Dyslipidemia in DM & CKD:

are all statins the same?

Syakib Bakri
1
Krikorian A, Chaiban JT. Diabetes and Kidney Disease. Springer. 2014: 141-152

2
ACC/AHA guidelines: Statin doses for high-, moderate-
and low intensity statin therapy

Bold type indicates doses evaluated in RCTs; italic type indicates statins and
doses approved by the FDA but not tested in the RCTs
reviewed in the guideline
• *Should be used in patients unable to tolerate moderate-to-high-intensity therapy (where indicated)
• Asian ancestry may influence the initial choice of statin intensity
• bid, twice daily; ESC, European Society of Cardiology
Stone NJ, et al. J Am Coll Cardiol 2014;63:2889–2934
3
Do statins (High Intensity especially) offer
cardiovascular protection in patients with CKD
and diabetes?

• Two approaches:

 To reduce the CVD burden in CKD & Diabetes patients

– In predialysis
– In dialysis

 To slow down / reduce CKD progression in CKD & Diabetes

patients in the context of Renal Safety

4
TNT Study Design

PATIENT POPULATION PRIMARY EFFICACY

OUTCOME MEASURE
– CHD
• Time to occurrence of a major CV event
– LDL: 130–250 mg/dL (≈3.4–6.5 mmol/L)
– CHD death
– TG: ≤600 mg/dL (≈6.8 mmol/L)
– Nonfatal, non-procedure-related MI
– Resuscitated cardiac arrest
Baseline
– Fatal or nonfatal stroke
Screening and
Open-label run-in
washout Double-blind period
n=15,464 n=10,001
n=18,469
LDL: <130 mg/dL
n=5006
Atorvastatin Atorvastatin 10 mg
10 mg LDL target: 100 mg/dL

n=4995
Atorvastatin 80 mg
LDL target: 75 mg/dL

1–8 Weeks 8 Weeks Median follow-up = 4.9 years

LaRosa JC et al. N Engl J Med 2005;352:1425–1435

5
 TNT: Time to first major CV event—
CHD patients with and without CKD
Patients with CKD* at baseline
Atorvastatin 10 mg (n=1505): End-of-Tx LDL = 99 mg/dL (≈2.6 mmol/L) 32%
14
Atorvastatin 80 mg (n=1602): End-of-Tx LDL = 79 mg/dL (≈2.1 mmol/L) RRR
Patients with major cardiovascular

HR = 0.68
Patients with normal eGFR at baseline (95% CI:
0.55–0.84)
12 Atorvastatin 10 mg (n=3324): End-of-Tx LDL = 102 mg/dL P=0.0003
(≈2.6 mmol/L) NNT=24

10 Atorvastatin 80 mg (n=3225): End-of-Tx LDL = 80 mg/dL

(≈2.1 mmol/L)
events (%)

6
15%
RRR
HR = 0.85
4 (95% CI:
0.72–1.00)
P=0.049
NNT=74
2

0
0 1 2 3 4 5 6
Time (years)

*eGFR <60 mL/min/1.73 m2 Reprinted from J Am Coll Cardiol, 51, Shepherd J et al, Intensive Lipid Lowering With
NNT, number needed to treat to prevent one Atorvastatin in Patients With Coronary Heart Disease and Chronic Kidney Disease, 1448–1454.
major cardiovascular event over 5 years Copyright (2008), with permission from Elsevier 6
 TNT: Effect of high- vs moderate-intensity atorvastatin on
major CV events in patients with CHD, diabetes and CKD

Major CV events*

Atorvastatin 10 mg (n=273). Mean LDL-C during study 99 mg/dL (≈2.5 mmol/L)

25
major cardiovascular event (%)

Atorvastatin 80 mg (n=273). Mean LDL-C during study 75 mg/dL (≈1.9 mmol/L)

20
35%
Patients with

RRR
15 HR=0.65
95% CI
0.43–0.98
(p=0.04)
10 ARR 7%
NNT 14
over 4.8 years
5

0
0 1 2 3 4 5 6
Time (years)

