Residual risk: Is LDL target enough?

An interpretation of the continuous relationship between LDL-C and CVD

Therefore, many men and most women with heart disease have lipid problems other than high total or LDL cholesterol that put them at risk for heart disease.

That there is no cut-off cholesterol number below which coronary heart disease cannot develop.

Edward F Gibbons MDEditor of New England Journal Medicine Heart Watch June 2001 Vol 5 #5 p3

Neovascularisation of vasa vasorum in unstable leisions: A source of plaque?

Normal High Cholesterol

High Cholesterol+ Simvastatin

Trial WOSCOP AFCAPS/ TexCAPS

HPS ASPEN CARDS 4S LIPID CARE TNTTotal

TNTMet S

TNTDiabetes

N 6.595 6.505 20.536 2.410 2.838 4.444 9.014 4.159 10.001

5.584 1.501

LDL-C -26% -27% -29% -29% -40% -36% -25% -28% -21% -24% -20%

75%75%62%

90%

73%62%70%

“Residual risk”: Percentage of Major CV Events in Patients on Therapy in statin trials

63%

82%72%

80%

Primary High Diabetics Secondary Aggressive LDL Lowering Risk (<1.8mmol/L -70 mg/dl)

The days of the statin “knee-jerk” are numbered

Residual risk on statin treatment in diabetes remains high(control Diabetic CVD rate set to = 100%)

0102030405060708090

100

4S LIPID HPS CARDS ASPEN

Placebo

0102030405060708090

100

4S LIPID HPS CARDS ASPEN

Placebo

statinNon-dbrisk

62%

78% 77%

64%

89%

HDL-C & TG remain predictive of CVD events even when LDL-C < 1.8 mmol/L: TNT & PROVE-IT

Barter P et al. NEJM 357:1301-10, 2007

On-Treatment Quintile of HDL-CIn Pts with LDL-C < 1.8 mmol/L

5 Y

r R

isk o

f M

ajo

r C

V E

ven

ts (

%)

12

10

8

6

4

2

0

Q1 Q2 Q3 Q4 Q5 (<38) (38<42) (42<46) (46<50) (>50)

Hazard Ratio vs Q1Q2 0.85Q3 0.57Q4 0.55Q5 0.61

+64%

≥2.3 mM/L(n=603)

< 2.3 mM/L(n=2796)

On-Treatment TGIn Pts with LDL-C < 1.8 mmol/L

20.3

13.5

30

-day r

isk o

f d

eath

, M

Ior

recu

rren

t A

CS

(%

)

RR 1.56 (1.28-1.89)p= 0.001

+56%

Miller et al. 2008

CV = cardiovascular

Adapted from Stamler J et al Diabetes Care 1993;16:434-444.

CV

mor

tali

ty p

er 1

0,00

0 pe

rson

-yea

rs

DiabetesNo diabetes

Total cholesterol (mmol/L)

0

20

40

60

80

100

120

140

<4.7 4.7–5.1 5.2–5.7 5.8–6.2 6.3–6.7 6.8–7.2 >7.3

160

Relationship between cholesterol and CVD mortality with and without diabetes

Statin (LIPID, HPS,

CARDS)

? Fibrate (FIELD)

FIELD2005

? HDLc, TG

Liver

IncreasedVLDL

Bloodstream

LDL

Dyslipidaemias Secondary to Hypertriglyceridaemia

Increased triglycerides

CETP

HDL

CETP

Hepatic lipase

Small, dense HDL

Small, dense LDL

Hepatic lipase

Rapid renal filtration of apo A-I

TG (> 1.5 mmol/l ?) drives cholesterol ester transfer via CETP :– 1) TG exchange reduces HDL-C

and impairs reverse cholesterol transport. TG and HDL-C levels are inversely correlated

– 2) TG exchange causes (pro-atherogenic) smaller, denser LDL. When TG is raised, LDL-C underestimates CVD risk.

