profiles
between the HD and the FD.
• In particular, in the HD they have had an
increased glycemic variability, which may
represent an adjunctive risk factor for
cardiovascular complications.
Mirani M et al.,Diabetes Technol Ther. 2010.
Inter-day glycemic variability assessed by continuous glucose
monitoring in insulin-treated type 2 diabetes patients on
hemodialysis

76. • Significant 25% reduction in basal insulin
requirements the day after dialysis
compared with the day before.
• No significant change in boluses was
observed
Day-to-Day Variation of Insulin Requirements of Patients With Type 2
Diabetes and End-Stage Renal Disease Undergoing Maintenance
Hemodialysis
Sobngwi E et al.,Diabetes Care.(2010)

78. conclusion
•Glycemic control and monitoring in ESRD
and HD are complex.
•Patients with ESRD are especially
susceptible to hypoglycemia, so diabetic drug
therapy requires special caution.
•Diabetic pharmacotherapy in ESRD should
be individualized.

79. conclusion
•For most HD patients with type 2 DM,initial
treatment is with insulin, rather than oral
agents
• The newer insulins such as glargine and
lispro are more favorable than NPH and
regular insulin, but they cost more, which can
be an obstacle for some patients

80. conclusion
•If an oral agent is used, the preferred agents
are glipizide or repaglinide.
• HbA1c is used to monitor hyperglycemia in
patients with diabetes on HD, although
HbA1c may not be as accurate among ESRD
patients as in the general population