CKD defined as eGFR <60 mL/min/1.73m2

*Primary endpoint: Death from CHD, nonfatal non– Reprinted from Mayo Clin Proc, 83, Shepherd J et al. Intensive Lipid Lowering With Atorvastatin in Patients
procedure-related myocardial infarction, resuscitation With Coronary Artery Disease, Diabetes, and Chronic Kidney Disease, 870–879. Copyright (2008), with
after cardiac arrest, or fatal or nonfatal stroke permission from Elsevier 7
 Statins in ESRD Patients (haemodialysis): 4D and
AURORA , Kaplan-Meier estimate of time to first
major CV event
4D AURORA
primary composite end point (%)

60 40
Cumulative incidence of the

Cumulative incidence of the

primary end point (%)
50 Placebo 35 Placebo
30
40
25
Rosuvastatin
30 Atorvastatin 20

20 15
Hazard ratio, 0.92 Hazard ratio, 0.96
10
10 95% CI 0.77–1.10 95% CI 0.84–1.11
P=0.37 5 P=0.59
0 0
0 1 2 3 4 5 6 0 1 2 3 4 5
Year Years
No. at Risk No. at Risk
Placebo 636 532 383 252 136 51 Placebo 1384 1163 952 809 534 153
19 Rosuvastatin 1390 1152 962 826 551 148
Atorvastatin 619 515 378 252 136 58
29
Annual mortality rate 12% 13.7%

From New Engl J Med, Wanner C, et al. Atorvastatin in patients From New Engl J Med, Fellström BC, et al. Rosuvastatin and
with type 2 diabetes mellitus undergoing hemodialysis, 353., cardiovascular events in patients undergoing hemodialysis, 360.,
238–248. Copyright © (2005) Massachusetts Medical Society. 1395–1407. Copyright © (2009) Massachusetts Medical Society.
8
Conclusion (CV protection)

 Statins offer CV protection in different CKD stages

 There is an indication that statins offer less protection

with declining renal function

 The reason for this attenuating effect of renal dysfunction

on statin CV protection remains unclear. It may have to
do with the different lipid abnormality profile of late stage
renal disease 1

1. Massy Z, de Zeeuw D. Kidney Int 2013;84:451–456.

9
Do statins (High Intensity especially) offer
cardiovascular protection in patients with CKD
and diabetes?

• Two approaches:

 To reduce the CVD burden in CKD & Diabetes patients

– In predialysis
– In dialysis

 To slow down / reduce CKD progression in CKD & Diabetes

patients in the context of Renal Safety

10
 CARDS
Renal analysis
Helen Colhoun, John Betteridge, et al

Colhoun HM et al American Journal of Kidney

Diseases. 54 (5). November 2009. 810-819
11
 CARDS: Type 2 diabetes outcomes trial
CARDS was a multicenter, randomized, double-blind study

Patient population
 Type 2 diabetes, no
clinically evident Atorvastatin 10 mg/day
CHD
 ≥1 other CHD risk
factor (smoking, n=2838
HTN, albuminuria,
retinopathy) Placebo
 LDL-C ≤160 mg/dL
 TG ≤600 mg/dL
 Aged 40–75 years 3.9-year median follow-up

 Primary endpoint: Time to first occurrence of a major CV event, defined as

acute CHD events (ie MI including silent MI, unstable angina, acute fatal CHD,
resuscitated cardiac arrest), coronary revascularization, or stroke

12
CARDS, Collaborative AtoRvastatin Diabetes Study Colhoun HM, et al. Lancet. 2004;364:685–696
CARDS renal analysis :
Atorvastatin was significantly effective at
decreasing CVD in Diabetics with or without a
moderately reduced eGFR, bigger risk reduction
seen on reduced eGFR patient

Endpoint Patients eGFR Risk Reduction p value

Status (mL/min)
Major CVD >60 35% 0.01

<60 42% 0.03

Stroke >60 40% 0.1

<60 61% 0.04

Colhoun HM et al American Journal of Kidney Diseases. 54 (5). November 2009. 810-819

13
CARDS renal analysis :
Atorvastatin significantly reduces CV events in
patients with diabetes and albuminuria

Atorvastatin on Kidney Outcomes and CV Outcomes in Patients with Diabetes: CARDS

Subanalysis
Endpoint Albuminuria at Risk Reduction p value
baseline
Major CV Event yes 41% 0.04
no 36% 0.007

Colhoun HM et al American Journal of Kidney Diseases. 54 (5). November 2009. 810-819

