5 Steps to prevent Heart Disease

Thursday, April 19, 2018

Dr Malcolm comments on PCSK9

Just before I head off on holiday for a couple of weeks, I thought I should make a quick comment on the Repatha trial (PCSK9- inhibitor). I have written much about this new class of cholesterol lowering drugs, and I have been highly skeptical that they would have any benefits on cardiovascular disease. [Mainly on the basis that I don’t believe raised LDL causes CVD, and these drugs have one action – to lower LDL].
As many of you will be aware, the data from a clinical trial on Repatha has just been released. It was reported by the BBC thus
‘Huge advance’ in fighting world’s biggest killer.’
An innovative new drug can prevent heart attacks and strokes by cutting bad cholesterol to unprecedented levels, say doctors. The results of the large international trial on 27,000 patients means the drug could soon be used by millions.
The British Heart Foundation said the findings were a significant advance in fighting the biggest killer in the world. Around 15 million people die each year from heart attacks or stroke. Bad cholesterol is the villain in the heart world – it leads to blood vessels furring up, becoming easy to block which fatally starves the heart or brain of oxygen.
It is why millions of people take drugs called statins to reduce the amount of bad cholesterol . The new drug – evolocumab – changes the way the liver works to also cut bad cholesterol. “It is much more effective than statins,” said Prof Peter Sever, from Imperial College London.
He organised the bit of the trial taking place in the UK with funding from the drug company Amgen. Prof Sever told the BBC News website: “The end result was cholesterol levels came down and down and down and we’ve seen cholesterol levels lower than we have ever seen before in the practice of medicine.”
And so on, and so forth. So, the Repatha trial was a huge success. Obviously, it certainly lowered LDL to levels never seen before. Or, maybe it was not quite such a huge success. Michel de Logeril, a professor of cardiology in France – who set up and ran the famous, and successful, Lyon Heart Study sent me this comment.
‘This is just junk science.
The calculated follow-up duration required to test the primary hypothesis was 4 years as written by the authors themselves (but only in the second last paragraph before the end of discussion…) but the actual median duration of follow-up has been 2.2 years; it is thus a biased trial (a similar bias as in JUPITER: 1.9 years instead of 4 years): early stop!
In addition, contrary to the misleading claims in the medias, there was no effect on both total [444 deaths with evolocumab vs. 426 with placebo] and cardiovascular [251 vs. 240] mortality; which is not unexpected with a so short a follow-up.
They pretend that they are differences for non-fatal AMI and stroke but there is no difference in AMI and stroke mortality… Very strange… It would be critical to get access to the raw clinical data to verify the clinical history of each case in both groups.
Well, in my opinion and given the present state of consciousness among US doctors, FOURIER is a flop!
Peter Attia The Straight Dope on cholesterol

Dr Attia is great at making complicated subjects easier to understand
Atherogenic particles article


Atherosclerosis is the underlying cause of heart attack and stroke. 
Early observations that cholesterol is a key component of arterial plaques gave rise to the cholesterol hypothesis for the pathogenesis of atherosclerosis.
 Population studies have demonstrated that elevated levels of LDL cholesterol and apolipoprotein B (apoB) 100, the main structural protein of LDL, are directly associated with risk for ACV events (ASCVE). 
1-Indeed, infiltration and retention of apoB containing lipoproteins in the artery wall is a critical initiating event that sparks an inflammatory response and promotes the development of atherosclerosis.
2-Arterial injury causes endothelial dysfunction promoting modification of apoB containing lipoproteins and infiltration of monocytes into the subendothelial space.

3-Internalization of the apoB containing lipoproteins by macrophages promotes foam cell formation, which is the hallmark of the fatty streak phase of atherosclerosis. 

4-Macrophage inflammation results in enhanced oxidative stress and cytokine/chemokine secretion, causing more LDL/remnant oxidation, endothelial cell activation, monocyte recruitment, and foam cell formation. 

5-HDL, apoA-I, and endogenous apoE
 prevent inflammation and oxidative stress and promote cholesterol efflux to reduce lesion formation. 

6-Macrophage inflammatory chemoattractants stimulate infiltration and proliferation of smooth muscle cells. 

7-Smooth muscle cells produce the extracellular matrix providing a stable fibrous barrier between plaque prothrombotic factors and platelets. 

