Cardiovascular Safety of Oral Semaglutide in Patients with Type 2 Diabetes

Cardiovascular Safety of Oral Semaglutide in Patients with Type 2 Diabetes

By Heather Nelson Cortes, PhD and Kevin C Maki, PhD

Cardiovascular disease (CVD) is the leading cause of mortality in patients with type 2 diabetes (T2D), therefore it is required that all new glucose-lowering therapies demonstrate no increase in cardiovascular risk with treatment.1  Glucagon-like-peptide-1 (GLP-1) receptor agonists have shown cardiovascular safety and in some cases, such as for semaglutide, benefit.2,3  The GLP-1 receptor agonists approved to date are administered subcutaneously, but a new oral semaglutide was recently developed, and the Peptide Innovation for Early Diabetes Treatment (PIONEER) 6 trial was conducted to rule out an excess in cardiovascular risk among patients with T2D treated with this product.4

PIONEER 6 was an event-driven, randomized, double-blind trial in which 3,183 patients with high CVD risk (≥50 y of age with established CVD or chronic kidney disease or ≥60 y of age with CVD risk factors only) were treated with 14 mg/day oral semaglutide or placebo.4  The primary outcome was the first occurrence of a major cardiovascular event (e.g., death from CVD, nonfatal myocardial infarction [MI], nonfatal stroke).

The mean age of the subjects was 66 y.  Subjects that were ≥50 y of age with either CVD or chronic kidney disease accounted for 2,695 (84.7%) of the subjects. The median time in the trial was 15.9 months with 61 of 1591 patients (3.8%) in the semaglutide and 76 of 1592 patients (4.8%) in the placebo group experiencing a major cardiovascular event.  Consistent with previous GLP-1 receptor agonist cardiovascular outcomes trials, this study demonstrated that oral semaglutide was non-inferior to placebo for the primary outcome (hazard ratio [HR] 0.79; 95% confidence interval [CI], 0.57-1.11) thus confirming that there is no excess CVD risk with oral semaglutide treatment.  The results for the individual components of the primary outcome and deaths from any cause are shown in the table below.

Table:  Major CVD outcomes in patients with high CVD risk receiving either oral semaglutide or placebo.

Primary Outcomes

Oral Semaglutide (n = 1591)

Placebo

 (n = 1592)

HR (95% CI)

 

 

                                            n (%)

 

Death from cardiovascular causes

15 (0.9%)

30 (1.9%)

0.49 (0.27-0.92)

Nonfatal MI

37 (2.3%)

31 (1.9%)

1.18 (0.73-1.90)

Nonfatal stroke

12 (0.8%)

16 (1.0%)

0.74 (0.35-1.57)

Death from any cause

23 (1.4%)

45 (2.8%)

0.51 (0.31-0.84)

 

Glycated hemoglobin was decreased with semaglutide compared to placebo (mean change from baseline to end of the trial, -1.0 vs. -0.3, respectively).  Body weight was also decreased from baseline to the end of the study by 4.2 kg with semaglutide compared to 0.8 kg with placebo.  Systolic blood pressure was also lower with semaglutide, compared to placebo, and there was a modest lowering of low-density lipoprotein cholesterol and triglycerides with semaglutide.

Comment.  These results showed that oral semaglutide has a similar cardiovascular safety profile to the subcutaneous form of semaglutide, and that the cardiovascular risk profile of oral semaglutide is not inferior to the cardiovascular risk profile of placebo.  It is notable that there were statistically significant reductions in secondary outcomes of cardiovascular and total mortality.  Because some patients may be reluctant to take an injectable medication, an orally administered GLP-1 receptor agonist may be an attractive alternative for patients with T2D.  Additional research is warranted to further investigate potential cardiovascular and mortality benefits of this agent.

 

References

  1. American Diabetes Association. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes – 2019. Diabetes Care. 2019;42(Suppl 1):S103-S123.

 

  1. Bethel MA, Patel RA, Merrill P, et al. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet Diabetes Endocrinol. 2018;6:105-113.

 

  1. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcome sin patients with type 2 diabetes. N Engl J Med. 2016;375:1834-1844.

 

  1. Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019; Epub ahead of print.

 

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Therapeutic potential of selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) for management of patients with atherogenic dyslipidemia

Therapeutic potential of selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) for management of patients with atherogenic dyslipidemia

By Heather Nelson Cortes, PhD and Kevin C Maki, PhD

 

Atherosclerotic cardiovascular disease (ASCVD) is associated with a significant public health burden around the world.  It is further exacerbated by chronic lifestyle-related diseases, such as visceral obesity, type 2 diabetes mellitus (T2D) and non-alcoholic fatty liver disease.  The morbidity and mortality of ASCVD is particularly high in low- and middle- income countries, which also have the largest number of people with obesity and diabetes.1-3  In these populations atherogenic dyslipidemia is a significant unmet clinical need.  Elevated plasma triglycerides (TG), with or without low levels of high-density lipoprotein cholesterol (HDL-C), are modifiable ASCVD risk factors, especially in insulin resistant conditions such as T2D.4

 

Some current ASCVD prevention guidelines recommend peroxisome proliferator-activated receptor alpha (PPARα) agonists (e.g., fibrates) for management of hypertriglyceridemia after statins.5  Unfortunately, these PPAR-α agonists have low potency and limited selectivity for PPARα.  They also have pharmacokinetic interactions and other side effects, including an increased risk of myopathy with gemfibrozil in combination with statin and reversible elevation in serum creatinine with fenofibrate, as well as liver enzyme elevation.6-9  Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα), which has a unique receptor-cofactor binding profile to identify the most potent molecules with PPARα-mediated effects while limiting unwanted side effects, has recently been developed.

