A recent meta-analysis of low-carb diets and cardiovascular risk factors found, predictably, that low carb diets decrease triglycerides (TG), increase HDL, and - significantly, on average, but not consistently, and only by a small amount - elevate LDL.
The authors argued that this was not evidence of cardiovascular safety. "Low-carbohydrate diets increase LDL-cholesterol, and thereby indicate increased risk of CVD."
Other cardiologists disputed this (including Axel F. Sigurðsson of the Doc's Opinion blog), citing evidence that TG and HDL are better markers of cardiovascular health than is LDL.[1]
The authors responded with a narrowly focussed argument [2] -
1) Mendelian randomisation shows the genes associated with LDL are associated with CVD, whereas genes associated with HDL are not, and those with TG only slightly.
I think this is faulty logic. Genes are the things we cannot change, so the association of TG and HDL with CVD risk, seen in the baseline characteristics of participants in drug trials (those with high HDL and low TG have low CVD risk in placebo arm and get no extra benefit in LDL-lowering arm - links to those studies in this post), is probably due to diet and lifestyle factors, as Mendelian randomisation seems to rule out a strong genetic influence; but it does suggest that these factors are downstream markers of some other, more proximal "root cause" factor.
2) Drugs that elevate HDL have no effect on CVD risk, whereas statins, which lower LDL, do have some effect.
As with their point 1), these authors simply did not look deeply enough into the literature. There are many drugs that have lowered LDL with no or harmful effects on CVD outcomes, which seem to have been ignored in this argument. As for HDL, alcohol, for example, is a drug that elevates HDL and decreases CVD risk, see e.g.[3]
However, this link is observational. Better data comes from the trials of a new class of drugs, the SGLT2 inhibitors. Empagliflozin elevates both HDL and LDL. "in T2DM patients with high CVD risk empagliflozin compared to placebo reduced the primary major adverse cardiac event end point (CV death, nonfatal myocardial infarction, nonfatal stroke) by 14%. This beneficial effect was driven by a 38% reduction in CV mortality with no significant decrease in nonfatal myocardial infarction or stroke. Empagliflozin also caused a 35% reduction in hospitalization for heart failure without affecting hospitalization for unstable angina."[4]
Empagliflozin was also shown to be renoprotective, significantly reducing the incidence of worsening nephropathy, by 39%. This is interesting because nephropathy is a vascular pathology of diabetes.
SGLT2 inhibitors mimic the effect of low-carbohydrate ketogenic diets over a wide range of metabolic parameters (increased sodium excretion, decreased extracellular volume, increased HDL and LDL, reduced requirement for insulin, increased ketogenesis). The doctors are still arguing about the mechanism of benefit.
However, we note that 48% of the subjects were receiving insulin at baseline (median daily dose 54 units) and 43% were using sulfonylureas (which increase insulin secretion). During the EMPA-REG trial the rate of addition of new medications was (drug vs placebo) 5.8% vs. 11.5% for insulin and 3.8% vs. 7.0% for sulfonylureas, consistent with studies in which SGLT2 inhibitors decrease insulin requirements in type 1 diabetes.[5]
Are there other drug trials that support this model? The STOP-NIDDM study tested acarbose for the prevention of diabetes in a group of patients with impaired glucose tolerance. Acarbose inhibits the digestion of starch, and side effects of diarroeah and flatulence limited compliance (how much simpler it would be to simply resist starch).
"211 (31%) of 682 patients in the acarbose group and 130 (19%) of 686 on placebo discontinued treatment early. 221 (32%) patients randomised to acarbose and 285 (42%) randomised to placebo developed diabetes (relative hazard 0.75 [95% CI 0.63-0.90]; p=0.0015). Furthermore, acarbose significantly increased reversion of impaired glucose tolerance to normal glucose tolerance."
Less carbohydrate entering the bloodstream from the gut = less progression of pre-diabetes to diabetes (and hence less CVD risk). It's not rocket science, unless you work for a pharmaceutical company in some capacity.
Acarbose doesn't alter LDL or HDL, but it does decrease triglycerides (thus improve the TG/HDL ratio) and VLDL. It also reduces the atherogenicity of LDL particles.
