diabetic dyslipidemia and saroglitazar
TRANSCRIPT
![Page 1: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/1.jpg)
Dr. Vivek BaligaConsultant Internal Medicine
Managing Partner, Baliga Diagnostics
Atherogenic Diabetic Dyslipidemia
Emerging concepts
![Page 2: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/2.jpg)
Major contributors of CV risk due to dyslipidemia
High LDLHigh TGs and Low HDLHigh Non-HDL
Diabetes
![Page 3: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/3.jpg)
Non HDL-C
• Non HDL-C = Total Cholesterol - HDL-C • Encompasses all cholesterol present in potentially
atherogenic lipoprotein particles
– VLDL-C– IDL-C– LDL-C– Lp(a)
Adv Stu Med 2007; 7(1):8-11
![Page 4: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/4.jpg)
4
![Page 5: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/5.jpg)
Why Non HDL Cholesterol?
• For many years, achieving LDL-C targets was given prime importance in dyslipidemia management
• However, the risk of CAD remains high despite bringing down LDL levels.
• PROVE-IT TIMI 22 trial– Patients who achieved LDL levels below 67 mg/dL still
had a 22.7% event recurrence at 2 years.– Probably an underestimation
• Other factors surely play a role (DM, HTN, smoking etc.), but non-HDL cholesterol would also explain this ‘residual risk’
• LDL cholesterol contributes very little to estimating cardiovascular risk as compared to non-HDL cholesterol**
5
**Sniderman AD et al. A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B as
markers of cardiovascular risk. Circ Cardiovasc Qual Outcomes. 2011;4:337–345.
![Page 6: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/6.jpg)
Non HDL-C – is it a new metric??
• Helsinki Heart study (1986):-– Non HDL-C used as a lipid parameter.– 4081 men with non-HDL > 200 randomized to
Gemfibrozil and placebo.– Primary end points: fatal and non-fatal MI and
cardiac death– Results:
• Non HDL-C declined by 14% from baseline in treatment arm (fibrate).
• Incidence of coronary heart disease – 34% risk reduction in treatment arm compared to placebo (p<0.02).
6
![Page 7: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/7.jpg)
NCEP ATP III guidelines
• Lowering non HDL-C as a secondary goal when TG >=200 mg/dL.
• Target goal recommended for non HDL-C is 30 mg/dL above the LDL target for each NCEP risk category.
7
![Page 8: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/8.jpg)
Is Non-HDL-C a better marker than LDL?
• Better marker than LDL in both primary and secondary prevention• 68 study analysis
– Non-HDL – C is a better predictor amongst all cholesterol measure for both CAD and stroke.
• IDEAL trial– non-HDL – C and ApoB were best predictors of adverse
cardiovascular outcomes following ACS; LDL – C was not.• Amongst statin treated patients, non – HDL cholesterol is a better
marker of future cardiovascular events compared to LDL and apoB.• Non-HDL – C is easier to calculate, and does not require fasting
(unlike LDL)• Unfortunately still a neglected marker – NEPTUNE II survey
– 62% of patients reached LDL –C goal <100 mg/dL– Only 33% reached non-HDL – C goals
8
![Page 9: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/9.jpg)
Non HDL-C is a better indicator of residual risk than LDL-C
A meta-analysis 25 trials (n=131,134) on lipid lowering therapy suggested that
Non HDL-C modestly outperforms Apo-B for prediction of CVD
Am J Cardiol 2012;110: 1468–1476
![Page 10: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/10.jpg)
Non HDL-C and CV risk
Meta-analysis of data obtained from 62,154 statin treated patients enrolled in 8 trials published between 1994 and 2008
Boekholdt SM et al. JAMA. 2012;307(12):1302-1309
Patient = XYZLDL-C = 110
Non-HDL = 126TG = (non HDL – LDL) x 5
TG = 80
Relative risk of CV event= 2%
Patient = ABCLDL-C = 96
Non-HDL = 138TG = (non HDL – LDL) x 5
TG = 210
Relative risk of CV event =32%
![Page 11: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/11.jpg)
AACE 2013 – Diabetes Guidelines
AACE have once again re-iterated in 2013
Non HDL goal to be achieved with TG lowering therapy after achievement of
desirable LDL-C level
Non HDL-C targets are 30 mg/dL higher than established LDL-C risk levels ENDOCRINE PRACTICE 2013;19 (Suppl 2):1-48
![Page 12: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/12.jpg)
ADA 2014 – 15th June 2014
• The Utility of Non-HDL Cholesterol Levels Compared to LDL Levels for Targets in Diabetes Individuals
• 798 diabetes patients, currently taking lipid-lowering medication
• Average A1c was 8.0±2.6%. • Mean lipid levels were
– Total cholesterol of 150.6 mg/dL – HDL-C of 49 mg/dL– TG of 148 mg/dL, – LDL-C of 72.6 mg/dL and – non-HDL-C 101 mg/dL
12
![Page 13: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/13.jpg)
ADA 2014 – 15th June 2014
• Furthermore, 42.5%of those who reached the LDL-C target, did not reach the non-HDL - C target, yet all of those who reached the non-HDL-C target also reached the LDL-C target.