– 3) Small, rather than large, TG-rich particles may carry cholesterol into the artery wall. The linear relationship between TG and CVD risk declines at very high levels

3

1Plasma Artery wall

2

How elevated triglyceride levels may damage the arterial wall

PROspective CArdiovascular Munster Study (PROCAM): Hypertriglycaeridemia

Eve

nts/

1000

in

8 y

ears

Assman, G et al., Am J Cardiol 1992;70:733-737

(157/3593) (84/903) (14/106)

TG (mmol/l)

0

20

40

60

80

100

120

140

<2.3 2.3-4.5 4.5-9.0 >9.0

44 93 132 81

(3/37)

An Independent Risk Factor For CAD

Dyslipidaemia (low HDL-C, high TG) is prevalent amongst high risk groups

• CCU: > 40% high TG, > 50% low HDLc

• ASPAC MI: 47% HDL-c < 1.0mM, 52% TG > 1.7mM

• T2DM: ~ 50% high TG, ~ 60% low HDLc

9 cis retinoic acid

RXR

Fenofibrate: PPAR α transcriptional activation -raises HDLc and lowers TG

PPAR Response Element

PPAR ligandEndogenous or synthetic

Promoter

Target Gene

DNA

Brown, Plutzky, Circulation, 2007

PPAR

PPAR-RXR complex

Fibrates regulate lipid metabolism…

Duval C, et al. Trends Mol Med. 2002;8:422-430.Lee CH, et al. Endocrinology. 2003;144:2201-2207.

Acyl-CoASynthase

Acetyl CoA

FFA

apo A-I

apo A-II

ABCA1

apo C-IIIApo A-V

TG

Liver Circulation

… by controlling the expressionof PPARtarget genes

Results

LPLReversal of CETP formation of small and dense LDLparticles

LDL

Increased VLDLClearance

Decreased VLDLProduction

VLDL

Increased HDLProduction

HDL

ABCG1

Decreased TGlevels

Comparison of ACCORD and FIELD subgroup results with those from prior fibrate studies

Trial(Drug)

Primary Endpoint: Entire Cohort (P-value)

Lipid Subgroup Criterion

Pre-specified Endpoint: Subgroup

HHS (Gemfibrozil) -34% (0.02)

TG > 200 mg/dlLDL-C/HDL-C > 5.0 -71%

BIP (Bezafibrate) -7.3% (0.24)

TG > 200 mg/dl -39.5%

FIELD(Fenofibrate) -11% (0.16)

TG > 204 mg/dlHDL-C < 42 mg/dl -27%

ACCORD(Fenofibrate) -8% (0.32)

TG > 204 mg/dlHDL-C < 34 mg/dl -31%

TGTG

VLDL-TGVLDL-TGFFA↓

HDL↑

VLDL ↓

CETP

Adipocyte

Liver

TGTG

FFAFFA

GPR109A

TG

CE

[cAMP]i↓[cAMP]i↓

A working hypothesis for niacin mechanism of action

OO

N

1: Inhibits hormone sensitive lipase

2: Inhibits DGAT 2

3: Hepatic lipase

McKenney J. Arch Intern Med 2004;164:697-705.Grundy SM, et al. Arch Intern Med 2002;162:1568-1576.

Brown BG. Am J Coll Cardiol 2007;99(suppl)6:32C-34C.

Niacin: Efficacy includes LDL-C reduction

• In patients with diabetes and mixed dyslipidaemia, Niacin has been shown to

• Increase HDL-C levels 15%-30%

• Decrease TG levels 15%-50%

• Have dose-dependent effects on LDL-C levels (up to 40%)

• Decrease lipoprotein(a) levels by 25%

• Decrease fibrinogen levels by 14%

• Decrease Lp-PLA2 by an additional 20% when added to statin therapy

Chesney C et al. Am Heart J. 2000;140-631-6.Kuvin J et al. Am J Cardiol 2006;98:743-745.

Steno 2: Multifactorial Intensive Intervention in Type 2 Diabetes

Percent of Patients Achieving Targets

Pat

ien

ts (

%)

P=0.06

P<0.001

P=0.19 P<0.001

P=0.21

Gaede et al. N Engl J Med 2003;348:383–393

0

20

40

60

80

100

HbA1c <

6.5%

Chol <4.5

mm

ol/L

TG<1.80 m

mol/

L

SBP<130 m

m H

g

DBP<80 m

m H

g

Intensive Conventional

Steno 2 CVD endpoints. 85 CVD events in 35 conventional patients (44%)versus 33 CVD events in 19 intensive patients (24%)

FIELD event rate: No longer ”coronary equivalent”, or only if prolonged?

