Transcript Slide 1

Management of Diabetic Nephropathy
&
What to prescribe!
Theingi Aung
Endocrinologist, RBH
4th Feb 2015
Diabetic nephropathy….
• General management
• Specific management
• Long term follow-up
• Referral to specialist
Diabetic nephropathy –T1DM
• T1D ~ 20-30% will have moderate albuminuria after mean
duration diabetes 15 years
• Prior to intensive combined control incidence of overt
nephropathy higher 25-45%, and progression from this to ESRD
• Lower rates due to intensive treatment of HbA1c and BP. In
DCCT <2% of intensively treated developed renal insufficiency
Stanton Am J Kidney Disease 2014(63)S3-21;Ritz NEJM 1999;341(15):1127;
Nathan Arch Intern Med 2009;169: 1307
Diabetic nephropathy T2DM
• T2D similar renal risk - time to proteinuria from diabetes
onset and time to ESRD from proteinuria onset similar
for T1 and T2
• UKPDS: 5100 patients, 10yrs after diagnosis-25%
albuminuria; 5% severe albuminuria; 0.8% Cr>175 or
needing RRT
Am J Kidney Disease 2014(63)S3-21;Ritz NEJM 1999;341(15):1127;
Adler Kidney Int 2003; 63(1):225
Risk Factors
• Non-modifiable
- Genetic predisposition
- Ethnicity
- Age
• Modifiable
- HbA1c
- BP
- lipids
- Weight, diet, smoking, other factors
General management
• Smoking cessation
• Drug history – stop nephrotoxins
- IV contrast, NSAIDs
- assess metformin
• Cardio-renal patients – severe CCF
• Weight, consider bariatric intervention
Health benefit of modest (10%) weight loss
Mortality
20-25% fall in overall mortality
30-40% fall in diabetes related deaths
40-50% fall in obesity-related cancer deaths
Diabetes
Up to 50% fall in fasting blood glucose
Reduces risk of developing diabetes by over
50%
Lipids
Fall of 10% total cholesterol, 15% LDL and 30%
TG
Increase of 8% HDL
Blood
Pressure
10 mmHg fall in diastolic and systolic pressures
Diet modification
• Uncertain if dietary protein restriction improves long-term
decline in GFR
• Small studies show some benefit
Diet – protein restriction
• Uncertain if dietary protein restriction slows long-term
decline in GFR
• Small studies show some benefit
• Recent prospective study – benefit uncertain
• Practical difficulties with low-protein diet
- compliance due to concurrent fat and simple CHO
restriction
- including risk protein malnutrition in diabetes
• Limit to a level not difficult for compliance: 0.6 -1g/kg/day
Hansen Kidney Int 2002; 62:220; Brodsky JCEM 1992; 75:351
Diet – salt restriction
• Fall in blood pressure with salt restriction
• High salt intake can blunt antiproteinuric effect of ACEi/ARBs
• Salt restriction to <70meq/day beneficial
• Difficult to maintain <100meq/day (5-6g/day) recommended
• If not possible, co administration of diuretic partially corrects
the loss of antiproteinuric effect due to high sodium intake
Bakris Ann Intern Med 1996; 125:201; Houlihan Diabetes Care 2002; 25:663;
Esnault J Am Soc Nephrol 2005; 16:474
Cochrane review/Database
Specific management
• Intensive combined therapy
• Target the many factors underlying disease
• Hyperglycaemia
• Hypertension
• Dyslipidaemia
Hyperglycaemia
•
In T1 or T2D hyperglycaemia major determinant of
progression of diabetic nephropathy
•
Evidence best established in T1D
•
Efficacy partly depends on stage at which begun and
degree of normalisation of glucose metabolism
Benefit of strict glycaemic control on kidney
Intensive therapy can
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•
•
•
Reverse glomerular hypertrophy and hyperfiltration
Delay development of elevated albumin excretion
Stabilize or even reverse microalbuminuria
Can slow progression of GFR decline
Hyperglycaemia
• In pancreas transplant patients restoring euglycaemia
prevented recurrent nephropathy in renal allografts
• Euglycaemic pancreatic transplant slow progressive
renal disease even after dipstick-positive proteinuria
Diabetes Care 2000; 23:B21;
Bilous NEJM 1989; 321:80; DCCT NEJM 2011; 365:2366; Fioretto Kidney Int 2006: 69:907
Main tissue and organ targets of glucose-lowering drugs.
Arnouts P et al. Nephrol. Dial. Transplant. 2013;ndt.gft462
© The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights
reserved.