• These results suggest that using the non-HDL-C may be a better target for CVD risk reduction than the LDL-C when the TG are elevated.
13
TG above average (>150mg/dL)n=313
TG below average (<150 mg/dL)n=485
% of patients on LDL goal
61.7%
69.48%
% of patients on Non-HDL goal
35.5% 72.2%
% of patients on both goal
35.5% 67.4%
![Page 14: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/14.jpg)
The most recent – NICE lipid management guidelines draft
• ‘Before starting lipid modification therapy for the primary prevention of CVD, take at least 1 lipid sample to measure a full lipid profile’
• This should include measurement of TC, HDL-C,
Non HDL-C, and Triglyceride concentrations.
• A fasting sample is not needed.
14
LDL-C measurement is not required
![Page 15: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/15.jpg)
Major contributors of CV risk due to dyslipidemia
High LDLHigh TGs and Low HDL
High Non-HDLDiabetes
![Page 16: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/16.jpg)
The role of insulin resistance in diabetic dyslipidemia
16
Mooradian AD (2009) Dyslipidemia in type 2 diabetes mellitus Nat Clin Pract Endocrinol Metab doi:10.1038/ncpendmet1066
![Page 17: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/17.jpg)
Selby JV et al. Am J Manag Care. 2004;10(part 2):163-70.
Globally almost 7 out of 10 diabetics suffer from dyslipidemia
![Page 18: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/18.jpg)
This suggests that there are >55 millions patients of diabetic dyslipidemia in India
RM Parikh et al. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 4 (2010) 10–12
85.5%
Dyslipidemia
97.8 %
Dyslipidemia
85.5 %
Prevalence of Dyslipidemia (%) in Male T2 DM
Prevalence of Dyslipidemia (%) in Female T2DM
But in India, almost 9 out of 10 diabetics have dyslipidemia
![Page 19: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/19.jpg)
Diabetes is CHD equivalent: NCEP ATP III guidelines^
*Balkau B, et al. Lancet 1997; 350:1680. ^SM Grundy et al,Circulation. 2004;110:227-239
0
5
10
15
20
25
30
35
Control (non-diabetes)
Diabetes
Ratio 2.5 Ratio 2.2 Ratio 2.1
WhitehallStudy
Mor
talit
y ra
te(d
eath
s pe
r 1,0
00 p
atie
nt-y
ears
)
Paris ProspectiveStudy
Helsinki Policemen Study
N = 10087 N= 6908 N= 657
Mortality rate is doubled in individualswith diabetes*
![Page 20: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/20.jpg)
J Stamler et al, Diabetes Care February 1993:16:434-444
In dyslipidemia patients with diabetes, CV risk is heightened by 3-4 times as compared to dyslipidemia without diabetes
![Page 21: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/21.jpg)
Lancet. 2009;373:1765–1772
BENEFITS OF DUAL CONTROL OVER 5 YEARS
![Page 22: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/22.jpg)
Prospective, randomised, double-blind, placebo-controlled, study
5238 patients with type 2 diabetes (with macrovascular disease)
PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events)JA Dormandy et al,Lancet 2005; 366: 1279–89
End Point: Time to death, MI (except silent MI) and stroke
Follow up: 34.5 months
Baseline Values:TG – 160 mg/dL
Pioglitazone 15-45 mg(n=2605)
Placebo(n=2633)
Let’s understand what the PROactive trial about the benefits of glycemic control and CV outcomes through PPAR γ therapy
![Page 23: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/23.jpg)
JA Dormandy et al, Lancet 2005; 366: 1279–89
