14th July, 2019

First, it’s not good, then it’s Ok and now we are not sure. Maybe it is, maybe it isn’t. We are talking about eggs and the association with cardiovascular disease and mortality. It’s stuck in many of our and our patients’ minds that eggs are no good. It doesn’t help when the 2015-2020 Dietary Guidelines for Americans came out with somewhat contradictory recommendations: “ (1) Cholesterol is not a nutrient of concern for overconsumption” and (2) “Individuals should eat as little dietary cholesterol as possible while consuming a healthy eating pattern” (1). So, are eggs associated with an increase in cardiovascular disease and mortality or not?

Let’s not get confused about the message like many of my patients who came running in to see me when they heard it on current affairs somewhere. High blood cholesterol has been proven to be strongly associated with cardiovascular disease and mortality. Further, reducing cholesterol levels in these patients have been proven to reduce those numbers. What the American guidelines conclude is that the evidence linking dietary cholesterol with cardiovascular disease (CVD) is tenuous and therefore, they cannot draw meaningful conclusions linking dietary cholesterol and CVD.

Overall, there were 29,615 participants with 524,376 person years of follow-up data. The median follow-up was 17.5 years. The 6 cohorts differed considerably in terms of sample size, age, sex, race/ethnicity, education level, BMI, and behavioural and clinical CVD risk factors, as well as incident CVD and all-cause mortality rates. Various modelling was used to identify any associations between dietary cholesterol or egg consumption and CVD and CV mortality adjusting for various confounding factors (e.g. BMI, diabetes, blood pressure, and serum lipids, dietary fats, animal protein, fibre, sodium, cholesterol-containing foods, or dietary patterns).

So, what did they find?

When they analysed the subgroups of participants, association between dietary cholesterol consumption and heart disease was stronger in participants who were more overweight (i.e. BMI lower than 25). The association was also stronger in participants high lipid levels, women and participants who consumed a high saturated fat diet.

This is one of many studies (again) looking at the association between dietary cholesterol and egg consumption and CVD and all cause mortality. Trying to answer this simple question is going to be difficult. Cholesterol, saturated fat, and animal protein often coexist in foods. The interaction and independence between dietary cholesterol and these nutrients in relation to CVD and mortality remain uncertain. Data linking dietary cholesterol or eggs are sparse. Pretty much all the studies are observational studies. The study methodology and study population are heterogeneous and therefore difficult to analyse.

Egg consumption was commonly correlated with unhealthy behaviours such as low physical activity, current smoking, and unhealthy dietary patterns. Eggs and processed or unprocessed red meat are rich in other nutrients such as choline, iron, carnitine, and added sodium (for processed meat) that have been implicated in CVD risk via different pathways.

The effect of dietary cholesterol or egg consumption appears to be different in men and women, different depending on the lipid levels and whether there is consumption of other saturated fats.

As you can see, the effects if they are correct, are only very small.

Primum non nocere (first do no harm) is quite an appropriate term when is comes to managing pregnant women who either have dysglycaemia or are at risk of dysglycaemia. While there is no question that hyperglycaemia during pregnancy is associated with both poor maternal and foetal outcomes as well as epigenetics changes which can affect the next generation, who and how to treat is still debatable.

Metformin is increasingly being prescribed to pregnant women with PCOS, gestational diabetes and obesity. In fact, metformin is recommended in line with insulin in a number of international guidelines (Norwegian guidelines, the guidelines of the National Institute for Health and Care Excellence, and the American Society of Maternal-Fetal Medicine (SMFM),) However, the evidence on safety or benefit of intrauterine metformin use and long-term cardio-metabolic health of offspring born to women with polycystic ovary syndrome is inconclusive.

When 182 kids were followed up over 4 years, kids who were exposed to metformin during pregnancy in the PregMet study were found to have higher BMI and higher prevalence of overweight or obesity (1). Similarly, kids born to mothers who had GDM and was exposed to metformin (+/- insulin) had increased weight and height at 18 months and altered fat distribution at 24 months (2,3). In another study, kids born to mothers who had taken metformin had a higher BMI, increased waist circumference, waist-to hip ratio, and abdominal fat when examined at 9 years old compared to children whose mothers were treated with insulin only (4).