 

Given the clear need for new therapeutic options for ASCVD, the Joint Consensus Panel from the International Atherosclerosis Society and the Residual Risk Reduction Initiative reviewed the scientific literature to help to determine if it is possible for pemafibrate to improve upon the beneficial lipid effects and safety profile demonstrated for PPARα agonists.10  In a randomized, double-blind clinical trial of 33 patients with atherogenic dyslipidemia, pemafibrate led to markedly decreased TG-rich lipoprotein levels and significantly increased concentrations of HDL-C, apolipoprotein (apo) A-I and apo-A-II, as well as improved markers of HDL function including pre-beta-HDL, smaller HDL particles (HDL3), and increased macrophage cholesterol efflux capacity.11  A pooled analysis of phase II/III studies showed that pemafibrate therapy over 12-24 weeks led to significant improvements in liver function tests (alanine aminotransferase, gamma glutamyl transferase, bilirubin).12  Also, unlike fenofibrate, pemafibrate did not elevate serum creatinine for up to 52 weeks in patients with or without pre-existing renal dysfunction.13  In general, the studies conducted to date have demonstrated that pemafibrate is well tolerated, especially with regard to renal and hepatic function, and that it may help in the management of atherogenic dyslipidemia, particularly by lowering elevated TG-rich lipoproteins and remnant cholesterol levels that are common in overweight patients with T2D.10

 

This Joint Consensus Panel concluded that pemafibrate, a SPPARMα agonist, represents a novel therapeutic class, distinct from fibrates according to its pharmacological activity, with a safe hepatic and renal profile.10  The Panel also recognized that the ongoing Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) trial of 10,000 patients with T2D, elevated TG, and low levels of HDL-C will help to determine if pemafibrate can be safely used to reduce residual cardiovascular risk.

 

References

  1. Joseph P, Leong D, McKee M, et al. Reducing the global burden of cardiovascular disease. Part 1: the epidemiology and risk factors. Circ Res. 2017;121:677–94.
  2. World Health Organization. Fact sheet. Obesity and overweight. http:// www.who.int/news-room/fact-sheets/detail/obesity-and-overweight. Accessed 21 Jan 2019.
  3. NCD Countdown 2030 collaborators. NCD Countdown 2030: worldwide trends in non-communicable disease mortality and progress towards Sustainable Development Goal target 3.4. Lancet. 2018;392:1072–88.
  4. Varbo A, Freiberg JJ, Nordestgaard BG. Remnant cholesterol and myocardial infarction in normal weight, overweight, and obese individuals from the Copenhagen General Population Study. Clin Chem. 2018;64:219–30.
  5. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: the Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2016;37:2315–81.
  6. Davidson MH. Statin/fibrate combination in patients with metabolic syndrome or diabetes: evaluating the risks of pharmacokinetic drug interactions. Expert Opin Drug Saf. 2006;5:145–56.
  7. Mychaleckyj JC, Craven T, Nayak U, et al. Reversibility of fenofibrate therapy-induced renal function impairment in ACCORD type 2 diabetic participants. Diabetes Care. 2012;35:1008–14.
  8. Davis TM, Ting R, Best JD, et al. Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. Diabetologia. 2011;54:280–90.
  9. Hedrington MS, Davis SN. Peroxisome proliferator-activated receptor alpha-mediated drug toxicity in the liver. Expert Opin Drug Metab Toxicol. 2018;14:671–7.
  10. Fruchart J-C, Santos RD, Aguilar-Salinas C, et al. The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm: conceptual framework and therapeutic potential. A consensus statement from the International Atherosclerosis Society (IAS) and the Residual Risk Reduction Initiative (R3i) Foundation. Cardiovasc Diabetol. 2019;18:71.
  11. Yamashita S, Arai H, Yokote K, et al. Effects of pemafibrate (K-877) on cholesterol efflux capacity and postprandial hyperlipidemia in patients with atherogenic dyslipidemia. J Clin Lipidol. 2018;12:1267–79.
  12. Matsuba I, Matsuba R, Ishibashi S, et al. Effects of a novel selective peroxisome proliferator-activated receptor-α modulator, pemafibrate, on hepatic and peripheral glucose uptake in patients with hypertriglyceridemia and insulin resistance. J Diabetes Investig. 2018;9:1323–32.
  13. Yokote K, Yamashita S, Arai H, et al. A pooled analysis of pemafibrate Phase II/III clinical trials indicated significant improvement in glycemic and liver function-related parameters. Atheroscler Suppl. 2018;32:155.

 

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Sub-optimal cholesterol response to initiation of statins and future risk of cardiovascular disease

Sub-optimal cholesterol response to initiation of statins and future risk of cardiovascular disease

By Heather Nelson Cortes, PhD and Kevin C Maki, PhD

 

Cardiovascular disease (CVD) continues to be the leading cause of death around the world and it is directly associated with blood levels of low-density lipoprotein cholesterol (LDL-C).1,2  In many clinical trials and in clinical practice, statins have been shown to be effective for lowering LDL-C, in both primary and secondary prevention, and to reduce the risk of future CVD events.3-6  The multi-society American College of Cardiology and American Heart Association guidelines for cholesterol management suggest that an adequate LDL-C lowering response with an intermediate-intensity statin is ≥30% and is  ≥50% with higher-intensity statins.5  The National Institute for Health and Care Excellence (NICE) guidelines defined sub-optimal responders as patients on treatment with statins for primary prevention of CVD who fail to achieve >40% reduction in LDL-C within the 24 months of statin initiation.6

 

Previous studies have identified individual biological and genetic variability of LDL-C response to statin therapy, as well as variation in treatment adherence, yet there is a paucity of literature on the variation of LDL-C response to statins in the general population.7,8  To address this issue, Akyea et al. examined the change in LDL-C and future risk of CVD in primary care patients over 24 months in response to initiation of statin therapy.9

 

This prospective cohort included 165,411 primary care patients, who were free of CVD at the initiation of statin therapy.  The data were collected from the UK Clinical Practice Research Datalink (CPRD), which is considered representative of the general population in the UK in terms of age, sex, and ethnicity.  Over half (51.2%, n=84,609) of patients had a sub-optimal LDL-C response to statin therapy within 24 months.  During the 1,077,299 person-years of follow-up (median follow-up 6.2 years) there were 22,798 CVD events.  Of these CVD events 12,142 were reported among the sub-optimal responders and 10,656 among the optimal responders (as defined by NICE).  The rates of CVD in the sub-optimal and optimal responders were 22.6 and 19.7/1000 person-years, respectively.