14
CARDS renal analysis: Atorvastatin preserved the kidney
function in patients with microalbuminuria at baseline
4

3
Atorvastatin
Normoalbuminuric
Change in eGFR

2
Placebo
1 Normoalbuminuric

-1 Atorvastatin
Albuminuric
Beneficial effect of atorvastatin
-2 on eGFR was observed in
p=0.03
Placebo
subjects with albuminuria
Albuminuric
p=0.03
(P=0.03). CVD reduction with
-3
atorvastatin was observed in
patients with or without a
-4 decreased eGFR.
Baseline Year 1 Year 2 Year 3 Year 4
Colhoun HM et al American Journal of Kidney Diseases. 54 (5). November 2009. 810-819 15
Effect of Intensive Lipid Lowering with
Atorvastatin on Renal Function in Patients with
Coronary Heart Disease: The Treating to New
Targets (TNT) Study

James Shepherd,* John J.P. Kastelein,† Vera Bittner,‡ Prakash Deedwania,§ Andrei
Breazna,Stephen Dobson,¶ Daniel J. Wilson,** Andrea Zuckerman,** and Nanette
K. Wenger,†† forthe Treating to New Targets Investigators*

J Am Coll Cardiol. 2008;51:1448-1454.

16
 Percent change from baseline eGFR in TNT patients
by CKD status
12 CKD patients
Atorvastatin 80 mg
10 Atorvastatin 10 mg
Patients with normal eGFR
LS Mean % change from

8 Atorvastatin 80 mg
Atorvastatin 10 mg
baseline eGFR

2 P<0.0001 for all comparisons of

atorvastatin 80 mg vs 10 mg
0

-2
Baseline 12 24 36 48 60
Study visit (months)
CKD 3107 3040 2955 2806 2681 2264
Normal eGFR 6549 6387 6207 5980 5779 5030

Mean changes from baseline with atorvastatin 10 mg

and 80 mg at the final visit (LOCF) were +6.6% and Renal Function in Patients with Coronary Heart Disease: The Treating to New Targets (TNT) Study, Shepherd
+9.9% in CKD patients (P<0.0001), and +5.2% and +7.6% J et al, 2, 2007
in patients with normal eGFR (P<0.0001). 17
Are all High Intensity Statins the same in Renal effect &
safety in patients with Diabetes & CKD?

 All the studies to date show variability in their results for both CV
protection as well as renal effect / safety with statins in CKD or dialysis
patients

 In these older studies different statins were used.

 No studies have up to now focused on comparing the effect of two statins.

 The PLANET studies looked at the effect of two statins (although no direct
comparison was pre-specified) on renal parameters

18
 PLANET I and II investigated the effects of atorvastatin and
rosuvastatin on renal function
in patients with CKD with and without diabetes
PLANET I and II were multicenter, randomized, double-blind studies

Patient population 52 weeks follow-up

PLANET I
 Type I or II diabetes
Rosuvastatin 40 mg/day
PLANET II
 No diabetes PLANET I: n=325*
Both studies PLANET II: n=220*
Rosuvastatin 10 mg/day
 Moderate proteinurea1
 Hypercholesterolemia2 Atorvastatin 80 mg/day
 ACEis or ARBs for ≥3
months prior to screening

 Primary endpoint: Within-group change in urinary protein/creatinine ratio (UPCR) from

baseline to Week 52 or last on-treatment observation carried forward (Week 52 LOCF)

*Intention-to-treat (ITT) populations

1.Urinary protein/creatinine ratio 500–5,000 mg/g;
2.Fasting LDL-C ≥90 mg/dL (2.33 mmol/L);
ACEi, angiotensin converting enzyme inhibitor; De Zeeuw D, et al. Lancet 2015. http://dx.doi.org/10.1016/S2213-
ARB, angiotensin receptor blocker 8587(14)70246-3 19
 PLANET I and II: Study Endpoints, Key Exclusion Criteria

 Primary endpoint
 Within-group change in urinary protein / creatinine ratio (UPCR) from baseline to Week
52 or last on-treatment observation carried forward (Week 52 LOCF)