"The density gradient lipoprotein separation and disk polyacrylamide gel electrophoresis analyses showed that acarbose reduced the amount of small dense LDL, a more atherogenic and oxidatively susceptible form of LDL. We also found that the fatty acid composition of LDL changed after the treatment: polyunsaturated (omega-3) fatty acid, a beneficial substance for preventing cardiovascular disease, was significantly increased, whereas saturated fatty acids and triglyceride were decreased in the LDL of the acarbose-treated group."[7]
Decrease in sdLDL and serum SFAs is also an effect of low carb diets.
Does acarbose lower CVD incidence? You bet it does. In a meta-analysis of 7 RCTs of acrabose vs placebo in patients with T2DM, "The treatment significantly reduced the risk for ‘myocardial infarction’ (hazards ratio=0.36 [95% Cl 0.16–0.80], P=0.0120) and ‘any cardiovascular event’ (0.65 [95% Cl 0.48–0.88], P=0.0061)."[8]
In an experiment in fructose fed rats, there was no difference in blood glucose, but fructose increased, and acarbose subsequently reduced, insulin levels.[9]
In a double-blind, placebo-controlled, randomised cross-over study in subjects (n=10) with type 1 diabetes, "Acarbose produced a statistically significant reduction in mean insulin requirement over a 3-hr period following the meal compared with placebo (5171.7+/-2282.6 mU vs 8074.5+/-3045.4 mU; p=0.003). The level of blood glucose control over the same period was similar in the two groups.".
We measure fasting glucose, HbA1c, and OGTT glucose response to diagnose type 2 diabetes because these are easy and cheap to measure, but if we could measure the insulin response as easily and cheaply we would have a better guide to risk of complications and CVD and to the type and stage of diabetes.
This is because most of the pathologies of type 2 diabetes - cardiovascular disease and vascular disease in particular, but also, probably, the progression of beta-cell failure - are driven by elevated insulin levels.[11]
On the other hand, drugs that reduce both glucose and insulin (secretion or requirement) by restricting uptake or increasing excretion of glucose - i.e. acarbose or SGLT2 inhibitors (EMPA-REG trial) - significantly reduce the risk of cardiovascular disease and vascular pathologies.
What of statins? These have some lesser effect on the incidence of cardiovascular and vascular disease, despite the potential for increased blood glucose.
Statins inhibit the synthesis of cholesterol in cells, and the synthesis of excessive cholesterol, which disrupts mitochondrial function, is driven by excessive insulin concentrations.
"β-Hydroxy-β-methylglutaryl coenzyme A reductase activity in rat liver increased 2 to 7-fold after subcutaneous administration of insulin into normal or diabetic animals. Reductase activity began increasing after one hour, rose to a maximum in two to three hours, and then declined to the control level after six hours. This response was elicited during the time of day when the normal diurnal variation in reductase activity approached a minimum. It was also elicited when animals did not have access to food. This stimulation of reductase activity was completely blocked when glucagon was administered in conjunction with insulin. The increase in reductase activity after insulin administration was accompanied by a proportionate increase in activity for the conversion of acetate to cholesterol."[12]
What therapy lowers the secretion of or requirement for insulin, but does not increase and will usually lower blood glucose?
A low carbohydrate, high fat diet.
Q.E.D.
[1] Thomas R. Wood, Robert Hansen, Axel F. Sigurðsson and Guðmundur F. Jóhannsson (2016). The cardiovascular risk reduction benefits of a low-carbohydrate diet outweigh the potential increase in LDL-cholesterol. British Journal of Nutrition, 115, pp 1126-1128. doi:10.1017/S0007114515005450.
[2] Nadia Mansoor, Kathrine J. Vinknes, Marit B. Veierød and Kjetil Retterstøl (2016). Low-carbohydrate diets increase LDL-cholesterol, and thereby indicate increased risk of CVD. British Journal of Nutrition, 115, pp 2264-2266. doi:10.1017/S0007114516001343.
[3] Roles of Drinking Pattern and Type of Alcohol Consumed in Coronary Heart Disease in Men
Kenneth J. Mukamal, M.D., M.P.H., Katherine M. Conigrave, M.B., B.S., Ph.D., Murray A. Mittleman, M.D., Dr.P.H., Carlos A. Camargo, Jr., M.D., Dr.P.H., Meir J. Stampfer, M.D., Dr.P.H., Walter C. Willett, M.D., Dr.P.H., and Eric B. Rimm, Sc.D.
N Engl J Med 2003; 348:109-118January 9, 2003DOI: 10.1056/NEJMoa022095
[4] SGLT2 Inhibitors and Cardiovascular Risk: Lessons Learned From the EMPA-REG OUTCOME Study.