 

Compared to optimal responders, sub-optimal responders had a hazard ratio (HR) for incident CVD of 1.17 (95% CI 1.13-1.20).  After adjusting for age and baseline untreated LDL-C, the sub-optimal vs. optimal responders had a HR of 1.22 (95% CI 1.19-1.25).  Consideration of competing risks (e.g., patients transferring out of the practice, death) led to a lower HR for sub-optimal responders of 1.13 (95% CI 1.10-1.16) and an adjusted HR of 1.19 (95% CI 1.16-1.23).  It is worth noting that in this cohort, a higher proportion of patients with sub-optimal responses were prescribed lower potency statins than those with an optimal response.

 

Comment.  Overall the results show that over half of the patients in this general population cohort did not achieve >40% LDL-C reduction over 24 months with statin therapy.  Patients with suboptimal LDL-C responses were at higher risk for future CVD events.  These findings further support the view that “lower is better” for LDL-C and suggest that patients with a suboptimal response to statin therapy should be identified and evaluated for possible additional intervention, which might include intensification of lifestyle therapies, counseling regarding adherence to the prescribed statin regimen, dose escalation, switching to a higher-potency statin, or adjunctive pharmacotherapy such as ezetimibe or a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor.

 

 

References

  1. Nichols M, Townsend N, Scarborough P, et al. Cardiovascular disease in Europe 2014: epidemiological update. Eur Heart J. 2014;35:2950–9.

  2. Mihaylova B, Emberson J, Blackwell L, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380:581–90.
  3. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ. 2003;326:1423.

  4. Cholesterol Treatment Trialists’ (CTT) collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet 2010;376:1670–81.

  5. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol. J Am Coll Cardiol. 2018;Epub ahead of print.
  6. National Institute for Health and Care Excellence. Cardiovascular disease: risk assessment and reduction, including lipid modification. London: National Institute for Health and Care Excellence, 2016.
  7. Mega JL, Morrow DA, Brown A, et al. Identification of genetic variants associated with response to statin therapy. Arterioscler Thromb Vasc Biol. 2009;29:1310–5.

  8. Mann DM, Woodward M, Muntner P, et al. Predictors of nonadherence to statins: a systematic review and meta-analysis. Ann Pharmacother. 2010;44:1410–21.
  9. Akyea RK, Kai J, QUreshi N, Iyen B, Weng SF. Sub-optimal cholesterol response to initiation of statins and future risk of cardiovascular disease. Heart. 2019;Epub ahead of print.

 

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Association of Long-term Consumption of Sugar-Sweetened and Artificially Sweetened Beverages with Total and Cause-specific Mortality

Association of Long-term Consumption of Sugar-Sweetened and Artificially Sweetened Beverages with Total and Cause-specific Mortality

By Heather Nelson Cortes, PhD and Kevin C Maki, PhD

In the United States, sugar sweetened beverages (SSBs) account for the largest source of added sugar in the diet 1,2.  These types of drinks (e.g., carbonated, noncarbonated, fruit, sports) have added caloric sweeteners like high fructose corn syrup, sucrose, or fruit juice concentrates.  Currently it is recommended that adults consume no more than 10% of their total energy intake from added sugar 3.

While consumption rates of SSBs had been declining in the US over the past 10 years, recent research has suggested a reversal in that trend, with increased consumption among adults of all ages averaging around 145 kcal/day (6% of energy)4.  In younger adults, SSBs are responsible for 9.3% of daily calories in men and 8.2% of daily calories in women 5-7.

Studies have shown a positive association between intake of SSBs and weight gain, as well as higher risks of type 2 diabetes, coronary heart disease and stroke 8-11.  Artificially sweetened beverages (ASBs) are used as alternatives to the calorically heavy SSBs, yet there has been little research on the long-term health effects of ASBs or on the relationship between SSB consumption and total mortality.

In an analysis of two ongoing prospective cohort studies, Malik et al. examined the association between intakes of SSBs and ASBs with total and cause-specific mortality 12.  The analysis included data from the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS).  The NHS study has been collecting data since 1976 and includes 121,700 female nurses, age 30-55 years at study entry.  The HPFS began in 1986 and includes 51,529 male health professionals, age 40-75 years at entry. 

Mean consumption of SSBs decreased in both cohorts over the follow-up periods, which were 34 years in the NHS and 28 years in the HPFS.  Intakes of SSBs and ASBs were inversely correlated in both the NHS (r = −0.06, P < 0.001) and the HPFS (r = −0.16, P < 0.001).  Overall, there were 36,436 deaths, including 7,896 from cardiovascular disease (CVD) and 12,380 from cancer during a total of 3,415,564 person-years of follow-up.

After adjusting for major diet and lifestyle factors, consumption of SSBs was associated with a higher risk of total mortality (Table).  SSBs were also associated with increased CVD mortality (hazard ratio comparing extreme categories of 1.31 [95% confidence interval, 1.15-1.50], P trend < 0.0001) and cancer mortality (1.16 [1.04-1.29], P trend = 0.0004).  ASB intake was associated with increased risk for total and CVD mortality only in the highest intake group (Table).  Interestingly, intake of ASBs was associated with total mortality in the NHS, but not the HPFS (P interaction = 0.01).  ASBs were not associated with cancer mortality in either cohort.