 Secondary endpoints
 Within-group change in UPCR from baseline to Week 26
 Within-group change in eGFR predicted from the modified MDRD equation from
baseline to Weeks 26 and 52
 Within-group change in urinary albumin / creatinine ratio (UACR) from baseline to
Weeks 26 and 52
 Within-group change in lipid levels from baseline to Weeks 26 and 52

 Exclusion criteria: HbA1c >11% ; History of statin intolerance, statin-induced myopathy, or serious
hypersensitivity reaction to other statins ; Homozygous FH ; Asian ethnic origin (because of the altered
Pharmacokinetic; a rise in plasma concentration with high dosage of rosuvastatin in Asian patients
with CKD was not appropriate) ; Significant kidney disease

eGFR, estimated glomerular filtration rate; LOCF, last

observation carried forward; MDRD, Modification of De Zeeuw D, et al. Lancet 2015. http://dx.doi.org/10.1016/S2213-
Diet in Renal Disease 8587(14)70246-3 20
PLANET I and II: Important considerations for
interpretation of results
 Decrease in urine protein/creatinine ratio or urine albumin/creatinine
ratio indicates improvement in renal function1
 Decrease in eGFR indicates worsening renal function1
 Smaller decreases in eGFR in CKD+DM indicate preservation of renal
function1
 PLANET paper2 includes atorvastatin vs rosuvastatin comparisons,
with p-values, but:
 Studies were designed and powered to estimate within-group
effects
 Comparisons between atorvastatin and rosuvastatin should be
interpreted with caution
 Trial had no placebo group as was considered unethical in this patient
population

1. KDIGO CKD Work Group. Kidney Int 2013; Suppl. 3: 1–150;

2. de Zeeuw D, et al. Lancet Diabetes Endocrinol 2015;3:181–190;
http://dx.doi.org/10.1016/S2213-8587(14)70246-3
21
 Primary and Selected Secondary Outcomes for PLANET I and for PLANET II, and
Exploratory post-hoc Outcomes for PLANET I and II Combined

De Zeeuw D, et al. Lancet Diabetes Endocrinol. 2015. 22

PLANET I: Effect of atorvastatin or rosuvastatin on
urinary protein/creatinine ratio
Rosuvastatin 10 mg
1.4 Rosuvastatin 40 mg
Atorvastatin 80 mg
UPCR (Baseline: on-treatment)

1.2

1.0 p=0.83
p=0.53
p=0.033
0.8

0.6
0
0 14 26 39 52 LOCF
Number of patients Time (weeks)
Rosuvastatin 10 mg 107 103 97 96 95 107
Rosuvastatin 40 mg 116 112 107 106 106 116
Atorvastatin 80 mg 102 96 91 88 82 102

Data are mean baseline: on-treatment ratios

Error bars are 95% CIs. LOCF marks 52-week data accounting for all
patients in ITT population Reprinted from The Lancet, 3, de Zeeuw D, et al, Renal effects of
LOCF, last observation carried forward; UPCR, urinary atorvastatin and rosuvastatin in patients with diabetes who
protein/creatinine ratio have progressive renal disease (PLANET I): a randomised clinical
p values are vs baseline trial, 181–190. Copyright (2015), with permission from Elsevier 23
 24
PLANET I: Effect of atorvastatin or rosuvastatin on
estimated glomerular filtration rate
Rosuvastatin 10 mg
2 Rosuvastatin 40 mg
Atorvastatin 80 mg
0
(mL/min per 1.73 m2)

p=0.21
Change in eGFR

–2

–4

–6
p=0.0098
p=0.0002
–8

–10
0 4 8 14 26 39 52 LOCF
Number of patients Time (weeks)
Rosuvastatin 10 mg 107 106 104 103 99 95 95 107
Rosuvastatin 40 mg 116 115 112 111 109 104 109 116
Atorvastatin 80 mg 102 99 98 97 92 86 86 102

Data are mean changes from baseline

Error bars are 95% CIs. LOCF marks 52-week data accounting for all
patients in ITT population Reprinted from The Lancet, 3, de Zeeuw D, et al, Renal effects of
eGFR, estimated glomerular filtration rate; LOCF, last observation atorvastatin and rosuvastatin in patients with diabetes who
carried forward have progressive renal disease (PLANET I): a randomised clinical
p values are vs baseline trial, 181–190. Copyright (2015), with permission from Elsevier 24
 PLANET I & II : Conclusions