12 24 36 48 60 72 84 960Months of follow-up

No. at risk

ConventionalIntensive 80

807278

7074

6371

5966

5063

4461

4159

1319

Hazard ratio 0.47 (0.24 to 0.73); p=0.007

Conventional

Intensive

Gæde P et al. N Engl J Med 2003;348:383-93

0.0

0.1

0.2

0.3

0.4

0.5

0.6

Pro

babi

lity

for

Pri

mar

y C

ompo

site

End

Poi

nt

Prevention of High-Risk and Recurrent Vascular Disease in 2012?

Primary Secondary• Fish/fish oils ?1B 1A• Fenofibrate 1A** 1A**• Statin 1A 1A• Aspirin small 1A• ACE-I/ARB 1A 1A• Beta-blocker 1A* 1A• Clopidogrel small 1B

** In dyslipidaemic subjects* in hypertension

Darapladib (opposite genetic paradigm)

Summary and link to cases

Mrs M. L.• This 56 year-old lady, who recently suffered a TIA, has a history of SVT, type

2 diabetes diagnosed 4 years ago, and hypertension treated from that point in time.

• Drug treatment includes Metformin 500 mg x 2 BD, Aspirin 100mg, enalapril 10 mg BD, indapamide 2.5 mg, atenolol 50 mg and maximal tolerated statin dose (simvastatin 40 mg)

• Her weight is 68 kg, BMI 28 kg/m2, • BP 155/98 mmHg

• Total cholesterol 5.4 mmol/l, fasting TG 3.9 mmol/l, HDL 1.1 mmol/l, calculated LDL 2.5 mmol/l.

• Urinary ACR is 4.2• HbA1C is 7.3%

Questions concerning Mrs M. L.

• Which aspect of her risk factor profile is of the greatest concern? A) BP and ACR B) Weight and BMI C) Total and LDL-C D) TG and HDL-C E) Plasma glucose and HbA1C

• Which aspect of her risk factor profile is most amenable to intervention? A) BP and ACR B) Weight and BMI C) Total and LDL-C D) TG and HDL-C E) Plasma glucose and HbA1C

• If refusal to take more than 1 extra tablet was a limitation, what would you do? A) Add an AII Receptor Blocker B) Add Ezetimibe

C) Add a Calcium Channel Blocker D) Add a sulphonylureaE) Add fenofibrate

• This 56 year-old lady, who recently suffered a TIA, has history of SVT, type 2 diabetes diagnosed 4 years ago, and hypertension treated from then.

• Drugs: Metformin 500 mg x 2 BD, Aspirin 100mg, enalapril 10 mg BD, indapamide 2.5 mg, atenolol 50 mg and maximal tolerated statin dose (simvastatin 40 mg)

• Weight is 68 kg, BMI 28 kg/m2, BP 155/98 mmHg, • Total cholesterol 5.4 mmol/l, fasting TG 3.9 mmol/l, HDL 1.1 mmol/l,

calculated LDL-C 2.5 mmol/l. • Urinary ACR is 4.2• HbA1C is 7.3%

Which aspect of her risk factor profile is of the greatest concern? A) BP and ACR B) Weight and BMI C) Total and LDL-C D) TG and HDL-C E) Plasma glucose and Hb A1C

• Which aspect of her risk factor profile is most amenable to intervention? A) BP and ACR B) Weight and BMI C) Total and LDL-C D) TG and HDL-C E) Plasma glucose and Hb A1C

• If refusal to take more than 1 extra tablet was a limitation, what would you do? A) Add an AII Receptor Blocker B) Add Ezetimibe

C) Add a Calcium Channel Blocker D) Add a sulphonylureaE) Add fenofibrate

Which aspect of her risk factor profile is of the greatest concern?

A) BP and ACR

B) Weight and BMI

C) Total and LDL-C

D) TG and HDL-C

E) Plasma glucose and HbA1C

Which aspect of her risk factor profile is of the greatest concern?