141 kids in the original PregMed study were followed up to between 5-10 years old. 71 mothers were exposed to metformin during the pregnancy while 70 were not. Kids in the metformin group had higher BMI, higher abdominal adiposity and weigh more than kids in the placebo group. There

was no difference between the groups in adiponectin, cholesterol, triglycerides, HDL-cholesterol, non-HDL cholesterol, alanine transaminase, glucose, HbA1c, insulin C-peptide, HOMA2-IR, blood pressure, or heart rate.

Maternal pre-pregnancy BMI had an effect on the metabolic effect of metformin: metformin-exposed children had higher measures of adiposity than placebo exposed children, higher triglycerides, and heart rate, and lower HDL-cholesterol only when maternal prepregnancy BMI was greater than 30 kg/m².

Among metformin-exposed children with overweight or obesity, 67% were overweight or obese already at 4 years of age. High BMI (obesity) in childhood often tracks into adulthood, and the risk of persistent high BMI increases with age. High BMI in childhood predicts cardiometabolic risk

factors, and moderately increases the risk of morbidity. 13 Early onset and duration of obesity are related to subsequent metabolic abnormal obesity phenotype.

Metformin treatment in polycystic ovary syndrome pregnancies is not without potential harm. It resulted in a higher mean BMI Z score accompanied by central adiposity and more children with obesity at 5–10 years of age. These results can have implications for future health.

Reference

1. Engen Hanem LG, Stridsklev S, Júlíusson PB, et al. Metformin use in PCOS pregnancies increases the risk of offspring overweight at 4 years of age; follow-up of two RCTs. J Clin Endocrinol Metab 2018; 103: 1612–1621.
2. Ijas H, Vaarasmaki M, Saarela T, Keravuo R, Raudaskoski T. A follow-up of a randomised study of metformin and insulin in gestational diabetes mellitus: growth and development of the children at the age of 18 months. BJOG 2015; 122: 994–1000.
3. Rowan JA, Rush EC, Obolonkin V, Battin M, Wouldes T, Hague WM. Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition at 2 years of age. Diabetes Care 2011; 34: 2279–84.
4. Rowan JA, Rush EC, Plank LD, et al. Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition and metabolic outcomes at 7–9 years of age. BMJ Open Diabetes Res Care 2018; 6: e000456.
5. Liv Guro Engen Hanem, Øyvind Salvesen, Petur B Juliusson, et al. Intrauterine metformin exposure and offspring cardiometabolic risk factors (PedMet study): a 5–10 year follow-up of the PregMet randomised controlled trial. Lancet Child Adolesc Health 2019; 3: 166–74

Increased oxidative stress appears to be a significant factor leading to insulin resistance, dyslipidaemia, β-cell dysfunction, impaired glucose tolerance and ultimately leading to type 2 diabetes (T2D). Ascorbic acid (AA) is a water soluble anti-oxidant that reduces oxidative damage at the cellular and tissue level. So, logically, AA supplementation should therefore reduce oxidate stress and lead to improvement in glycaemic control in patients with diabetes. Does it?

Logically, if you reduce oxidative stress, insulin sensitivity should improve. However, randomised control trials exploring whether AA improves glycaemic control have mixed findings. (1-4). Ashor AW et al conducted a systematic review and meta-analysis of the RCTs (5). Overall, AA did not modify glucose, HbA1c and insulin concentrations. However, in subgroup analysis, they did find AA improved glucose concentrations in patients with T2D, older individuals and if given for more than 30 days. AA had greater effects on fasting than post prandial glucose.

The latest study looking at the effect of AA on glycaemic control is an Australian study published in the Diabetes, Obesity and Metabolism this week (6). It is a randomised, cross over trial in individuals with T2D. 27 patients on oral therapy or diet were randomised to received either 500mg of ascorbic acid or placebo. Continuous glucose monitoring was used for 48 hours to monitor the post prandial glucose for 3.5 hours post prandial for the three meals. The cumulative total of 10.5 hours were compared between the groups.