 

 

Table:  SSB and ASB Consumption and Mortality Risk (Total, CVD, Cancer)

Pooled Hazard Ratios (95% confidence intervals) from NHS and HPFS

 

<1/month

1-4/month

2-6/week

1-<2/d

>2/d

P trend

Total Mortality

SSB

1.0

 

1.01

(0.98, 1.04)

1.06

(1.03, 1.09)

1.14

(1.09, 1.19)

1.21

(1.13, 1.28)

<0.0001

ASB

1.0

 

0.96

(0.93, 0.99)

0.97

(0.95, 1.00)

0.98

(0.94, 1.03)

1.04

(1.02, 1.12)

0.01

CVD Mortality

SSB

1.0

1.06

(1.00, 1.12)

1.10

(1.04, 1.17)

1.19

(1.08, 1.31)

1.31

(1.15, 1.50)

<0.0001

ASB

1.0

0.93

(0.87, 1.00)

0.95

(0.89, 1.00)

1.02

(0.94, 1.12)

1.13

(1.02, 1.25)

0.02

Cancer Mortality

SSB

1.0

1.03 

(0.98, 1.08)

1.06

(1.01, 1.11)

1.12

(1.03, 1.21)

1.16

(1.04, 1.29)

0.0004

ASB

1.0

1.01

(0.96, 1.07)

0.99

(0.94, 1.04)

1.00

(0.93, 1.07)

1.04

(0.96, 1.12)

0.58

 

Comment.  Results from this study highlight the importance of minimizing SSB intake because consumption of SSBs has been consistently associated with adverse health outcomes and a less favorable cardiometabolic risk factor profile.8-11  Substituting ASBs for SSBs will help decrease added sugar intake, but it is important to note that the possible health impacts of long-term consumption have not been well documented.  It is uncertain whether the modest increases in total (4%) and CVD (13%) mortality associated with consuming ≥2 ASBs per day represent causal relationships.  Nevertheless, it is reasonable to recommend moderation in the consumption of these products.

 

References

  1. Hu FB, Malik VS. Sugar-sweetened beverages and risk of obesity and type 2 diabetes: epidemiologic evidence. Physiol Behav. 2010;100:47–54.
  2. National Cancer Institute: Division of Cancer Control & Population Sciences. Epidemiology and Genomics Research Program. Sources of Calories from Added Sugars among the US population, 2005–2006. Updated April 20, 2018. http://riskfactor.cancer.gov/diet/foodsources/added_sugars/.
  3. S. Department of Health and Human Services and U.S. Department of 
Agriculture. 2015–2020 Dietary Guidelines for Americans. 8th Edition. December 2015. http://health.gov/dietaryguidelines/2015/guidelines/.
  4. Welsh JA, Sharma AJ, Grellinger L, Vos MB. Consumption of added sugars is decreasing in the United States. Am J Clin Nutr. 2011;94:726–734.
  5. Ogden CL, Kit BK, Carroll MD, Park S. Consumption of sugar drinks in the United States, 2005–2008. NCHS Data Brief. 2011:1–8. 

  6. Rosinger A, Herrick K, Gahche J, Park S. Sugar-sweetened beverage consumption among U.S. adults, 2011–2014. NCHS Data Brief. 2017:1–8. 

  7. Malik VS, Pan A, Willett WC, Hu FB. Sugar-sweetened beverages and weight gain in children and adults: a systematic review and meta-analysis. Am J Clin Nutr. 2013;98:1084–1102.
  8. Malik VS, Popkin BM, Bray GA, Després JP, Willett WC, Hu FB. Sugar- sweetened beverages and risk of metabolic syndrome and type 2 diabetes: a meta-analysis. Diabetes Care. 2010;33:2477–2483.
  9. Fung TT, Malik V, Rexrode KM, Manson JE, Willett WC, Hu FB. Sweetened beverage consumption and risk of coronary heart disease in women. Am J Clin Nutr. 2009;89:1037–1042.
  10. de Koning L, Malik VS, Kellogg MD, Rimm EB, Willett WC, Hu FB. Sweetened beverage consumption, incident coronary heart disease, and biomarkers of risk in men. Circulation. 2012;125:1735–41, S1.
  11. Bernstein AM, de Koning L, Flint AJ, Rexrode KM, Willett WC. Soda consumption and the risk of stroke in men and women. Am J Clin Nutr. 2012;95:1190–1199.
  12. Malik VS, Li Y, Pan A, De Koning L, Schernhammer E, Willett WC, Hu FB. Long-term consumption of sugar-sweetened and artificially sweetened beverages and risk of mortality in US adults.  2019;139: doi: 10.1161/circulationaha.118.037401.

 

 

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Potential Role of Nut Consumption for Improving Insulin Sensitivity : Results from a Systematic Review and Meta-analysis of Randomized Controlled Trials

Potential Role of Nut Consumption for Improving Insulin Sensitivity : Results from a Systematic Review and Meta-analysis of Randomized Controlled Trials

By Heather Nelson Cortes, PhD and Kevin C Maki, PhD

 

Worldwide incidence and prevalence of type 2 diabetes mellitus (T2D) diabetes are increasing at alarming rates, largely following increases in incidence of overweight and obesity.  The World Health Organization reports that ~1.9 billion adults are overweight in 2019, including 600 million that are obese and thus at heightened risk for T2D1.  Overweight and obesity are associated with impaired whole-body insulin sensitivity (i.e., increased insulin resistance), which is believed to be the key pathophysiologic link to increased risk for T2D 2.

 

Many epidemiological studies have examined the association of nut consumption with risks for T2D and mortality.  Systematic reviews and meta-analyses of prospective cohort studies have suggested a reduction in T2D risk with regular nut consumption 3-5

 

Tindall and colleagues recently published a review of 40 randomized, controlled trials with a median duration of 3 months (N = 2,832 subjects), that examined the effects of consuming tree nuts and peanuts on glycemic markers, including homeostasis model assessment of insulin resistance (HOMA-IR), fasting insulin and glucose, and glycated hemoglobin (HbA1C) 6.  The median intake of nuts was 52 g/d (range: 20-113 g/d).

 

In pooled analyses, consumption of tree nuts or peanuts reduced both HOMA-IR (weighted mean difference [WMD] −0.23; 95% confidence interval [CI] −0.40, −0.06; I2 = 51.7%) and fasting insulin (WMD −0.40 μU/mL; 95% CI −0.73, −0.07 μU/mL; I2 = 49.4%) compared to the control conditions 6.  However, there were no effects of nut consumption on fasting blood glucose (WMD −0.52 mg/dL; 95% CI −1.43, 0.38 mg/dL; I2 = 53.4%) or HbA1C (WMD 0.02%; 95% CI −0.01%, 0.04%; I2 = 51.0%).
 Further analyses showed no associations between the dose of nuts/peanuts consumed and the mean difference between nut and control treatments for any of the measured outcomes.  Analysis by nut type showed no deviations from the main results.