 In people with proteinuria with diabetes (PLANET I) or without

diabetes (PLANET II):
 Atorvastatin 80 mg reduced proteinuria; rosuvastatin 10 or 40
mg had no effect
 Atorvastatin 80 mg had no effect on eGFR; rosuvastatin 10 or
40 mg reduced eGFR
 Doubling of serum creatinine and acute renal failure were more
common with rosuvastatin
 Results suggest that atorvastatin and rosuvastatin have different
renal profiles

 According to the authors, atorvastatin seems to have more

renoprotective effects for the studied CKD population

De Zeeuw D, et al. Lancet 2015.http://dx.doi.org/10.1016/S2213-8587(14)70246-3

25
What is new in 2017?
Atorvastatin VS Rosuvastatin renal safety in Asian DM patients
using lower dosage (moderate intensity dose)

Han E, et al. Endocrinol Metab 2017;32:274-280

26
 Background
• Hyperglycemia and dyslipidemia is an important risk factor for renal function loss
• When DM and Dyslipidemia co-occur  risk of CKD is synergistically increased

Research Study shown that statins have the potential to protect kidney via anti-
inflammatory and anti-proliferative pathway
How about the effect of statin in Diabetic Asian Patient on kidney function in clinical practice?
1. Han E, et al. Endocrinol Metab 2017;32:274-280 ;2. Campese VM, Park J. Kindney Int 2007;71:1215-1222 27
Methods

Patient Population Baseline: End of Study:

• FBG, HbA1C • FBG, HbA1C
• Lipid profile (TC, LDL-C, • Lipid profile (TC, LDL-C,
• Aged ≥ 20 years HDL-C, Triglyceride) HDL-C, Triglyceride)
• Diabetes Mellitus • eGFR • eGFR
• Naïve and started
moderate-intensity
statin
Atorvastatin 10 – 20 mg/day
484 patients
Rosuvastatin 5 – 10 mg/day
Primary Endpoint

• Change in eGFR
• Rapid renal decline - 12 months
>3% reduction in eGFR Clinical Parameter at baseline:
• Age, sex, height, weight eGFR : estimated GFR; FBG : fasting Blood Glucose;
• Duration of DM TC : Total Cholesterol; DM : Diabetes Mellitus; HTN :
Hypertension
• History of HTN and cardiac
disease
• Statin treatment information Han E, et al. Endocrinol Metab 2017;32:274-280

28
Han E, et al. Endocrinol Metab 2017;32:274-280

29
 Primary Endpoint : Change in eGFR

eGFR Reduction
eGFR Change
Atorvastatin Rosuvastatin
81
80.3 0
80
79.1 -0.5
79 * 78.7
mL/min/1.73m2

78 -1

77 -1.5
76.1 -1.6 *
76 **
-2
75
-2.5
74
Baseline 12 months
-3 **
* p = 0.012 -3
** p = 0.01 Atorvastatin Rosuvastatin

• Among all patients, eGFR was slightly decreased from 79.8 to 77.7 mL/min/1.73m 2 (P<0.001)
• There was a greater reduction of eGFR in rosuvastatin-treated group compared to
atorvastatin
Han E, et al. Endocrinol Metab 2017;32:274-280 30
Renal Function Decline
Renal Function Decline
P = 0.029

50.0%
45.0%
40.0%
35.0%
30.0%
48.7%
25.0%
20.0% 36.8%
15.0%
10.0%
5.0%
0.0%
Atorvastatin Rosuvastatin

• More individuals receiving rosuvastatin treatment experienced rapid renal function

decline than those receiving atorvastatin treatment.
• After adjusting confounding factors : compared with atorvastatin, rosuvastatin
treatment increased risk for rapid renal function loss by approximately 60% (OR,
1.60; 95% CI, 1.06 to 2.42)
Han E, et al. Endocrinol Metab 2017;32:274-280
31
 Other Parameters

The proportion of individuals who achieved an LDL-C response (>30% reduction) was similar
between the statin groups (52% and 59.6% for atorvastatin and rosuvastatin, respectively,
P=0.115)
Han E, et al. Endocrinol Metab 2017;32:274-280 32
Discussion

 There is increasing evidence that statin have reno-protective effect.