Over the study period of 4 months, daily 10.5-hour postprandial glucose decreased by 36% (P < 0.01) during AA supplementation. The mean post prandial glucose was reduced by 1.1 mmol/L with AA supplementation. The duration of day spent with hyperglycaemia (>10.0 mmol/L) also significantly decrease by 2.8 hours per day with AA supplementation. The average 24-hour glucose also significantly decreased with AA supplementation but only by 0.8mmol/L. However, the HbA1c, fasting glucose and fasting insulin did not differ between the groups.

Systolic and diastolic pressure were also significantly reduced by 7mm and 5mm Hg respectively. Body composition, lipids, energy expenditure and renal and liver function were not affected by AA supplementation.

The effects of AA on glycaemic control in patients with T2D seems very impressive but is the effect clinically significant? The reduction in post prandial glucose did translate to a reduction in time with hyperglycaemia. This have potential clinical importance given that post-prandial hyperglycaemia has been considered an independent risk factor for cardiovascular disease and cardiovascular events in individuals with T2D.(7-9).

Previous studies that reported significant improvements in HbA1c after AA supplementation included more participants, enrolled participants with a higher baseline HbA1c and/or undertook AA supplementation for a longer period (10–13). Perhaps, HbA1c may be improved with a more prolonged supplementation period.

AA is an antioxidant and it is thought that the anti-oxidant effect may have decreased the oxidative stress on muscles which leads to improved peripheral glucose disposal.  Perhaps, patients with T2D have a greater need for AA. Indeed, patients with T2D have been found to have lower plasma Vitamin C concentrations compared with subjects with normal glucose tolerance (14-16). There are several proposed mechanisms including:

(1) increased ascorbate excretion in those with microalbuminuria,

(2) blood glucose may compete with vitamin C for uptake into cells due to its structural similarity to the oxidised form (dehydroascorbic acid), and

(3) increased oxidative stress may deplete antioxidant stores.

AA could be useful as an adjunct in patients with T2D for better control of glucose but the clinical significance is uncertain.

Access the latest study here.

References:

1. Davison GW, Ashton T, George L, Young IS, McEneny J, Davies B et al. Molecular detection of exercise-induced free radicals following ascorbate prophylaxis in type 1 diabetes mellitus: a randomised controlled trial. Diabetologia 2008; 51: 2049–2059.
2. Ellulu MS, Rahmat A, Patimah I, Khaza’ai H, Abed Y. Effect of vitamin C on inflammation and metabolic markers in hypertensive and/or diabetic obese adults: a randomized controlled trial. Drug Des Devel Ther 2015; 9: 3405–3412.
3. Gutierrez AD, Duran-Valdez E, Robinson I, de Serna DG, Schade DS. Does short term vitamin C reduce cardiovascular risk in type 2 diabetes? Endocr Pract 2013; 19: 785–791.
4. Klein F, Juhl B, Christiansen JS. Unchanged renal haemodynamics following high dose ascorbic acid administration in normoalbuminuric IDDM patients. Scand J Clin Lab Invest 1995; 55: 53–59.
5. AW Ashor1,, AD Werner, J Lara1,, ND Willis, JC Mathers and M Siervo. Effects of vitamin C supplementation on glycaemic control: a systematic review and meta-analysis of randomised controlled trials. European Journal of Clinical Nutrition (2017) 71, 1371–1380
6. Mason SA, Rasmussen B, van Loon LJC, Salmon J, Wadley GD. Ascorbic acid supplementation improves postprandial glycaemic control and blood pressure in individuals with type 2 diabetes: Findings of a randomized cross-over trial. Diabetes Obes Metab. 2019 Mar;21(3):674-682.
7. Bonora E, Muggeo M. Postprandial blood glucose as a risk factor for cardiovascular disease in Type II diabetes: the epidemiological evidence. Diabetologia. 2001;44:2107-2114.
8. Cavalot F, Pagliarino A, Valle M, et al. Postprandial blood glucose predicts cardiovascular events and all-cause mortality in type 2 diabetes in a 14-year follow-up: lessons from the San Luigi Gonzaga Diabetes study. Diabetes Care. 2011;34:2237-2243.
9. Esposito K, Giugliano D, Nappo F, Marfella R. Regression of carotid atherosclerosis by control of postprandial hyperglycemia in type 2 diabetes mellitus. Circulation. 2004;110:214-219.
10. Paolisso G, Balbi V, Volpe C, et al. Metabolic benefits deriving from chronic vitamin C supplementation in aged non-insulin dependent diabetics. J Am Coll Nutr. 1995;14:387-392.
11. Eriksson J, Kohvakka A. Magnesium and ascorbic acid supplementation in diabetes mellitus. Ann Nutr Metab. 1995;39:217-223.
12. Afkhami-Ardekani M, Shojaoddiny-Ardekani A. Effect of vitamin C on blood glucose, serum lipids & serum insulin in type 2 diabetes patients. Indian J Med Res. 2007;126:471-474.
13. Gillani SW, Sulaiman SAS, Abdul MIM, Baig MR. Combined effect of metformin with ascorbic acid versus acetyl salicylic acid on diabetes related cardiovascular complication; a 12-month single blind multicentre randomized control trial. Cardiovasc Diabetol. 2017;16:103.
14. Will, J.C.; Byers, T. Does diabetes mellitus increase the requirement for vitamin C? Nutr. Rev. 1996, 54, 193–202.
15. Sargeant, L.; Wareham, N.; Bingham, S.; Day, N. Vitamin C and hyperglycemia in the European prospective investigation into cancer-Norfolk (EPIC-Norfolk) study: A population-based study. Diabetes Care. 2000, 23, 726–732.
16. Kositsawat, J.; Freeman, V.L. Vitamin C and A1c relationship in the National Health and Nutrition Examination Survey (NHANES) 2003–2006. J. Am. Coll. Nutr. 2011, 30, 477–483.