Muhammad Abdul-Ghani, Stefano Del Prato, Robert Chilton and Ralph A. DeFronzo.
Diabetes Care 2016 May; 39(5): 717-725.
[5] https://www.wikijournalclub.org/wiki/EMPA-REG_OUTCOME
[6] Lancet. 2002 Jun 15;359(9323):2072-7.
Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial.
Chiasson JL1, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M; STOP-NIDDM Trail Research Group.
[7] Acarbose ameliorates atherogenecity of low-density lipoprotein in patients with impaired glucose tolerance.
Inoue I, Shinoda Y, Nakano T, Sassa M, Goto S, Awata T, Komoda T, Katayama S.
Metabolism. 2006 Jul;55(7):946-52.
[8] Drugs Exp Clin Res. 2005;31(4):155-9.
Acarbose, an alpha-glucosidase inhibitor, improves insulin resistance in fructose-fed rats.
Nakamura K, Yamagishi S, Matsui T, Inoue H.
[9] Diabetes Nutr Metab. 2000 Feb;13(1):7-12.
Influence of acarbose on post-prandial insulin requirements in patients with Type 1 diabetes.
Juntti-Berggren L, Pigon J, Hellström P, Holst JJ, Efendic S.
[10] Acarbose reduces the risk for myocardial infarction in type 2 diabetic patients: meta-analysis of seven long-term studies
M. Hanefeld, M. Cagatay, T. Petrowitsch, D. Neuser, D. Petzinna, M. Rupp.
European Heart Journal. Volume 25, Issue 1. Pp. 10 - 16
[11] Exposure to excess insulin (glargine) induces type 2 diabetes mellitus in mice fed on a chow diet.
Xuefeng Yang, Shuang Mei, Haihua Gu, Huailan Guo, Longying Zha, Junwei Cai, Xuefeng Li, Zhenqi Liu and Wenhong Cao.
Journal of Endocrinology (2014) 221, 469–480
[12] Stimulation by insulin of rat liver β-hydroxy-β-methylglutaryl coenzyme A reductase and cholesterol-synthesizing activities.
M.R. Lakshmanan, Carl M. Nepokroeff, Gene C. Ness, Richard E. Dugan, John W. Porter. Biochemical and Biophysical Research Communications. Volume 50, Issue 3, 5 February 1973, Pages 704-710
Tuesday, 23 August 2016
Thursday, 18 August 2016
Glucokinase mutations, diabetic complications, and cardiovascular disease
This is a very interesting study that was posted by Richard Lehman on his BMJ blog a few years ago. It contains much food for thought.
People with this mis-sense mutation in the gene that encodes glucokinase (GCK), part of the pancreatic beta cell glucose sensor, basically have their sugar thermostat, their glucostat, set too high. They don't produce insulin in response to blood glucose in the pre-diabetic range. In this study, average HbA1c is 6.9%. But the incidence of insulin resistance, obesity, dyslipdaemia, and hypertension in this population is the same as in the normal controls, who have average HbA1c of 5.8% here.
So basically we are looking at mild hyperglycaemia without hyperinsulinaemia and its sequelae.
I think this is a good model for people with type 2 diabetes who have reversed the disease to a pre-diabetic level on a low carb diet, lost weight, and corrected hypertension. No carbs = low insulin, so how much of a problem is mild hyperglycaemia if it persists?
Also, do some people diagnosed with T2DM or prediabetes who go low carb have the GCK mutation without knowing it, meaning they will not get normal blood sugars?
JAMA. 2014 Jan 15;311(3):279-86. doi: 10.1001/jama.2013.283980.
Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia.
Steele AM, Shields BM, Wensley KJ, Colclough K, Ellard S, Hattersley AT.
IMPORTANCE:
Glycemic targets in diabetes have been developed to minimize complication risk. Patients with heterozygous, inactivating glucokinase (GCK) mutations have mild fasting hyperglycemia from birth, resulting in an elevated glycated hemoglobin (HbA1c) level that mimics recommended levels for type 1 and type 2 diabetes.
OBJECTIVE:
To assess the association between chronic, mild hyperglycemia and complication prevalence and severity in patients with GCK mutations.