8-Unresolved inflammation results in formation of vulnerable plaques characterized by enhanced macrophage apoptosis and defective efferocytosis of apoptotic cells resulting in necrotic cell death leading to increased smooth cell death, decreased extracellular matrix production, and collagen degradation by macrophage proteases. 

8-Rupture of the thinning fibrous cap promotes thrombus formation resulting in clinical ischemic ASCVE. 

9-Surprisingly, native LDL is not taken up by macrophages in vitro but has to be modified to promote foam cell formation. 

10-Oxidative modification converts LDL into atherogenic particles that initiate inflammatory responses.

11- Uptake and accumulation of oxidatively modified LDL (oxLDL) by macrophages initiates a wide range of bioactivities that may drive development of atherosclerotic lesions. 

12-Lowering LDL-cholesterol with statins reduces risk for cardiovascular events, providing ultimate proof of the cholesterol hypothesis. 

13-All of the apoB containing lipoproteins are atherogenic,
 and both triglyceride rich remnant lipoproteins and Lp(a) promote atherothrombosis. 

14-Non-HDL cholesterol levels capture all of the apoB containing lipoproteins in one number and are useful in assessing risk in the setting of hypertriglyceridemia. 

15-Measures of apoB and LDL-P are superior at predicting risk for ASCVE, when levels of LDL-C and LDL-P are discordant.

16-Here, we also describe the current landscape of HDL metabolism. 
Epidemiological studies have consistently shown that HDL-C levels are inversely related to ASCVE.
 We highlight recent clinical trials aimed at raising HDL-C that failed to reduce CVE and the shifting clinical targets of HDL-C, HDL particle numbers, and HDL function (e.g. cholesterol efflux capacity). Furthermore, we describe many beneficial properties of HDL that antagonize atherosclerosis and how HDL dysfunction may promote cardiometabolic disease.

Extremely low LDLc not associated with serious side effects with PCSK9 therapy

Journal of Clinical Lipidology (2018) 12, 292–299 original

Easier version to read at my documents with edited version


Many patients on proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors achieve extremely low low-density lipoprotein cholesterol (LDL-C) levels.

Extremely low LDL-C levels are associated with even less cardiovascular risk.

Extremely low LDL-C concentrations cause no clinically relevant side effects.Low LDL-C levels due to higher clearance are a marker of adequate LDL–LDLreceptor function.


In conclusion, the clinical and physiological evidence makes the case that extremely low LDL-C plasma concentrations mediated by increased LDLR activity are not associated with significant adverse effects, within the limitations of the available clinical trial data.
Given that the main function of LDL metabolism is cholesterol excretion, therapies that increase LDLR activity could provide optimization of this physiological role.
In other words, extremely low LDL-C concentrations due to increased receptor-mediated clearance should be interpreted as a marker of adequate LDL-LDLR pathway function.

Summary of the Sponge Syndrome

I am updating and reposting one of my most popular posts.
I write about the Sponge Syndrome in my new book The Chronic Disease of Obesity which is available on Amazon for $4.00 on kindle version.

1- People can lose weight on any diet. But if you are pre-diabetic with insulin resistance or have DM2, then you really should go on Atkins (LCHF).

2- You can't outrun your fork.

3-The Sponge Syndrome makes the reduced obese regain weight unless they faithfully stay on a 1200-1500 calorie a day for the rest of their life. 

4- Only 5% of the reduced obese accomplish maintaining weight loss long term documented in the National Weight Control Registry (NWCR)

5- Very low calorie diets (VLCD) of around 800 calories cause nutritional ketosis (not ketoacidosis as with Diabetes Mellitus) which helps control appetite.

6- Atkins (Low cab high fat) satiates hunger at low calories due to nutritional ketosis. 

7- LCHF =  protein 3-5 times a day for satiety
 with fat for taste and
no carbs is simple to follow for the rest of your life.

8- However, because of the trials of life and stress,  Atkins (LCHF) can regain weight because of occasional binges (The Sponge Syndrome: shrunken fat cells regain fat even with slight increases in calories over the long term)

9- Ultimately in the long run (5-10 years) people who lost weight (the reduced obese) due to any diet or Bariatric surgery will regain and need to be treated with diet medications for the rest of their lives. 

10- Exercise has little to do with maintaining weight loss without staying on a 1200-1500 calorie diet.

11- Sponge Syndrome:  80 billion fat cells that never go away.  These shrunken fat cells with low leptin tell your brain you are starving.

12- You don't feel leptin's effects until you are low in it.  Increased hunger and decreased metabolism.