The case for “B” overall (others individually)

DietPhysical activity/

fitnessSocioeconomic

statusBirth size,

childhood growthGenes

Hypertension

METABOLIC

SYNDROME

Hypercoagulability,impaired fibrinolysis

Hypoandrogenism (men),Hyperandrogenism (women)

Endothelial dysfunction

Hyperuricemia

Adipose hormones

Inflammation

Abdominal obesity/Ectopic fat deposition

Insulin resistance/Hyperinsulinemia

Overweight

Diabetes CVD

Dyslipidemia• Low HDL, high TG• High ApoB, low Apo A• Small dense LDL

Elevated fasting or2-h post-load glycemia

Which aspect of her risk factor profile is most amenable to intervention?

• A) BP and ACR

• B) Weight and BMI

• C) Total and LDL-C

• D) TG and HDL-C

• E) Plasma glucose and Hb A1C

Which aspect of her risk factor profile is most amenable to intervention? The case for “D”

•  The three specific primary ACCORD hypotheses were as follow. In middle-aged or older people with type 2 diabetes who are at high risk for having a cardiovascular disease (CVD) event because of existing clinical or subclinical CVD or CVD risk factors:• does a therapeutic strategy that targets a HbA1c of < 6.0% reduce the

rate of CVD events more than a strategy that targets a HbA1c of 7.0% to 7.9% (with the expectation of achieving a median level of 7.5%) ?

• in the context of good glycaemic control, does a therapeutic strategy that uses a fibrate to raise HDL-C/lower triglyceride levels and uses a statin for treatment of LDL-C reduce the rate of CVD events compared to a strategy that only uses a statin for treatment of LDL-C?

• In the context of good glycaemic control, does a therapeutic strategy that targets a systolic blood pressure (SBP) < 120 mm Hg reduce the rate of CVD events compared to a strategy that targets a SBP of < 140 mm Hg?

If refusal to take more than 1 extra tablet was a limitation, what would you do?•

A) Add an AII Receptor Blocker

B) Add Ezetimibe

C) Add a Calcium Channel Blocker

D) Add a sulphonylurea

E) Add fenofibrate

If refusal to take more than 1 extra tablet was a limitation, what would you do?

The case for “E”Trial(Drug)

Overall Effect1ry EP (P-value)

Lipid Subgroup Subgroup Effect1ry EP (P-value)

HHS (Gemfibrozil)

-34%(0.02)

TG > 200 mg/dlLDL-C/HDL-C > 5.0

-71%(p=0.005)

BIP (Bezafibrate)

-7.3%(0.24)

TG > 200 mg/dl -39.5%(p<0.01)

VA-HIT(Gemfibrozil) -22%

(0.006)Diabetes

-32%(p=0.004)

FIELD(Fenofibrate)

-11%(0.16)

TG > 204 mg/dlHDL-C < 42 mg/dl

-27% (p=0.005) (31%*; 0.002*)

ACCORD(Fenofibrate)

-8%(0.32)

TG > 204 mg/dlHDL-C < 34 mg/dl

-31% (p=0.03)

Mrs M. L.• You cheat. You replace her Enalapril and Indapamide with a higher dose combination

agent and replace her simvastatin with a tolerable dose of the atorvastatin felodipine combination. (or change her metformin 500 mg ii bd to I g bd or Metformin XR daily)

• Having done so, this leaves room to add Fenofibrate 145 mg/day.

• Repeat results reveal : weight is 65 kg (3kg decrease), BP 125/85, • Total cholesterol 4.4 mmol/l, fasting TG 1.9 mmol/l, HDL 1.4 mmol/l, calculated LDL

2.1 mmol/l. • Urinary ACR is 3.2 and HbA1C is 7.1%.

More questions concerning Mrs M. L.

• Fenofibrate may have contributed towards:

A) Weight loss B) Lower BP C) Lower HbA1C

• Fenofibrate lowers which 1 of the following

A) Homocysteine B) Serum Creatinine C) Fibrinogen

• Fenofibrate also increases which 1 of the following A) LDL particle size B) Urinary ACR C) Urate

• The lipid changes associated with fenofibrate use predict its ability to protect against A) Retinopathy B )Neuropathy C) Nephropathy D) Amputation

• You cheat. You replace her Enalapril and Indapamide with a higher dose combination agent and repalce her simvastatin with a tolerable dose of the atorvastatin felodipine combination.

• Having done so, this leaves room to add Fenofibrate 145 mg/day. • Repeat results reveal : weight is 65 kg (3kg decrease), BP 125/85, • Total cholesterol 4.4 mmol/l, fasting TG 1.9 mmol/l, HDL 1.4 mmol/l, calculated LDL

2.1 mmol/l. Urinary ACR is 3.2 and HbA1C is 7.1%.