DESIGN, SETTING, AND PARTICIPANTS:
Cross-sectional study in the United Kingdom between August 2008 and December 2010. Assessment of microvascular and macrovascular complications in participants 35 years or older was conducted in 99 GCK mutation carriers (median age, 48.6 years), 91 nondiabetic, familial, nonmutation carriers (control) (median age, 52.2 years), and 83 individuals with young-onset type 2 diabetes (YT2D), diagnosed at age 45 years or younger (median age, 54.7 years).
MAIN OUTCOMES AND MEASURES:
Prevalence and severity of nephropathy, retinopathy, peripheral neuropathy, peripheral vascular disease, and cardiovascular disease.
RESULTS:
Median HbA1c was 6.9% in patients with the GCK mutation, 5.8% in controls, and 7.8% in patients with YT2D. Patients with GCK had a low prevalence of clinically significant microvascular complications (1% [95% CI, 0%-5%]) that was not significantly different from controls (2% [95% CI, 0.3%-8%], P=.52) and lower than in patients with YT2D (36% [95% CI, 25%-47%], P<.001). Thirty percent of patients with GCK had retinopathy (95% CI, 21%-41%) compared with 14% of controls (95% CI, 7%-23%, P=.007) and 63% of patients with YT2D (95% CI, 51%-73%, P<.001). Neither patients with GCK nor controls required laser therapy for retinopathy compared with 28% (95% CI, 18%-39%) of patients with YT2D (P<.001). Neither patients with GCK patients nor controls had proteinuria and microalbuminuria was rare (GCK, 1% [95% CI, 0.2%-6%]; controls, 2% [95% CI, 0.2%-8%]), whereas 10% (95% CI, 4%-19%) of YT2D patients had proteinuria (P<.001 vs GCK) and 21% (95% CI, 13%-32%) had microalbuminuria (P<.001). Neuropathy was rare in patients with GCK (2% [95% CI, 0.3%-8%]) and controls (95% CI, 0% [0%-4%]) but present in 29% (95% CI, 20%-50%) of YT2D patients (P<.001). Patients with GCK had a low prevalence of clinically significant macrovascular complications (4% [95% CI, 1%-10%]) that was not significantly different from controls (11% [95% CI, 5%-19%]; P=.09), and lower in prevalence than patients with YT2D (30% [95% CI, 21%-41%], P<.001).
CONCLUSIONS AND RELEVANCE:
Despite a median duration of 48.6 years of hyperglycemia, patients with a GCK mutation had low prevalence of microvascular and macrovascular complications. These findings may provide insights into the risks associated with isolated, mild hyperglycemia.
BAM! as they say. Without high insulin, glucose at this level doesn't damage the blood vessels any more than "normal" BG does in a population with "normal" insulin responses to carbohydrate.
It does damage the eyes (but not the nerves), probably because the polyol pathway is insulin-independent, but the rate of retinopathy is already high, at 14%, in the "normal" population. Neuropathy has both a glycotoxic and a microvascular pathology, so is more dependent on hyperinsulinaemia than retinopathy.
A feature of GCK mutation is that blood glucose is highest in the most overweight individuals; this seems to show increased FFA flux boosting gluconeogenesis, or some extra effect of NAFLD increasing insulin resistance.
This is from a paper comparing a sample with the GCK mutation with their normal, non-diabetic family members.[1]
"In subjects with the mutation, beta cell function was impaired, being geometric mean 63 % (normal-100 %) compared with 126 % in the subjects without the mutation (p less than 0.001) measured by HOMA and in a subset assessed by CIGMA 59 % and 127 % (p less than 0.01 ), respectively. There was no difference in fasting insulin concentrations, insulin sensitivity, lipid concentrations or blood pressure between the groups. The haemoglobin A was raised (mean 6.5 % compared with 5.5 % in the subjects without the mutation), but microvascular and macrovascular complications were uncommon."
The authors of the first paper think this is a model for glycaemic control that attains recommended HbA1c targets for T1D and T2D. I don't think this can be the case if extra insulin or sulfonylureas are being used to meet these targets because the diet is still high in carbs. It is a model for the early stages of dietary control of diabetes, with reduced insulin levels or requirements and HbA1c trending down, and weight and blood pressure normalising.
The mechanisms that cause vascular disease in diabetes, including smooth muscle cell dysfunction and impaired eNOS signalling, are the same ones that are supposed to initiate atherosclerosis, whatever the role of lipoproteins in its development. Say it again - it's the insulin stupid.
[1] Diabet Med. 1995 Mar;12(3):209-17.
Clinical characteristics of subjects with a missense mutation in glucokinase.