13- Diet pills are the only way to fight the long term starvation hunger from low leptin except to refill those shrunken fat cells with more fat which produces more leptin and relieves the hunger as it reduces high ghrelin (hunger hormone).

14- Most people don't want to give up carbs.  You can have a carb night once a week.  Eat a bite of dessert if it is not a trigger for binge eating.

15- Atkins (LCHF) is among the least of restrictive diets that you can stay on for the rest of your life because:
a- don't count calories
b- don't need diet diary.
c- eat ad libitum (eat till you are full)
d- high protein for satiety
e- high fat for taste
f- salt encouraged (unless you are hypertensive and salt sensitive)
g-walk at least 20 minutes a day for health

Wednesday, April 18, 2018

Leptin in commercial form for insulin resistance

From UpToDate  Literature reviewed through March 2018

My comments in purple
LIPODYSTROPHIES AND INSULIN RESISTANCE — The results of studies of the pathogenesis of insulin resistance in the context of lipoatrophy have varied regarding the presence or absence of defects at the level of insulin receptor expression, function, and signaling 
Transgenic mice devoid of white adipose tissue have 
2-increased appetite,
3- hyperinsulinemia, 
4-diabetes, and 
i.e., phenotypes remarkably similar to those of humans with generalized lipodystrophy [54,55]. 
These mice have decreased expression of several molecules, including 
1-peroxisome proliferator-activator receptor gamma (PPARG), 
2-insulin receptors, 
3-insulin receptor substrates 1 and 2, and 
5-whereas expression of tumor necrosis factor alpha is increased. 
Thus, it has been proposed that possible mediators of insulin resistance in lipodystrophy include
1- increased tumor necrosis factor,
2- free fatty acids, or 
3-leptin and/or adiponectin deficiency 

In his interview with Dr. Gabor, Ivor Cummings referred to this fat transplant experiment in mice.
Transplantation of even small amounts of adipose tissue or leptin treatment in diabetic, insulin-resistant mice with lipodystrophy and low serum leptin concentrations results in improved glycemia and decreased serum insulin concentrations 
In addition, replacing either adiponectin or leptin in an animal model of lipodystrophy, insulin resistance, and the metabolic syndrome improves insulin resistance, whereas replacing both adiponectin and leptin fully normalizes insulin resistance
These results are consistent with the hypothesis that leptin, adiponectin, and/or other substances secreted by adipose tissue are critical mediators of insulin resistance but their role in humans remains to be fully elucidated.
General approach — The approach to treatment discussed below is based upon observational or interventional studies and clinical experience.
The initial treatment of the metabolic disturbances associated with lipodystrophy (eg, diabetes, hypertriglyceridemia) is the same as in patients without lipodystrophy.
1-Lifestyle modification (appropriate diet and exercise as needed), 
2-metformin, and 
3-statins (and/orfibrates)
 are typically prescribed. 
Insulin or other antidiabetics (eg, thiazolidinediones, which increase adiponectin levels) can also be used if needed.
 If metabolic disturbances persist, one could potentially administer metreleptin to patients with acquired or congenital generalized lipodystrophy, as part of a Risk Evaluation and Mitigation Strategy (REMS) program, with careful monitoring. 
There are few data on the risks and benefits of metreleptin in this patient population. It is likely that more certainty regarding the risk-benefit ratio of using metreleptin will be obtained as results of the REMS program are published.