• Fenofibrate may have contributed towards: A) Weight loss B) Lower BP C) Lower HbA1C

• It lowers which 1 of the following A) Homocysteine B) Creatinine C) Fibrinogen

• It also increases which 1 of the following A) LDL particle sizeB) Urinary ACR C) Urate

• The lipid changes associated with fenofibrate use predict its ability to protect against A) Retinopathy B )Neuropathy C) Nephropathy D) Amputation

Fenofibrate may have contributed towards:

• A) Weight loss

• B) Lower BP

• C) Lower HbA1C

Fenofibrate may have contributed towards:The case for “B”

0

5

10

15

20

25

30

Lipid-lowering *

Antithrombotic

ACEinhibitor*

ARB β blocker* Ca++antagonist

Digoxin* Nitrate Diuretic*

BP (mm Hg)

Plac Feno

Weight (kg)

Plac Feno

Study entry

Study end

140/82 140/82

138/78 136/77

86 86

86 86

- 2 /1 mmHg P=0.001

Fenofibrate lowers which 1 of the following

• A) Homocysteine

• B) Serum Creatinine

• C) Fibrinogen

Fenofibrate lowers which 1 of the followingThe case for “C”

Biochem Inflammation Oxidation Obesity/db Thrombosis

Cystatin C Hs-CRP Ox LDL Adiponectin tPA activity

Uric acid VCAM-1 Ox PL Leptin PAI 1

NTproBNP ICAM-1 lmw AGEs resistin D-dimer

ANP IL6 MPO Apo CIII Fibrinogen

– 11%

Adrenomed IL10 LpPLA2 Apo E VWF

Neopterin IL18 HbA1c Tissue factor

Creatinine

+ 13%

sTNF Rc insulin TF inhibitor

HCYS + 40% SAA C peptide

Ur ACR TIMP 1

Fenofibrate also increases which 1 of the following

• A) LDL particle size

• B) Urinary ACR

• C) Urate

Fenofibrate also increases which 1 of the following?

The case for “A”

Lemieux I, Laperrière L, Dzavik V, Tremblay G, Bourgeois J, Després JP, Atherosclerosis 2002, 162:363-371

RESULTS: Whereas significant improvements in the plasma lipoprotein-lipid variables were observed with both fenofibrate and pravastatin treatments, LDL peak particle size was only significantly increased withfenofibrate therapy (+2.11+/-5.18 A, P<0.05). Among patients under fenofibrate therapy, changes in TG levels were negatively associated with changes in LDL peak particle size (r=-0.54, P<0.0007)

The lipid changes associated with fenofibrate use predict its ability to protect against

• A) Retinopathy•

• B) Neuropathy •

• C) Nephropathy•

• D) Amputation

The lipid changes associated with fenofibrate use predict its ability to protect against?

The case for “ C”

Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study.Davis TM, Ting R, Best JD, Donoghoe MW, Drury PL, Sullivan DR, Jenkins AJ, O'Connell RL, Whiting MJ, Glasziou PP, Simes RJ, Kesäniemi YA,Gebski VJ, Scott RS, Keech AC; Fenofibrate Intervention and Event Lowering in Diabetes Study investigators.Diabetologia. 2011;54:280-90.

Greater preservation of estimated GFR with fenofibrate was observed with baseline hypertriacylglycerolaemia (n = 169 vs. 491 without) alone, or combined with low HDL-cholesterol (n = 140 vs. 520 without) and reductions of ≥ 0.48 mmol/l in triacylglycerol over the active run-in period (pre-randomisation) (n = 356 vs. 303 without)

Mr G.E.• This non-diabetic 49 year - old male was a smoker until he required

CABG at age 43. • Despite treatment with aspirin 100mg and Vytorin 40/10mg he required

stenting recently. Hypercholesterolaemia persists at a level of 5.2 mmol/l (fasting TG 1.1 mmol/l, HDL 0.9 mmol/l, calculated LDL 3.8 mmol/l).

• He had resumed occasional use of cannabis.