 

Comment. While there were no effects of nut consumption on HbA1C or fasting glucose, there were statistically significant reductions in HOMA-IR and fasting insulin, suggesting improved insulin sensitivity.  Future studies are needed to help determine the mechanisms through which nut/peanut consumption affects insulin sensitivity. 

 

References

  1. World Health Organization. Global report on diabetes. Geneva, Switzerland: World Health Organization; 2016. 

  2. Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature. 2006;444:840–6.
  3. Afshin A, Micha R, Khatibzadeh S, Mozaffarian D. Consumption of nuts and legumes and risk of incident ischemic heart disease, stroke, and diabetes: a systematic review and meta-analysis. Am J Clin Nutr 2014;100(1):278–88. 

  4. Aune D, Keum N, Giovannucci E, et al. Nut consumption and risk of cardiovascular disease, total cancer, all-cause and cause-specific mortality: a systematic review and dose-response meta-analysis of prospective studies. BMC Medicine 2016;14(1):207.
  5. Luo C, Zhang Y, Ding Y, et al. Nut consumption and risk of type 2 diabetes, cardiovascular disease, and all-cause mortality: a systematic review and meta-analysis. Am J Clin Nutr 2014;100(1):256–69. 

  6. Tindall AM, Johnston EA, Kris-Etherton PM, Petersen KS. The effect of nuts on markers of glycemic control: a systematic review and meta-analysis of randomized controlled trials. Am J Clin Nutr. 2019;109:297–314.


 

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No Additional Benefits on Cardiometabolic Risk Parameters of Reduced Red Meat or Increased Fiber Intake in an Energy-restricted Diet

No Additional Benefits on Cardiometabolic Risk Parameters of Reduced Red Meat or Increased Fiber Intake in an Energy-restricted Diet

By Heather Nelson Cortes, PhD and Kevin C Maki, PhD

 

To date, results from epidemiological studies have suggested that a high intake of red meat is associated with a higher risk of developing type 2 diabetes (T2D) while high fiber intake is associated with a lower risk 1-5. Furthermore, high intakes of red meat have also been suggested to be linked to increased risks of cardiovascular disease (CVD) and mortality 6,7.  One of the main approaches for reducing risk of T2D and CVD is weight loss 8-10. Research findings have also suggested that cardiometabolic risk can be improved with dietary modification independent of weight loss 11,12.

 

Willman et al. completed a 6-month, randomized controlled dietary intervention trial to assess whether lower intake of meat or higher intake of dietary fiber would have additional benefits when incorporated into an energy-restricted diet 13.  Subjects were randomized to one of three groups with all groups being instructed to reduce their caloric intakes by 400 kcal/d below their weight-maintenance requirements and exercise 3 hours/week.  The control group just decreased their caloric intake.  The “no red meat” group avoided red meat, but was able to eat turkey, fish or chicken, and subjects in the “fiber” group increased their fiber intake to at least 40 g/day.  The researchers also analyzed 9-month follow-up data from the Tuebingen Lifestyle Intervention Program (TULIP) cohort, which included subjects (n = 229) at increased risk of diabetes 14.  The intervention in TULIP consisted of increased physical activity and decreased caloric intake.

 

All participants in the 6-month trial lost weight (mean 3.3 ± 0.5 kg, P < 0.0001). Glucose tolerance and insulin sensitivity improved (P < 0.001), and body and visceral fat mass decreased in all groups (P < 0.001), with no difference among the groups.  Similarly, liver fat content decreased (P < 0.001) with no differences among the groups.  The liver fat decrease correlated with the decrease in ferritin during intervention (r2 = 0.08, P = 0.0021). This association between ferritin and liver fat changes was confirmed in TULIP (P = 0.0084).

 

Comment.  Neither the absence of dietary red meat nor the increase in fiber intake had an additional effect beyond calorie restriction and exercise on risk markers for T2D or CVD.  These results confirm that weight loss can lead to improvement in glucose metabolism, body fat composition and liver fat content and do not indicate incremental benefits for restriction of red meat intake or increasing dietary fiber intake.  Additional research is needed to assess effects of these dietary factors during weight loss maintenance.

 

References

  1. The InterAct Consortium. Association between dietary meat consumption and incident type 2 diabetes: The EPIC-InterAct study. Diabetologia 2013;56:47–59.
  2. Fretts AM, Howard BV, McKnight B, et al. Associations of processed meat and unprocessed red meat intake with incident diabetes: The Strong Heart Family Study. Am J Clin Nutr 2012;95:752–8.
  3. Lajous M, Tondeur L, Fagherazzi G, et al. Processed and unprocessed red meat consumption and incident type 2 diabetes among French women. Diabetes Care 2012;35:128–30.
  4. Pan A, Sun Q, Bernstein AM, et al. Red meat consumption and risk of type 2 diabetes: 3 cohorts of US adults and an updated meta-analysis. Am J Clin Nutr 2011;94:1088–96.
  5. Wittenbecher C, Mühlenbruch K, Kröger J, et al. Amino acids, lipid metabolites, and ferritin as potential mediators linking red meat consumption to type 2 diabetes. Am J Clin Nutr 2015;101:1241–50.
  6. Etemadi A, Sinha R, Ward MH, et al. Mortality from different causes associated with meat, heme iron, nitrates, and nitrites in the NIH-AARP Diet and Health Study: Population based cohort study. BMJ 2017;357:1957.
  7. Sun Q. Red meat consumption and mortality: Results from 2 prospective cohort studies. Arch Intern Med 2012;172:555.
  8. Tuomilehto J, Lindström J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343–50. 

  9. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393– 403. 

  10. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol 2014;63:2985– 3023. 