Persistent metabolic disturbances — For patients with acquired or congenital generalized lipodystrophy (not partial lipodystrophy) with persistent metabolic disturbances, one could potentially administer metreleptin, as part of an REMS program, with careful monitoring. The safety and efficacy of metreleptin (leptin analog) have only been evaluated in small numbers of patients with congenital or acquired generalized lipodystrophy.
Leptin (metreleptin by subcutaneous injection) is approved in Japan as a therapy indicated specifically for the treatment of diabetes and/or hypertriglyceridemia in patients with congenital or acquired lipodystrophy. 
In 2014, the US Food and Drug Administration (FDA) approved metreleptin for injection, in conjunction with diet, to treat leptin deficiency in patients with congenital generalized or acquired generalized lipodystrophy. 
It is not approved for use in patients with human immunodeficiency virus (HIV)-related lipodystrophy or in patients with metabolic diseases (eg, diabetes mellitus and hypertriglyceridemia) or other lipodystrophies without concurrent evidence of generalized lipodystrophy.
 Metreleptin should not be used in patients with obesity, and it is not approved for partial lipodystrophy.
Efficacy – Metreleptin is an analog of human leptin made through recombinant DNA technology. Leptin replacement therapy may be effective in patients with generalized lipodystrophy who are leptin-deficient. 
In open-label, non-randomized, uncontrolled studies that included small numbers of patients with congenital or acquired generalized lipodystrophy who had diabetes, hypertriglyceridemia, and/or elevated levels of fasting insulin, recombinant leptin administered subcutaneously once or twice daily for up to 12 months to achieve physiologic serum leptin concentrations resulted in significant clinical improvements. 
The studies showed reductions in glycated hemoglobin (A1C), fasting glucose, and triglycerides. 
In a subset of patients undergoing hyperinsulinemic-euglycemic clamp studies, leptin therapy improved peripheral glucose disposal and decreased both hepatic glucose output and hepatic steatosis. Satiation (time to voluntary cessation of eating) and satiety (inter-meal interval) also improved with exogenous leptin therapy.
 Long-term (12 months) recombinant human leptin therapy was effective in treating insulin resistance in two subjects with type 1 diabetes and acquired lipodystrophy with insulin resistance.
Randomized trials of metreleptin in patients with various metabolic abnormalities and lipodystrophy are necessary to confirm its therapeutic role, mechanism of action, and longer-term safety.
Adverse effects – The most common side effects observed in patients treated with metreleptin were fatigue, hypoglycemia, headache, decreased weight, and abdominal pain [2,65]. The development of non-neutralizing and, rarely, neutralizing antibodies to leptin has been reported [71,72]. Development of neutralizing antibodies is the reason underlying the FDA's restriction of metreleptin use exclusively to subjects with generalized lipodystrophy who have minimal, if any, circulating leptin levels to start with. In addition, the development of T-cell lymphoma has been described in patients with acquired lipodystrophy who had immunodeficiency before beginning metreleptin [65,71,75].
REMS program – Given the reported risk for development of neutralizing antibodies and lymphomametreleptin is available in the United States only through an REMS program. 
Under this REMS program, prescribers must be certified by enrolling in and completing specific training. Pharmacies must also be certified and only dispense metreleptin after receipt of the REMS Prescription Authorization Form for each new prescription. Metreleptin will be accompanied by a medication guide and instructions for use that provide patients with important information about the medication, which will be distributed each time a patient fills a prescription. Health care professionals should carefully consider the benefits and risks of treatment with metreleptin in lipodystrophy.