Prescribing in diabetic nephropathy
1. Metformin
•
Eliminated unchanged via the kidney, partly by
glomerular filtration and partly by tubular secretion
•
Avoid accumulation of excess metformin: a risk of
lactic acidosis
•
not recommended with eGFR<30
•
use with caution eGFR 30-44
Prescribing in diabetic nephropathy
2. Sulphonylureas
•
Proportion of these metabolites will be eliminated via
the kidney
•
Risk of accumulation
•
Use with care in CKD – risk hypoglycaemia
•
Use lowest dose that adequately controls blood
glucose
Prescribing in diabetic nephropathy
3. DPP4 inhibitors
•
Sitagliptin
–
–
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Saxagliptin
–
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can prescribe upto 5mg daily; with GFR<50 reduce to 2.5mg
Aloglitpin
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80% cleared by kidney – dose reduction with reduced GFR;
100mg standard dose – reduce to 50mg with GFR 30-50ml/min;
reduce to 25mg with GFR<30
reduce from 25 to 12.5mg with GFR<60; reduce to 6.25mg if GFR<30
Linagliptin
–
no dose reduction needed with reduced GFR
Diabetes Care 2007;30(7):1862; Expert Opin Drug Metab Toxicol. May 2013;9(5):529
Prescribing in diabetic nephropathy
4. Sodium-glucose cotransporter 2 (SGLT2) inhibitors
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Dapaglifozin not recommended with eGFR<60
Canagliflozin reduce to 100mg with GFR 45-60; not
recommended with eGFR<45
Empagliflozin reduce to 100mg with GFR 45-60; not
recommended with eGFR<45
Prescribing in diabetic nephropathy
5. GLP1 receptor agonists
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Exenatide clearance is GFR dependant; use with
caution at eGFR 30-50ml/min and avoid if GFR<30
Liraglutide not metabolized by kidney; no dose
adjustment required with reduced eGFR inc those with
ESRD – data limited in this group
ABCD audit showed liraglutide safe and effective in
GFR>30ml/min
Br J Clin Pharmacol. 2007;64(3):317; Endocr Pract. 2011;17(3):345;
Practical Diabetes 2013; 30(2): 71
Suggested use and dose adaptation of glucose-lowering drugs according to the CKD stages
(see also Table 1 for details). *1.5 g with eGFR > 45 mL/min and 850 mg with eGFR 30–45
mL/min; **to be temporarily witheld in periods of unstable eGFR.
Arnouts P et al. Nephrol. Dial. Transplant. 2013;ndt.gft462
© The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights
reserved.
Insulin prescribing in diabetic
nephropathy
• In advanced CKD - reduced degradation insulin and
marked reduction in insulin requirement
• Can partially reverse with dialysis
• Careful individualised therapy and dosing
• Reduce insulin dose with GFR<50 (~75%)
• Significantly reduce with GFR<10 (~50%)
Specific management
• Intensive combined therapy
• Target the many factors underlying
disease
• Hyperglycaemia
• Hypertension
• Dyslipidaemia
Hypertension
• Strict blood pressure control is important for preventing
progression of diabetic nephropathy and other
complications in patients with type 2 diabetes
• In the United Kingdom Prospective Diabetes Study
(UKPDS), each 10 mmHg reduction in systolic pressure
was associated with a 12 percent risk reduction in
diabetic complications (P<0.001); the lowest risk
occurred at a systolic pressure below 120 mmHg
Hypertension
Adler BMJ 2000;321:412
Hypertension: ACEi and T1D
ACEi delays development of diabetic nephropathy
NEJM 1993; 329:1456; Kidney Int 2001; 60
Hypertension: ACEi and T1D
• ACEi delays development of diabetic nephropathy
• Beneficial effect of preventing progression from
microalbuminuria to overt nephropathy is longlasting (8y)
and associated with preservation of GFR
• Beneficial effect seen in normotensive and hypertensive
subjects
• Remission or regression can occur with aggressive control of
BP particularly with ACEi
NEJM 1993; 329:1456; Kidney Int 2001; 60
Renin Angiotensin system in T2D
• Much less data on effect of ACEi on nephropathy in T2D
but similar benefit appears to be present
• More data on efficacy of angiotensin II receptor blockers
(ARBs)
• IDNT and RENAAL trials showed ARBs superior to
conventional therapy and amlodipine in slowing the
progression of overt nephropathy
Am J Kid Dis 2005;45:281; Kidney Int 2004;65:2309
RENAAL
• 1513 patients with type 2 diabetes with nephropathy
• randomly assigned to losartan (50 titrating up to 100 mg
once daily) or placebo
• Every 10 mmHg increase in the baseline systolic blood
pressure was associated with an enhanced risk of endstage renal disease or death of 6.7 percent
• Lowering albuminuria within the first six months correlated
with a decreased subsequent cardiovascular risk
ACEi vs ARBs
• No good head to head comparisons of ACEi and ARBs
• ACEi or ARBs appear beneficial for renoprotection in
diabetic nephropathy
• MICRO-HOPE, ramipril reduced the risk for myocardial
infarction, stroke, or cardiovascular death by 26% after 2
years
Lancet 2000;355:253
Combination of ACEi & ARB better?
