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 SLGT2 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.
SLGT2 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 SLGT2 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.0>
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
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 SLGT2 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.
SLGT2 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 SLGT2 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.0>
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