16% risk reduction
PPAR-γ agonist reduced CV end points (Death, MI, stroke) significantly (by 16%) in DM patients with baseline TG 160 mg/dL
![Page 24: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/24.jpg)
HR 0.8295% CI 0.72-0.94
P=0.005
Lincoff et al. JAMA 2007;298:1180-1188
Composite Events (Death, Nonfatal MI, Stroke)P
atie
nts
%
Pioglitazone Control
4.4%
5.7%
A meta analysis of 19 trials, 16,390 patients with T2DM suggested that PPAR-γ agonist agent reduces CV events by 18%
![Page 25: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/25.jpg)
So to control diabetic dyslipidemia effectively we need to address LDL, non-HDL
& glycemic parameters by additional measures apart from statins
Research in the 90s focused on PPARs for their role in metabolic disorders
![Page 26: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/26.jpg)
Diabetes. 2005 Aug;54(8):2460-70
Dual PPAR α/γ agonists can control dyslipidemia and in addition they also help to maintain glycemic control
![Page 27: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/27.jpg)
Why DUAL PPAR agonists?
Combined activation of PPAR α & γ is believed to induce
complementary and synergistic action on
– lipid metabolism
– insulin sensitivity
– inflammation control
![Page 28: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/28.jpg)
Combination therapy of PPARα & PPARγ agonists, results in reduction of TG & A1c levels without increasing body weight in T2DM patients
• In a study, obese, T2DM patients were treated with placebo for 2 months and then rosiglitazone (8 mg/day) + Fenofibrate (160 mg/day)(RGZ/FEB) or rosiglitazone (8 mg/day) (RGZ) alone for 2 months.
• RGZ/FEB was more effective and safe than RGZ alone
• RGZ/FEB lowered fasting plasma FFA more effectively than RGZ alone (22 vs. 5%, P < 0.05), and
• More effective than RGZ alone in lowering A1c (0.9 vs. 0.4%)and TG levels (38 vs. 5%)
• RGZ/FFB prevented the fluid retention usually associated with RGZ (1.6 vs. 5.6%, P < 0.05)
Boden G, et al. Diabetes 56:248–255,2007
Conclusion
![Page 29: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/29.jpg)
Change in body water with Rosiglitazone Vs Rosiglitazone + Fenofibrate
R/F: Rosiglitazone/FenofibrateR: Rosiglitazone Boden G, et al. Diabetes 56:248–255,2007
![Page 30: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/30.jpg)
The synergistic beneficial actions of balanced PPAR/ dual agonists
P. Balakumar et al. / Pharmacological Research 56 (2007)
![Page 31: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/31.jpg)
Saroglitazar is the world’s first approved dual PPAR-α/γ agonist
![Page 32: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/32.jpg)
Previous concerns
32
A balance must be achieved in both agonistic activities to reduce side effect profile
![Page 33: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/33.jpg)
A milestone in Indian history……
LIPAGLYNTM
A novel, first-in-class NCE with beneficial effects on both lipid and glycemic parameters
![Page 34: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/34.jpg)
PRESS VI TRIAL
PRESS V TRIAL
Published clinical trials of Saroglitazar
![Page 35: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/35.jpg)
Saroglitazar: PPAR- induced triglyceride lowering plus PPAR- induced glucose lowering
Level Fenofibrate (200 mg/day) 2
Saroglitazar1,*(4 mg/day)
Pioglitazone1 (45 mg/day)