As GPs, we often see little kids already carrying extra weight and we know that many of these will go on to become overweight or obese adults. Many overweight kids and overweight adults will go on to develop type 2 diabetes. Interestingly, some obese kids don’t go on to become diabetic. Which subsets of these overweight kids don’t go on to develop diabetes? What if the overweight kid skinny up when they become adults? Are they still at risk? What about normal weight kids that become overweight adolescents and young adults? Are they at risk too?

We know that high BMI at a young adult age is associated with T2D later on in life (1,2). High childhood BMI or low birth weight is also associated with increased risk of adult T2D (3-10).  The physiology during childhood and during puberty are actually very different. Is the childhood BMI the risk factor or the adult BMI the risk factor? Does the degree of weight gain matter?

In a study from four populations where BMI was measured both in childhood at 3-19

years of age and later in the same participants at 30-40 years of age, overweight adults had increased risk of adult type 2 diabetes regardless of BMI status during childhood (6). The risk in overweight children was similar to the risk in participants who were never overweight. However, the number of overweight subjects in that study was too underpowered to draw a valid conclusion (10). On the other hand, excessive BMI increase during puberty has been associated with CVD, stroke and heart failure in a number of studies (11-13).

The BMI Epidemiology Study Gothenburg (BEST Gothenburg) studied the impact of birthweight, childhood and adolescent BMI on adult diseases. 36,176 men born between 1945-1961 with information on both childhood BMI at age 8 and BMI change during puberty (BMI at age 20 – BMI at age 8) were included and followed until December 2013.

There were 1,777 cases of type 2 diabetes before the end of follow-up and the median age at diagnosis was 55.7 years. When they break down those that developed diabetes, they found:

High adult BMI and a high childhood BMI are associated with increased risk of T2D

Overweight kids and a high BMI increase during puberty was associated with increased risk of adult T2D. The risk was more pronounced for early (<55.7 years) compared with late (>55.7 years) onset T2D.

Overweight adolescents also had a substantially increased risk of T2D compared with men who were never overweight (as kids or as young adults) irrespective of whether they were overweight as a child

Men who were overweight both at childhood and young adult age had a nearly four-fold increased risk of adult T2D compared with men that were never overweight

Most interestingly, men who were overweight as kids but skinny up (normalised) during puberty did not have an increased risk of T2D

The authors speculate that a high BMI increase during puberty might result in increased risk of type 2 diabetes via expansion of visceral fat mass, resulting in low-grade inflammation and insulin resistance.

It would appear that childhood and adult BMI are independent risk factor for the development of T2D. From this study, the BMI change during puberty is an important determinant of adult T2D risk. As these overweight kids frequent our practices during that period, we could reduce their adult T2D risk.