Page RC1, Hattersley AT, Levy JC, Barrow B, Patel P, Lo D, Wainscoat JS, Permutt MA, Bell GI, Turner RC.
People with this mis-sense mutation in the gene that encodes glucokinase (GCK), part of the pancreatic beta cell glucose sensor, basically have their sugar thermostat, their glucostat, set too high. They don't produce insulin in response to blood glucose in the pre-diabetic range. In this study, average HbA1c is 6.9%. But the incidence of insulin resistance, obesity, dyslipdaemia, and hypertension in this population is the same as in the normal controls, who have average HbA1c of 5.8% here.
So basically we are looking at mild hyperglycaemia without hyperinsulinaemia and its sequelae.
I think this is a good model for people with type 2 diabetes who have reversed the disease to a pre-diabetic level on a low carb diet, lost weight, and corrected hypertension. No carbs = low insulin, so how much of a problem is mild hyperglycaemia if it persists?
Also, do some people diagnosed with T2DM or prediabetes who go low carb have the GCK mutation without knowing it, meaning they will not get normal blood sugars?
JAMA. 2014 Jan 15;311(3):279-86. doi: 10.1001/jama.2013.283980.
Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia.
Steele AM, Shields BM, Wensley KJ, Colclough K, Ellard S, Hattersley AT.
IMPORTANCE:
Glycemic targets in diabetes have been developed to minimize complication risk. Patients with heterozygous, inactivating glucokinase (GCK) mutations have mild fasting hyperglycemia from birth, resulting in an elevated glycated hemoglobin (HbA1c) level that mimics recommended levels for type 1 and type 2 diabetes.
OBJECTIVE:
To assess the association between chronic, mild hyperglycemia and complication prevalence and severity in patients with GCK mutations.
DESIGN, SETTING, AND PARTICIPANTS:
Cross-sectional study in the United Kingdom between August 2008 and December 2010. Assessment of microvascular and macrovascular complications in participants 35 years or older was conducted in 99 GCK mutation carriers (median age, 48.6 years), 91 nondiabetic, familial, nonmutation carriers (control) (median age, 52.2 years), and 83 individuals with young-onset type 2 diabetes (YT2D), diagnosed at age 45 years or younger (median age, 54.7 years).
MAIN OUTCOMES AND MEASURES:
Prevalence and severity of nephropathy, retinopathy, peripheral neuropathy, peripheral vascular disease, and cardiovascular disease.
RESULTS:
Median HbA1c was 6.9% in patients with the GCK mutation, 5.8% in controls, and 7.8% in patients with YT2D. Patients with GCK had a low prevalence of clinically significant microvascular complications (1% [95% CI, 0%-5%]) that was not significantly different from controls (2% [95% CI, 0.3%-8%], P=.52) and lower than in patients with YT2D (36% [95% CI, 25%-47%], P<.001). Thirty percent of patients with GCK had retinopathy (95% CI, 21%-41%) compared with 14% of controls (95% CI, 7%-23%, P=.007) and 63% of patients with YT2D (95% CI, 51%-73%, P<.001). Neither patients with GCK nor controls required laser therapy for retinopathy compared with 28% (95% CI, 18%-39%) of patients with YT2D (P<.001). Neither patients with GCK patients nor controls had proteinuria and microalbuminuria was rare (GCK, 1% [95% CI, 0.2%-6%]; controls, 2% [95% CI, 0.2%-8%]), whereas 10% (95% CI, 4%-19%) of YT2D patients had proteinuria (P<.001 vs GCK) and 21% (95% CI, 13%-32%) had microalbuminuria (P<.001). Neuropathy was rare in patients with GCK (2% [95% CI, 0.3%-8%]) and controls (95% CI, 0% [0%-4%]) but present in 29% (95% CI, 20%-50%) of YT2D patients (P<.001). Patients with GCK had a low prevalence of clinically significant macrovascular complications (4% [95% CI, 1%-10%]) that was not significantly different from controls (11% [95% CI, 5%-19%]; P=.09), and lower in prevalence than patients with YT2D (30% [95% CI, 21%-41%], P<.001).
CONCLUSIONS AND RELEVANCE:
 |
| Left columns - GCK, Middle columns - normal, Right columns T2D Complications, left to right, microvascular, retinopathy, macrovascular. |
BAM! as they say. Without high insulin, glucose at this level doesn't damage the blood vessels any more than "normal" BG does in a population with "normal" insulin responses to carbohydrate.