Monday, April 16, 2018

It's not your thyroid.

I discussed my success with:
 Invokana (canagliflozin)  link

Halls article link 

Highlights edited by me to facilitate reading:

In summary, our results provide the first quantification of the energy intake feedback control system in free‐living humans. 

We found that appetite increased by ∼100 kcal/day above baseline per kilogram of lost weight
—an effect several‐fold larger than the corresponding energy expenditure adaptations. 

The few individuals who successfully maintain weight loss over the long term do so by heroic and vigilant efforts to maintain behavior changes in the face of increased appetite along with persistent suppression of energy expenditure  
in an omnipresent obesogenic environment. 
Permanently subverting or countering this feedback control system poses a major challenge for the development of effective obesity therapies.


Body weight is believed to be regulated by feedback control of both energy intake and energy expenditure. 
Several experiments in humans have quantified how energy expenditure adapts in response to alterations of energy intake and body weight. 
For example, Leibel et al. found energy expenditure adaptations of several hundreds of kilocalories per day acting to resist weight loss  
In contrast, energy intake adaptations have yet to be accurately quantified in humans despite the widespread belief that feedback control of energy intake is critical for body weight regulation and acts as part of a complex neurobiological system to determine overall human food intake behavior 2.
First, we lacked the ability to accurately measure changes in free‐living energy intake in large numbers of people over extended time periods. ... Therefore, observations over long time scales are required, thereby making laboratory‐based studies impractical....To address this important problem, we recently validated an inexpensive mathematical method for calculating energy intake changes 
The second impediment to quantifying energy intake control in humans is that we lacked an intervention that increases energy output by a known amount without participants consciously knowing that this is occurring. 
Rather, most interventions that alter body weight or energy expenditure also evoke cognitive responses that may mask the effect of weight changes per se on the feedback control of energy intake. 
For example, engaging in an exercise program might increase energy expenditure and lead to weight loss, but exercise is a conscious behavior that does not have an effective placebo control. 
Furthermore, exercise has a complex role in modulating appetite and may induce compensatory changes in other components of total energy expenditure that are difficult to quantify. 
Therefore, changes in energy intake during an exercise program may not solely be due to feedback mechanisms controlling body weight but are likely to also involve conscious changes in behavior.
Here, we used data from a placebo‐controlled trial in patients with type 2 diabetes who were treated for 1 year with canagliflozin(Invokana), an inhibitor of sodium glucose transporter 2 (SGLT2), thereby increasing energy output in the form of urinary glucose excretion (UGE) 
In patients with type 2 diabetes, treatment with canagliflozin at a dose of 300 mg/day increases mean daily UGE(urinary glucose excretion) by approximately 90 g/day which is sustained at the same level throughout the duration of treatment without directly altering energy expenditure  or central pathways controlling energy intake and without the patients being directly aware of the energy deficit. 
In other words, SGLT2 inhibition provides a novel way to covertly perturb human energy balance that largely bypasses the volition and conscious awareness of the subjects. Any observed increased energy intake countering the weight loss induced by SGLT2 inhibition therefore likely reflects the activity of the feedback control system.
 We found that the feedback control of energy intake in humans was proportional to the amount of weight lost and was substantially stronger than the control of energy expenditure.


 In response to the sustained increase in UGE (urine glucose excretion) with canagliflozin (Invokana) treatment, mean body weight declined and reached a new equilibrium several kilograms lower and significantly more than the placebo group whose mean body weight loss was less than 1 kg 

To explain the measured body weight changes in the treatment group given the estimated increases in UGE, energy intake was calculated to have increased by ∼350 kcal/day at steady state.

 In the placebo group, mean energy intake was calculated to transiently decrease by ∼100 kcal/day over the first several weeks and return to near baseline after 15 weeks.


In the absence of ongoing efforts to restrain food intake (this means staying on a low calorie around 1500 cal for the rest of your life) following weight loss, feedback control of energy intake will result in eating above baseline levels with an accompanying acceleration of weight regain. 
This phenomenon has been also observed in lean men following experimental semi-starvation or short‐term underfeeding.
 Hyperphagia in these studies was believed to result from homeostatic signals arising from loss of both body fat and lean tissues  but a conscious desire to regain lost weight cannot be ruled out and may have contributed to increased food intake attributed to increased food intake.
Long‐term inhibition of SGLT2 (by Invokana) provides a unique probe for assessment of human energy homeostasis since :
1-the mechanism of action is clear, 
2-its effect on energy output is consistent, and 
3-the intervention is unlikely to directly affect central pathways involved in regulation of food intake. 
In contrast, other interventions aimed at increasing energy expenditure, such as exercise  or exogenous delivery of thyroid hormone 33, have pleiotropic effects and their impact on energy expenditure can be highly variable.
The suggestion that the signals controlling energy intake act as a proportional feedback system without integral feedback is consistent with 
the roughly proportional changes in appetite‐regulating hormones that occur rapidly in response to weight loss and do not further increase as weight loss is sustained (as would occur with integral feedback) 
 We do not yet know whether the simple proportional controller represented by Equation is valid for a range of weight losses. 
For example, it may be possible that small weight changes are uncompensated by changes in energy intake such that the control system engages only after sufficient weight loss to cross some threshold (usually 8-10% weight loss)
 Furthermore, larger weight losses may result in energy intake adaptations corresponding to a nonlinear function of body weight change.
Proportional feedback control of energy intake may help explain why the calculated exponential decay of diet adherence during weight loss interventions markedly contrasts with self‐reported measurements that indicate persistence of diet adherence and no significant differences in caloric consumption between the period of early weight loss compared with the later time when weight has plateaued  
This has led to speculation that the 6‐ to 8‐month weight plateau may be entirely due to slowing of metabolic rate rather than loss of diet adherence.
 Our results suggest otherwise and further illustrate that self‐reported energy intake measurements are quantitatively unreliable. (I think what they are saying here is the tremendous hunger from low leptin plays a big role)
Nevertheless, the relative constancy self‐reported energy intake over the first 6 months corresponds well with the calculated persistent effort to resist the increased appetite and the drive to overeat at above baseline levels.
 Therefore, self‐reported measurements of energy intake may more accurately reflect the perceived effort of the dieter to adhere to the intervention rather than their actual energy intake.