Questions concerning Mr G.E.• What test would be the most helpful to investigate “residual risk”

A) hs-CRP B) Total homocysteine C) Lipoprotein (a) D) Lipoprotein-associated Phospholipase A2 E) Urinary ACR

• Which of the following interventions might help to improve HDL-C? A) Increased activity B) Weight loss C) Cessation of

cannabis D) All of the above E) Change from beer to wine consumption

• This non-diabetic 49 year - old male was a smoker until he required CABG at age 43.

• Despite treatment with aspirin 100mg and Vytorin 40/10mg he required stenting recently.

• Hypercholesterolaemia persists at a level of 5.2 mmol/l (fasting TG 1.1 mmol/l, HDL 0.9 mmol/l, calculated LDL 3.8 mmol/l).

• He had resumed occasional use of cannabis.

• What test would be the most helpful to investigate “residual risk” A) hs-CRP B) Total homocysteine C) Lipoprotein

(a) D) Lipoprotein-associated Phospholipase A2 E) Urinary ACR

• Which of the following interventions might help to improve HDL-C? A) Increased activity B) Weight loss C) Cessation of

cannabis D) All of the above E) Change from beer to wine consumption

What test would be the most helpful to investigate “residual risk”

• A) hs-CRP

• B) Total homocysteine

• C) Lipoprotein (a)

• D) Lipoprotein-associated Phospholipase A2

• E) Urinary ACR

What test would be the most helpful to investigate “residual risk”

The case for “C”

Emerging Risk Factor Collaboration. JAMA 2009; 302: 412-23

Which of the following interventions might help to improve HDL-C?

• A) Increased activity

• B) Weight loss

• C) Cessation of cannabis

• D) All of the above

• E) Change from beer to wine consumption

Which of the following interventions might help to improve HDL-C?

The case for “C”, but “D” rarely considered

The mean triglyceride level in the 18 marijuana users was 1.5 mmol/l, compared with 1.0 mmol/l in the 24 controls. This is consistent with a previous paper that reported significant increases in HDL-triglyceride concentrations in marijuana users compared with controls.

Jayanthi S, Buie S, Moore S, et al. Heavy marijuana users show increased serum apolipoprotein C3 levels: evidence from proteomic analyses. Mol Psychiatry 2008.

More questions concerning Mr G.E. • Mr G.E’s Lipoprotein (a) level was very high (1,783 mg/l). With this in

mind, how would you intensify lipid management?

A) Add a fibrate B) Add a bile acid resin C) Increase Vytorin (to 80/10mg) D) Replace Vytorin with Rosuvastatin plus Ezetimibe E) Add Niacin 1 to 2 gm / day, as tolerated.

• How much improvement do you anticipate? A) 50% decrease in TGB) 30% increase in HDL-C C) 25% decrease in Lp(a)D) 30% decrease in LDL-C E) All of the above

• Niacin affects plasma glucose becauseA) It affects pancreatic beta cell functionB) It increases plasma free fatty acid levels C) It reduces plasma free fatty acid levels which then re-bound D) It increases the speed of intestinal absorption. E) The mechanism is unknown

How would you intensify lipid management?

A) Add a fibrate

B) Add a bile acid resin

C) Increase Vytorin (to 80/10mg)

D) Replace Vytorin with Rosuvastatin plus Ezetimibe

E) Add Niacin 1 to 2 gm / day, as tolerated.

How would you intensify lipid management? The case for “E”

Hepatocyte

Inhibits hepatic lipase activity which reduces lipolysis of large HDL

Inhibits hepatic lipase activity which reduces lipolysis of large HDL

No effect on increasing Apo A1 synthesis

A-ICE

HDL2

apoA-I

HDL3

Nascent HDL

How much improvement do you anticipate?

• A) 50% decrease in TG

• B) 30% increase in HDL-C

• C) 25% decrease in Lp(a)

• D) 30% decrease in LDL-C

• E) All of the above

How much improvement do you anticipate? The case for “E”

Niacin used at pharmacologic doses (2 g/d) has been shown to reduce serum levels of Lp(a) by 20% to 25%.

Niacin affects plasma glucose because...

• A) It affects pancreatic beta cell function

• B) It increases plasma free fatty acid levels

• C) It reduces plasma free fatty acid levels which then re-bound

• D) It increases the speed of intestinal absorption.

• E) The mechanism is unknown

Niacin affects plasma glucose because...The case for “C”