It does damage the eyes (but not the nerves), probably because the polyol pathway is insulin-independent, but the rate of retinopathy is already high, at 14%, in the "normal" population. Neuropathy has both a glycotoxic and a microvascular pathology, so is more dependent on hyperinsulinaemia than retinopathy.
A feature of GCK mutation is that blood glucose is highest in the most overweight individuals; this seems to show increased FFA flux boosting gluconeogenesis, or some extra effect of NAFLD increasing insulin resistance.
This is from a paper comparing a sample with the GCK mutation with their normal, non-diabetic family members.[1]
"In subjects with the mutation, beta cell function was impaired, being geometric mean 63 % (normal-100 %) compared with 126 % in the subjects without the mutation (p less than 0.001) measured by HOMA and in a subset assessed by CIGMA 59 % and 127 % (p less than 0.01 ), respectively. There was no difference in fasting insulin concentrations, insulin sensitivity, lipid concentrations or blood pressure between the groups. The haemoglobin A was raised (mean 6.5 % compared with 5.5 % in the subjects without the mutation), but microvascular and macrovascular complications were uncommon."
The authors of the first paper think this is a model for glycaemic control that attains recommended HbA1c targets for T1D and T2D. I don't think this can be the case if extra insulin or sulfonylureas are being used to meet these targets because the diet is still high in carbs. It is a model for the early stages of dietary control of diabetes, with reduced insulin levels or requirements and HbA1c trending down, and weight and blood pressure normalising.
The mechanisms that cause vascular disease in diabetes, including smooth muscle cell dysfunction and impaired eNOS signalling, are the same ones that are supposed to initiate atherosclerosis, whatever the role of lipoproteins in its development. Say it again - it's the insulin stupid.
[1] Diabet Med. 1995 Mar;12(3):209-17.
Clinical characteristics of subjects with a missense mutation in glucokinase.
Page RC1, Hattersley AT, Levy JC, Barrow B, Patel P, Lo D, Wainscoat JS, Permutt MA, Bell GI, Turner RC.
Sunday, 7 August 2016
Problems with Song et al Animal Protein vs Plant Protein study
 |
| According to Harvard, this truck has saved more lives than an ambulance. |
There are a number of methodological flaws in all these studies, and they are worth highlighting.
Firstly, the authors have combined two somewhat heterogenous cohort studies, previously published separately, and which present different findings, into what they now call one cohort.
Another way of describing this method is to say that they have cherry-picked two studies to put together. There are other studies that they could have combined with HPfS, or with NHS, to dilute or amplify their results. Of course they chose these studies because they are in charge of both of them, but nonetheless this is probably a unique proceeding.
Secondly, the results are now presented as person-years. This creates a larger number which looks impressive, but obscures the actual n= in each result.
Thirdly, the validity of the data is more questionable than the authors admit. Respondents were asked to estimate how many times they had eaten listed foods on average in the past year. The only verification seems to have been a comparison between a sample of the respondents completing both the FFQ and a 7-day food diary.
"In each FFQ, participants were asked how often, on average, they consumed a standardized portion size of each food during the previous year."
"The Spearman correlation coefficient of intake assessed by the FFQs and 7-day dietary record was 0.56 for animal protein and 0.66 for plant protein."
A Spearman correlation of 1 would have meant that the results were identical. 0.56 may be considered "high validity" in diet epidemiology, but wouldn't be accepted at the vehicle testing station. The results are meant to estimate 365 days not 7 days, so this comparison was incomplete.
So incomplete that the NHS cohort (the female half of this population) has reported eating 1,500 kcal/day on average for many years by the FFQ system.
"Among participants who returned baseline questionnaires, we excluded those who had a history of cancer (except nonmelanoma skin cancer), CVD, or diabetes at baseline, left more than 10 items blank on the baseline FFQ in the NHS and more than 70 items blank in the HPFS, or reported implausible energy intake levels (under 500 or over 3500 kcal/d for women, or under 800 or over 4200 kcal/d for men)."
This seems to state that respondents who seriously under- or over-stated energy intake were still included in the two studies.
Those are objections that pertain to the studies as a whole, but what of the specific findings of this study?