The Veterans Affairs Nephropathy in
Diabetes study (VA NEPHRON-D)
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Randomized placebo-controlled double-blind trial
1448 with diabetic nephropathy
All patients received 100 mg/day of losartan
Randomly assigned to placebo or lisinopril (10 to 40 mg/day
as tolerated);
• Primary endpoint was a composite of a 50 percent
estimated GFR decline (or more than 30 mL/min/1.73 m2),
end-stage renal disease, or death.
• The trial was discontinued early after a median of 2.2 years
because of safety concerns.
Combination ACEi and ARB therapy
not recommended
• Combined therapy with ACEi and ARB decreases
proteinuria in T1 and T2D compared with either therapy
alone
• Several combination trials now shown higher rates acute
kidney injury (requiring dialysis) and hyperkalaemia
(NEPHRON-D; ONTARGET)
• Thus combination ACEi and ARB not recommended
NEJM 2013; 31:414; NEJM 2013; 369:1892
Other agents
• Direct renin inhibitors (aliskiren) – did not preserve renal function
and increased adverse events (ALTITUDE)
• Aldosterone antagonists have additive antiproteinuric effect but
significant risk hyperkalaemia; Finerenone-ARTS-DN
• Endothelin antagonists showed antifibrotic, anti-inflammatory, and
antiproteinuric effects in experimental studies
• Avosentan administered in addition to standard treatment with an
ACE inhibitor or an ARB, reduced proteinuria after 3-6months
(ASCEND)
NEJM 2012; 367:2204J Am Soc Neph 2009; 20:2641; Br J Clin Pharm 2013;76:573
Management HTN
• ACEi are superior to beta-blockers, diuretics, and calcium channel
blockers in reducing urinary albumin excretion in normotensive and
hypertensive T1 and T2D
• Treatment with an ACE inhibitor for 12 months has significantly reduced
mean arterial blood pressure and the urinary albumin excretion rate in
type 2 DM patients who have microalbuminuria
• In addition to beneficial cardiovascular effects, ACE inhibition shown
benefit on progression of diabetic retinopathy and development of
proliferative retinopathy
• Recommendation is to aim for BP 130/80 or lower. Almost all patients
will need more than one agent. Combination ACEi and ARB not
recommended
Standard of care in Diabetes-2015
(ADA position statement)
Specific management
• Intensive combined therapy
• Target the many factors underlying
disease
• Hyperglycaemia
• Hypertension
• Dyslipidaemia
Hyperlipidaemia
• Aggressive lipid lowering important part of medical
management all patients with diabetes
• High Lipid promote systemic atherosclerosis
• Contribute to glomerulosclerosis in CKD
• Lipid lowering may slow rate of progression of CKD including
diabetic nephropathy
• Less progression to microalbuminuria in patients on
fenofibrate treatment (DAIS) – possible mechanism
suppression of inflammation and decreased type 1 collagen
in mesangial cells
Kidney Int 2006;70:177; Am J Kidney Dis 2012; 60:896
Standard of care in Diabetes-2015
(ADA position statement)
Other complications
• Patients with nehropathy and T1D almost always have
other signs microvascular disease – retinopathy and
neuropathy
• Retinopathy can be detected clinically and typically
precedes onset of overt nephropathy
• Less clear in T2D, T2D with marked proteinuria and
retinopathy most likely have diabetic nephropathy, those
without retinopathy have high frequency of nondiabetic
glomerular disease
Clin Nephrol 2007; 67:293
Long term monitoring
• Regular outpatient follow-up
• Regular annual urinalysis is recommended for screening
for microalbuminuria
• Ensuring optimal glucose control
• Optimizing blood pressure
• Screening for other associated complications of diabetes
(eg, retinopathy, diabetic foot, cardiovascular disease)
• Referral to Diabetes renal clinic
Diabetes-Renal clinic at RBH
Intervene before too late!!
Diabetic nephropathy CKD 3
One-stop new patient clinic
To review and investigate accordingly
To develop individualised care plan for patients before
refer them back to primary care physician
ESRD/RRT – Nephrologist referral
Diabetic nephropathy….
• General management
• Specific management
• Long term follow-up
• Referral to specialist
Primary prevention
• Treat associated risk factors such as hyperlipidemia, smoking, and
hypertension (BP < 130/80 Hg)
• Early detection and optimal management of diabetes(HbA1c <
6.5%), especially in the setting of family history of diabetes
• Avoidance of potentially nephrotoxic substances such as NSAIDs
and aminoglycosides
• No evidence that ACEi or ARBs are effective for the primary
prevention of microalbuminuria in normoalbuminuric and
normotensive T1D. These patients should be screened yearly for
microalbuminuria and ACEi initiated if persistent moderately
increased albuminuria is documented