  11. Estruch R, Ros E, Salas-Salvadó J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368:1279–90.
  12. Estruch R, Martínez-González MA, Corella D, et al. Effect of a high-fat Mediterranean diet on bodyweight and waist circumference: A prespecified secondary outcomes analysis of the PREDIMED randomised controlled trial. Lancet Diabetes Endocrinol 2016;4:666–76.
  13. Willmann C, Heni M, Linder K, et al. Potential effects of reduced red meat compared with increased fiber intake on glucose metabolism and liver fat content: a randomized and controlled dietary intervention study. Am J Clin Nutr. 2019;109:288–96.
  14. Schmid V, Wagner R, Sailer C, et al. Non-alcoholic fatty liver disease and impaired proinsulin conversion as newly identified predictors of the long-term non-response to a lifestyle intervention for diabetes prevention: Results from the TULIP study. Diabetologia 2017;60:2341– 51. 


 

Photo by Jez Timms

Suboptimal Triglyceride Levels Among Statin Users in the National Health and Nutrition Examination Survey

Suboptimal Triglyceride Levels Among Statin Users in the National Health and Nutrition Examination Survey

By Heather Nelson Cortes, PhD and Kevin C Maki, PhD

 

Statin therapy is the primary treatment for dyslipidemia, even in those with moderately elevated triglycerides (TG).1  Hypertriglyceridemia, an independent risk factor of coronary heart disease (CHD), is defined as fasting TG >150 mg/dL.2  Meta-analyses have shown a 1.7-fold greater risk for CHD in those in the highest TG tertile compared to those in the lowest tertile.2,3  In a more recent longitudinal, real-world administrative database analysis, increased cardiovascular disease risk and direct healthcare costs were associated with hypertriglyceridemia, despite statin therapy and controlled low-density lipoprotein cholesterol (LDL-C) when compared to those with TG <150 mg/dL.4,5  Another study has also reported that approximately one-third of patients treated for dyslipidemia still have suboptimal TG levels.6

In the US population, limited data have been available on the prevalence and impact of hypertriglyceridemia in patients treated for dyslipidemia or with normal LDL-C levels, especially given the increase in statin use.  To help address this gap, Fan et al. analyzed National Health and Nutrition Examination Surveys (NHANES) from 2007-2014 to determine the prevalence of elevated TG levels in adults with and without statin use, as well as the associated 10-year predicted atherosclerotic cardiovascular disease (ASCVD) risk.7  The study included 9,593 US adults aged 20 years (219.9 million projected) and determined the proportion of persons with TG levels according to the categories of <150, 150-199, 200-499, and 500 mg/dL for both non-statin and statin users.

Proportion of US adults According to TG Category7

 

<150 mg/dL

150-199 mg/dL

≥ 200 mg/dL

Non-statin users

75.3%

12.8%

11.9%

Statin Users

68.4%

16.2%

15.4%

 

Among those with LDL-C <100 mg/dL (or <70 mg/dL in those with ASCVD), 27.6% had TG 150 mg/dL, despite statin use.  Significantly greater odds of TG 150 mg/dL in statin users were associated with higher age, higher body mass index, lower high-density lipoprotein cholesterol, higher LDL-C, and diabetes.  The estimated mean 10-year ASCVD risk from TG <150 to 500 mg/dL, ranged from 6.0-15.6% in those not taking statins, and 11.3-19.1% in statin users. This translates to a predicted 3.4 million ASCVD events over the next 10 years in those with TG 150 mg/dL.

Comment.  Based on these results in US adults, suboptimal TG levels are found in ~25% of the overall population and nearly one-third of adults on statin therapy.  TG elevation is associated with increased ASCVD risk, even when the LDL-C level is low.8  Lifestyle therapies are key in the management of an elevated TG level, including increased physical activity, weight loss, reduced glycemic load and alcohol restriction.1,9  The recently published results from the Reduction of Cardiovascular Events with Icosapent Ethyl (REDUCE-IT) trial demonstrated that ASCVD event risk was lowered by an impressive 25% in statin-treated high-risk patients with elevated TG by the addition of 4 g/d of icosapent ethyl (eicosapentaenoic acid [EPA] ethyl esters).10  Two additional large-scale trials are underway with TG-lowering drug therapies (Outcomes Study to Assess Statin Residual Risk Reduction with Epanova in High CV Risk Patients [STRENGTH] and Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes [PROMINENT]), which are evaluating effects of EPA + docosahexaenoic acid (DHA) carboxylic acids and pemafibrate, respectively.11,12  The results from the present survey suggest that the population-attributable risk due to elevated TG in the US is substantial, which underscores the importance of recognizing hypertriglyceridemia as a marker for ASCVD risk that can be addressed through lifestyle and pharmacologic therapies.

References

 

  1. Stone NJ, Robinson JG, Lichtenstein AH, et al. American College of Cardiology/American Heart Association task force on practice guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2889–2934
  2. Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation. 2007;115(4): 450–458.
  3. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk. 1996;3(2):213–219.
  4. Toth PP, Granowitz C, Hull M, et al. High triglycerides are associated with increased cardiovascular events, medical costs, and resource use: a real-world administrative claims analysis of statin-treated patients with high residual cardiovascular risk. J Am Heart Assoc. 2018;7:e008740.
  5. Nichols GA, Philip S, Reynolds K, et al. Increased cardiovascular risk in hypertriglyceridemic patients with statin-controlled LDL cholesterol. J Clin Endocrinol Metab. 2018;103:3019–3027.
  6. Wong ND, Chuang J, Wong K, et al. Residual dyslipidemia among United States adults treated with lipid modifying therapy (Data from National Health and Nutrition Examination Survey 2009-2010). Am J Cardiol. 2013;112:373–379.
  7. Fan W, Philip S, Granowitz C, et al. Hypertriglyceridemia in statin-treated US adults: the National Health and Nutrition Examination Survey. J Clin Lipidol. 2019;13:100–108.
  8. Miller M, Cannon CP, Murphy SA, et al. Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol. 2008;51:724–730.
  9. Jacobson A, Savji N, Blumenthal RS, Martin SS. American College of Cardiology Expert Analysis. Hypertriglyceridemia management according to the 2018 AHA/ACC guideline. January 11, 2019. Available at https://www.acc.org/latest-in-cardiology/articles/2019/01/11/07/39/hypertriglyceridemia-management-according-to-the-2018-aha-acc-guideline.
  10. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380:11–22.
  11. Nicholls SJ, Lincoff AM, Bash D, et al. Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol: rationale and design of the STRENGTH trial. Clin Cardiol. 2018;41:1281–1288.
  12. Pradhan AD, Paynter NP, Everett BM, et al. Rationale and design of the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study. Am Heart J. 2018;206:80–93.