"Of the 131 342 participants, 85 013 were women (64.7%) and 46 329 were men (35.3%) (mean [SD] age, 49 [9] years). The median protein intake, as assessed by percentage of energy, was 14% for animal protein (5th-95th percentile, 9%-22%) and 4% for plant protein (5th-95th percentile, 2%-6%). After adjusting for major lifestyle and dietary risk factors, animal protein intake was weakly associated with higher mortality, particularly cardiovascular mortality (HR, 1.08 per 10% energy increment; 95% CI, 1.01-1.16; P for trend = .04), whereas plant protein was associated with lower mortality (HR, 0.90 per 3% energy increment; 95% CI, 0.86-0.95). These associations were confined to participants with at least 1 unhealthy lifestyle factor based on smoking, heavy alcohol intake, overweight or obesity, and physical inactivity, but not evident among those without any of these risk factors. Replacing animal protein of various origins with plant protein was associated with lower mortality. In particular, the HRs for all-cause mortality were 0.66 (95% CI, 0.59-0.75) when 3% of energy from plant protein was substituted for an equivalent amount of protein from processed red meat, 0.88 (95% CI, 0.84-0.92) from unprocessed red meat, and 0.81 (95% CI, 0.75-0.88) from egg.
There are two things that should jump out here. The first is that intakes of animal protein and plant protein differ by a factor of 3. Most people on LCHF and paleo diets are eating more plant protein than the people in NHS and HPFS cohorts. For the people in the lowest quintile of plant protein, this supplied 2.6% of energy. That's consistent with bread and processed meat being the main sources of plant protein. (wheat is 14% protein, most cheap commercial sausages contain wheat and soy protein. I'm not sure if Song et al factored this latter into their analysis).
The comparison between high and low plant protein intake is between median 2.6%E (about 10 grams of protein for NHS) and 6.6%E (about 25 grams). 25 grams is associated with less mortality than 10g. Neither amount is sufficient to sustain life.
In the animal protein stakes, median of lowest quintile is 8.9%E and highest is 20%E, and this is a range of protein intake consistent with life.
We're not really comparing like with like.
The second thing that jumps out is this:
"These associations were confined to participants with at least 1 unhealthy lifestyle factor based on smoking, heavy alcohol intake, overweight or obesity, and physical inactivity, but not evident among those without any of these risk factors."
This screams "residual confounding". If your associations disappear when you minimise confounding variables, you probably haven't measured or adjusted for these properly.
To their credit, Song et al do recognise this;
"First, given the remaining variation of health behaviors across protein intake categories in the unhealthy-lifestyle group, residual confounding from lifestyle factors may contribute to the observed protein-mortality associations. However, our results are robust to adjustment for a wide spectrum of potential confounders and the propensity score. "
This seems to be saying that because they performed adjustments, and this produced consistent results, therefore those results are likely to be correct.
However, in the last paper by this group based on the exact same data sets, there was evidence of residual confounding, in the form of a positive correlation between respiratory disease mortality and saturated fat (HR 1.56; 95% CI, 1.30-1.87). Saturated fat consumption was associated with a higher incidence of smoking, but this had been adjusted for.
This finding was described as "novel", because it had no support in the literature. Respiratory disease mortality is usually associated with smoking (which was controlled for) and other air quality factors (passive smoking and traffic proximity) which were not.
There are two possible explanations for this correlation.
Either saturated fat strongly increases respiratory mortality via unknown mechanisms which are only operative in doctors and nurses living in the USA in 1980-2012, or,
Doctors and nurses living in the USA between 1980 and 2012, years of strong anti-smoking campaigns and adjusted insurance premiums, are more likely to underreport smoking than the other, non-medical populations in other cohort studies.
I leave it to you to judge which of these explanations is more ontologically parsimonious.
[Edit 18/04/17; Wang et al have confirmed that the low SFA quintile was 15 years older than the high SFA quintile, due to their cumulative method and changes made by health-conscious individuals. This introduces a larger possibility of both unmeasured confounding and over-adjustment than suggested by baseline data. Individuals have moved between quintiles since baseline, rendering baseline data useless.]
Let us, for arguments sake, take the results at face value; there is no harm from eating extra animal protein from mixed sources instead of carbohydrate, especially if you don't eat commercial crap, and some benefit from eating plant protein (probably from its richer, higher fat sources, as only these will supply extra protein in replacement for carbohydrate).
Imagine a diet where you replace carbohydrate from wheat flour with protein from almond flour. Why, such a diet will reduce your chances of dying, according to Harvard!
Subscribe to:
Posts (Atom)