However renal outcome according to statin potency is more controversial.

 Regarding statin types and renal function, atorvastatin seems to be more

beneficial than rosuvastatin

 Although differences between mechanism in kidney function remains

unknown, previous study demonstrated
 greater decrease in serum uric acid level with atorvastatin than with
rosuvastatin treatment
 Increased endothelial function and renal blood flow on atorvastatin

1. Massy Z, de Zeeuw D. Kidney Int 2013;84:451–456.

33
 TAKE HOME MESSAGES (1)

• CKD patients have a greater risk for CV events

• Pre-dialysis CKD patients should use statin therapy for

cardiovascular protection

• Going into dialysis, statin therapy should not be stopped

• One could question whether one should start statin

therapy in dialysis patients that are statin-naïve

• The choice of the statin appears to matter, not all high

intensity statins are the same in renal safety

34
 TAKE HOME MESSAGES (2)

 ATV and RSV has similar result in lipid lowering effects in diabetic CKD
and non-diabetic CKD.

 However, at similar level of lipid profile, ATV shown greater

renoprotective effects (reducing microalbuminuria/proteinuria and
progression of CKD) than RSV.

35
THANK YOU

36
37
 PLANET I

 For PLANET I (diabetic patients): “ATV significantly reduces the

proteinuria in these patients on top of ACE/ARB therapy, with around
a 15% reduction in proteinuria, whereas RSV, both 10 and 40 mg, had
no significant effect at all on proteinuria.”

 The effect of ATV was evident by week 26 and continued through

week 52, but neither RSV dose lowered proteinuria at either time
point

38
 PLANET II

 In PLANET II (the nondiabetic cohort): ATV reduced proteinuria by

more than 20% at 26 and 52 weeks, but there was no significant
effect with either dose of RSV. The results for albuminuria were very
similar to those for proteinuria.

39
 PLANET I and PLANET II

 For eGFR: patients on RSV lost more kidney function over 52 weeks
than did those on ATV. Patients on ATV lost about 1 to 2 mL/min per
1.73 m2 over 52 weeks, those on RSV 10 mg/day lost about 4 mL/min
per 1.73 m2, and those on RSV 40 mg/day lost close to 8 mL/min per
1.73 m2.

 In nondiabetic patients (PLANET II), the effects of the treatments on

kidney function were slightly less pronounced. There was a significant
decline in eGFR with RSV 40 mg/day but not in the other 2 treatment
groups.
 The differential effects on proteinuria and eGFR in the treatment
groups was not a result of differences in lipid lowering. All the
treatments lowered total and LDL cholesterol, and there were no
significant differences in the amount of lipid lowering.

40
 PLANET I and PLANET II : CONCLUSION

In diabetic and nondiabetic patients with proteinuria, using optimal

therapy, including ACE inhibitors and ARBs:

 ATV 80 mg/day significantly reduced proteinuria by about 20%;

 RSV 10 or 40 mg/day had no effect on proteinuria;
 RSV 40 mg/day was associated with a significant decline in eGFR of
about 8 mL/min per 1.73 m2 per year;
 ATV 80 mg/day had no effect on eGFR;
 ATV 80 mg/day has a clear advantage over RSV 40 mg/day in terms of
renal protection and renal damage.

41
 PLANET I and PLANET II

 The two randomized double-blind multinational PLANET trials tested

the effects of Atorvastatin (ATV) 80 mg/day or Rosuvastatin (RSV) 10
or 40 mg/day on urinary protein excretion and renal function in
hypercholesterolemic patients with moderate proteinuria.

 PLANET I involved 325 patients with Type 1 or 2 diabetes, and

PLANET II involved 220 patients without diabetes in the intent-to-
treat populations. Patients had urinary protein/creatinine ratios of
500 to 5000 mg/g, a fasting low-density-lipoprotein (LDL)-cholesterol
level of 90 mg/dL or higher, and had used ACE inhibitors or ARBs for
at least 3 months prior to screening.
 Patients with severe renal disease, defined as an estimated
glomerular filtration rate (eGFR) below 40 mL/min per 1.73 m2, or
PLANET I patients with a hemoglobin A1c level above 11% were
excluded from the study, as were people with active liver disease.
42
43