 

 

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Association of Statin Adherence with Mortality in Patients with Atherosclerotic Cardiovascular Disease

Association of Statin Adherence with Mortality in Patients with Atherosclerotic Cardiovascular Disease

By Heather Nelson Cortes, PhD and Kevin C Maki, PhD

 

There is little doubt of the role that statins play in the reduction of mortality risk, mainly attributable to a benefit on death from cardiovascular causes.  A meta-analysis of statin clinical trials reported a 12% proportional reduction in all-cause mortality per mmol/L reduction in low-density lipoprotein cholesterol (LDL-C) with the use of statins (rate ratio [RR] 0.88, 95% confidence interval [CI] 0.84-0.91; p < 0.0001).1  In a systematic review, De Vera et al. reported an increased risk of adverse outcomes with poor statin therapy adherence.2  With such a strong link between statin adherence and decreased mortality, it is unclear why so many patients stop taking their statins or what the long-term effects on health and healthcare costs will be.  Results from surveys of statin adherence suggest that as many as 50% of patients for whom statin therapy is prescribed stop taking the medication within 12 months.3,4  Rates of discontinuation and poor adherence are high even among those with known atherosclerotic cardiovascular disease (ASCVD).3,4

 

To further assess the association between statin adherence and all-cause mortality, Rodriguez et al. conducted a retrospective cohort analysis of patients between the ages of 21-85 years with one or more International Classification of Diseases, Ninth Revision, Clinical Modification codes for ASCVD on two or more dates in the previous two years without intensity changes to their statin prescription.5  All patients were treated within the Veterans Affairs Health System between January 1, 2013 and April 2014.

 

The primary outcome was death from all causes adjusted for demographic and clinical characteristics, and adherence to other cardiac medications.  Secondary outcomes included 1-year mortality, 1-year hospitalization for ischemic heart disease or ischemic stroke.  A sensitivity analysis was also conducted to investigate an association between statin adherence and hospitalization for gastrointestinal bleeding and pneumonia.  Finally, the researchers sought to determine if the association between statin adherence and mortality was modified by statin intensity (low, medium, high) or by patient-level or system-level characteristics.

 

The medication possession ratio (MPR) was used to measure patient medication adherence.  The MPR is the number of days of outpatient statin supplied during a 12- month period divided by the number of days the patient was not hospitalized and alive in the same 12-month time frame.  Medication adherence was categorized as <50% MPR, 50-69% MPR, 70-89% MPR and ≥90% MPR.

 

The study included 347,104 patients with ASCVD on stable statin prescriptions.  The overall mean statin adherence in this population was ~88%; ~6% had a MPR of <50% and ~64% had a MPR of ≥90%.  Overall, women were less adherent than men (odds ratio, 0.89; 95% CI, 0.84-0.94), as were minority groups, while younger and older patients were less likely to be adherent compared with those aged 65-74 years.  During a mean (standard deviation) follow up of 2.9 (0.8) years there were 85,930 deaths (24.8%).  Compared to the most adherent patients (MPR ≥90%), patients with a MPR <50% had a hazard ratio (HR) adjusted for clinical characteristics and adherence to other cardiac medications of 1.30 (95% CI, 1.27-1.34), while those with a MPR of 50-69% had a HR of 1.21 (95% CI, 1.18-1.24), and those with an MPR of 70-89% had a HR of 1.08 (95% CI, 1.06-1.09).

 

After one year, hospitalizations for ischemic heart disease and stroke were more frequent in patients who were less adherent to their statin therapy.  The proportion of patients with a hospitalization for ischemic heart disease or ischemic stroke was 13.4% (n = 2653) for an MPR<50%, 13.1% (n = 4018) for an MPR of 50-69%, 11.5% (n = 8729) for an MPR of 70-89%, and 11.5% (n = 25434) for an MPR of ≥90% (p < 0.001).  This association remained even after adjusting for baseline characteristics.  There was no association between MPR and hospitalization for gastrointestinal bleeding or pneumonia.

 

Finally, in this cohort 42,010 (12%) patients were on low-intensity therapy, 217,570 (63%) were on moderate-intensity therapy, and 87,524 (25%) were on high-intensity treatment.  Patients on moderate-intensity statin therapy were more likely to adhere to statin therapy compared to patients in the low- and high-intensity therapy groups.  Patients with the highest MPR had lower LDL-C values (77.2 mg/dL for MPR ≥90% compared with 92.1 mg/dL for MPR <50%).

 

Comment.  The role that statins play in the reduction of mortality is not surprising.  When a patient consistently takes the statin as prescribed, their risk of cardiovascular mortality will likely decrease.  What is surprising is the lack of adherence by patients, especially over time, given the evidence supporting statin effectiveness.  Further research should focus on how to improve patient adherence to statin therapy.6

 

Another important consideration that is illustrated by the present study is that it is important to consider the effects of healthy and unhealthy user bias in observational studies.  Ann Marie Navar makes this point in an editorial accompanying the paper.6  Those with the poorest adherence to statin therapy (MPR <50%) had a 30% increase in mortality.  Adjustment for follow-up LDL-C levels reduced the mortality hazard by 10%.  Thus, only one third of the effect appears to be attributable to the main pathway through which statins alter risk.  This suggests the presence of residual confounding by other factors.  People who are adherent to therapy recommendations differ in numerous ways relevant to health outcomes from those who do not.  It is difficult, if not impossible, to fully account for differences in potential confounders through statistical modeling.  Thus, while a portion of the higher mortality risk among those with poor adherence is likely due to less impact of the drug itself, other factors also likely contribute to a similar or even larger degree.