HbA1c -- -0.3% -0.4%
Triglycerides -30.2% -45.0% -15.5%
HDL-C +4.5% +7.6%* +7.1%
LDL-C -11.9% -5.0% +4.8%
Non HDL-C -32.5%*
Apo B -32%*
1 PRESS V study, 2FIELD study (Lancet, 2005)* PRESS VI study DIABETES TECHNOLOGY & THERAPEUTICS; volume 16.
% Change from baseline
![Page 36: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/36.jpg)
Safety of Saroglitazar:PRESS V & PRESS VI studies
• Saroglitazar was found to be safe: – Cardiac parameters (ECG & 2D Echo)– LFT– RFT– CPK– Edema, weight gain
2-years preclinical studies:- no carcinogenicity
![Page 37: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/37.jpg)
Mr SN
• 43 yr old male with a +ve TMT and recent diagnosis of DM• CAG showed 2 vessel disease – PCI to distal RCA.• Bloods prior to PCI
– TC 221– HDL 28– LDL 129– TG 485– Non – HDL 193– VLDL 97– FBS – 164
• Commenced on usual therapy with 40mg Atorvastatin and Metformin
37
![Page 38: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/38.jpg)
Mr SN
• Lipaglyn 4mg daily commenced• 1 month later
• TC 180• HDL 42• LDL 100• TG -140• Non – HDL 138• VLDL 23• FBS 93
• Significant improvement• Metformin dose halved• Continues treatment – awaiting 3 month review.
38
![Page 39: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/39.jpg)
Mr JD 55yrs
• 7 yr h/o DM (A1c 7.2%), Stage II HTN, Obese.• Previous IHD and CABG.• Rx - Metformin, Glimipride, Aspirin, Statin, Beta blockers,
ARB. Previous side effects with fibrates.• Lipid Profile
o TC 230o HDL 44, LDL 126, VLDL 56o TG 280o Non HDL 182
![Page 40: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/40.jpg)
Treatment
• Started on Lipaglyn 4mg daily• 3 months lipid profile
o TC 190o HDL 50, LDL 88, VLDL 36o TG 180o Non HDL 140
o Yet to achieve targets – treatment continues.
![Page 41: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/41.jpg)
Mr S, 55yrs
• Type 2 DM, HTN, previous PCI (SVD)• Ex-smoker, clinically stable. BP 150/90• Beta blockers, statins, ARB, Aspirin+Clopidogrel.• No response to fibrates (years)• Lipids
o TC 180o HDL 40, LDL 90, VLDL 44o TG 220o Non-HDL 140
![Page 42: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/42.jpg)
Treatment
• 3 months post treatment on 4mg Lipaglyn o TC 174o HDL 50, LDL 74, VLDL 38o TG 190o Non-HDL 124
![Page 43: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/43.jpg)
To sum up
• CVD - growing epidemic in India with dyslipidemia being the most important risk factor and diabetes also contributes to increased CV risk
• Statin therapy alone still leaves a residual risk of 70-80%• High TG is an important factor contributing to residual risk
• Non HDL-C is a better indicator of residual risk than LDL-C
• Saroglitazar is a dual PPAR alpha/gamma agonist – effective in reducing High TG by 45%– Reduces Non HDL by 32%– Improves insulin sensitivity & glycemic parameters.• Statin plus saroglitazar is a comprehensive management of
Diabetic Dyslipidemia
![Page 44: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/44.jpg)
The future? My thoughts
• Applicability in non-diabetic dyslipidemia – Indian population are inherently insulin resistant
• Studies on effect on endothelial progenitor cells – NO mediated vasodilatation and athero-protection ? pleiotropism
• Long term studies looking at dual PPAR agonists and CV events in type 2 diabetic patients
44
![Page 45: Diabetic dyslipidemia and Saroglitazar](https://reader036.vdocument.in/reader036/viewer/2022081420/58eec6fc1a28ab4d348b45d1/html5/thumbnails/45.jpg)
Thank you for listening
45