Access the abstract here.

References:

1. de Mutsert R, Sun Q, Willett WC, Hu FB, van Dam RM. Overweight in early adulthood, adult weight change, and risk of type 2 diabetes, cardiovascular diseases, and certain cancers in men: a cohort study. Am J Epidemiol 2014; 179:1353-1365
2. Tirosh A, Shai I, Afek A, Dubnov-Raz G, Ayalon N, Gordon B, Derazne E, Tzur D, Shamis A, Vinker S, Rudich A. Adolescent BMI trajectory and risk of diabetes versus coronary disease. N Engl J Med 2011; 364:1315-1325
3. Zimmermann E, Bjerregaard LG, Gamborg M, Vaag AA, Sorensen TIA, Baker JL. Childhood body mass index and development of type 2 diabetes throughout adult life-A large-scale danish cohort study. Obesity (Silver Spring) 2017; 25:965-971
4. Eriksson JG, Kajantie E, Lampl M, Osmond C. Trajectories of body mass index amongst children who develop type 2 diabetes as adults. J Intern Med 2015; 278:219-226
5. Charakida M, Khan T, Johnson W, Finer N, Woodside J, Whincup PH, Sattar N, Kuh D, Hardy R, Deanfield J. Lifelong patterns of BMI and cardiovascular phenotype in individuals aged 60-64 years in the 1946 British birth cohort study: an epidemiological study. Lancet Diabetes Endocrinol 2014; 2:648-654
6. Juonala M, Magnussen CG, Berenson GS, Venn A, Burns TL, Sabin MA, Srinivasan SR, Daniels SR, Davis PH, Chen W, Sun C, Cheung M, Viikari JS, Dwyer T, Raitakari OT. Childhood adiposity, adult adiposity, and cardiovascular risk factors. N Engl J Med 2011; 365:1876-1885
7. Morrison JA, Glueck CJ, Horn PS, Wang P. Childhood predictors of adult type 2 diabetes at 9- and 26-year follow-ups. Arch Pediatr Adolesc Med 2010; 164:53-60 Sabin MA, Magnussen CG, Juonala M, Shield JP, Kahonen M, Lehtimaki T, Ronnemaa T, Koskinen J, Loo BM, Knip M, Hutri-Kahonen N, Viikari JS, Dwyer T, Raitakari OT. Insulin and BMI as predictors of adult type 2 diabetes mellitus. Pediatrics 2015; 135:e144-151
8. Hypponen E, Power C, Smith GD. Prenatal growth, BMI, and risk of type 2 diabetes by early midlife. Diabetes Care 2003; 26:2512-2517
9. Park MH, Sovio U, Viner RM, Hardy RJ, Kinra S. Overweight in childhood, adolescence and adulthood and cardiovascular risk in later life: pooled analysis of three british birth cohorts. PLoS One 2013; 8:e70684
10. Zimmermann E, Gamborg M, Sorensen TI, Baker JL. Sex Differences in the Association Between Birth Weight and Adult Type 2 Diabetes. Diabetes 2015; 64:4220-4225
11. Ohlsson C, Bygdell M, Sonden A, Rosengren A, Kindblom JM. Association between excessive BMI increase during puberty and risk of cardiovascular mortality in adult men: a population-based cohort study. Lancet Diabetes Endocrinol 2016; 4:1017-1024
12. Ohlsson C, Bygdell M, Sonden A, Jern C, Rosengren A, Kindblom JM. BMI increase through puberty and adolescence is associated with risk of adult stroke. Neurology 2017; 89:363-369
13. Kindblom JM, Bygdell M, Sonden A, Celind J, Rosengren A, Ohlsson C. BMI change during puberty and the risk of heart failure. J Intern Med 2018;
14. Claes Ohlsson M.D., Ph.D., Maria Bygdell Pharm.D., Maria Nethander M.Sc., Annika Rosengren M.D., Ph.D., Jenny M Kindblom M.D., Ph.D. BMI change during puberty is an important determinant of adult type 2 diabetes risk in men. The Journal of Clinical Endocrinology & Metabolism. First Online: December 04, 2018. DOI: 10.1210/jc.2018-01339