 

This concept was recently illustrated in an analysis from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.7,8  Healthy 55- to74-year old participants were randomly assigned to receive usual care or a more intensive screening program.  Among those randomized to more intensive screening, 10.8% did not complete any of the recommended screening tests.  After 10 years, those non-adherent subjects had 50% higher mortality compared to those with full adherence who completed all recommended tests.  However, the increased mortality was not attributable only to cancers, but to a wide range of causes.  Thus, non-adherence to recommended screening (or to prescribed medication) is likely a marker for an array of behaviors associated with increased mortality risk.  This unhealthy or healthy user bias should be kept in mind when evaluating the results from observational studies of behaviors associated with health outcomes.  Those who choose to engage in a behavior they view as health-promoting, such as taking prescribed medication, undergoing recommended screening tests, following a diet or exercise program, or taking a dietary supplement, may differ in important ways from those who choose not to engage in the behavior, resulting in healthy user bias.  Conversely, those who engage in behaviors they know are unhealthy, such as cigarette smoking, may also engage in other unhealthy behaviors (unhealthy user bias).  Thus, estimates of the effects of behavioral exposures from observational studies should be interpreted with caution and should ideally be verified in prospective, randomized, controlled trials.

 

References

 

  1. Baigent C, Keech A, Kearney PM, et al. Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267-1278.
  2. DeVera MA, Bhole V, Burns LC, Lacaille D. Impact of statin adherence on cardiovascular disease and mortality outcomes: a systematic review. Br J Clin Pharmacol. 2014;78:684-698.
  3. Maddox TM, Chan PS, Spertus JA, et al. Variations in coronary artery disease secondary prevention prescriptions among outpatient cardiology practices: insights from the NCDR (National Cardiovascular Data Registry). J Am Coll Cardiol. 2014;63:539-546.
  4. Hirsh BJ, Smilowitz NR, Rosenson RS, et al. Utilization of and adherence to guideline-recommended lipid-lowering therapy after acute coronary syndrome: opportunities for improvement. J Am Coll Cardiol. 2015;66:184-192.
  5. Rodriguez F, Maron DJ, Knowles JW, et al. Association of statin adherence with mortality in patients with atherosclerotic cardiovascular disease. JAMA Cardiol. 2019; Epub ahead of print.
  6. Navar AM. Statins work, but only in people who take them. JAMA Cardiol. 2019; Epub ahead of print.
  7. Pierre-Victor D, Pinsky PF. Association of nonadherence to cancer screening examinations with mortality from unrelated causes: a secondary analysis of the PLCO Cancer Screening trial. JAMA Intern Med. 2019;179:196-203.
  8. Grady D. Why is nonadherence to cancer screening associated with increased mortality? JAMA Intern Med. 2018; Epub ahead of print.

 

OLYMPUS DIGITAL CAMERA

Viscous Fiber Supplements in Diabetes Control: Results from a Systematic Review and Meta-analysis of Randomized Controlled Trials

Viscous Fiber Supplements in Diabetes Control: Results from a Systematic Review and Meta-analysis of Randomized Controlled Trials

By Heather Nelson Cortes, PhD and Kevin C Maki, PhD

According to the recent 2019 American Diabetes Association (ADA) Standards of Medical Care in Diabetes, people with diabetes should increase their intake of viscous fiber from sources such as oats, legumes, and citrus to help regulate blood glucose levels and lower risk of cardiovascular disease1. Viscous fibers are described as such because they increase viscosity in the human gut, thereby reducing the rate at which carbohydrates are digested and the glucose molecules from them absorbed.  These effects occur because the viscous solution impedes the ability of digestive enzymes to reach starch molecules and slows the rate at which glucose molecules reach the brush border in the intestinal lumen, where absorption can occur.  The result is flattening of the postprandial glycemic and insulinemic responses.  While these acute effects are well established, the longer-term impacts of viscous fibers on glycemic control markers are not well known2.

 

In a systematic review and meta-analysis, Jovanovski2 investigated the effect of viscous dietary fiber supplementation on markers of glycemic control in people with type 2 diabetes (T2D).  A comprehensive literature search on MEDLINE, Embase, and Cochrane Central Register of Controlled Trials through June 15, 2018 identified 2,716 potential RCTs.  After reviewing the studies based on the inclusion/exclusion criteria, 27 studies (n = 1,394) were identified for the review and meta-analysis.  Inclusion criteria were: ≥3 weeks in duration, studied viscous fiber supplementation (β-glucan, guar gum, konjac, psyllium, pectin, xanthan gum, locust bean gum, alginate, agar) compared to an appropriate control (i.e., fiber-free supplement or one containing insoluble fiber, background diet, or placebo), and included at least one glycemic measurement (glycated hemoglobin [HbA1c], fasting glucose, fasting insulin, homeostatic model assessment of insulin resistance [HOMA-IR], or fructosamine).

 

The median age of subjects was 60 years (range 48-67) and they had a median body mass index of 27 kg/m2 (range 26-32 kg/m2).  The median dose of viscous fibers in the studies was 13.1 g/day (range 2.55-21.0 g/day) and the median study duration was 8 weeks (range 3-52 weeks).

 

Compared to control groups, inclusion of viscous fiber in the diet was associated with significant reductions in HbA1c, fasting blood glucose and HOMA- IR. 

 

  • HbA1c: mean difference (MD) -0.58% 95% confidence interval (CI) -0.88%, -0.28%; p = 0.0002;
  • Fasting blood glucose: MD -14.8 mg/dL 95% CI -23.8, -5.59; p = 0.001
  • HOMA-IR: MD -1.89 95% CI -3.45, -0.33; p = 0.02.

 

There were no differences between viscous fiber groups and controls for fasting insulin (MD -2.53 µU/mL 95% CI -5.41, 0.35; p = 0.08) or fructosamine (MD -0.12 mmol/L 95% CI -0.39, 0.14; p = 0.37).  Only 2 studies reported fructosamine, so this finding should be interpreted with caution.  There was no evidence of a significant dose-response effect.  Results for HbA1c, fasting glucose, fasting insulin, and HOMA-IR were graded moderate for certainty of evidence, while fructosamine was graded low.

 

Comment.  Viscous fiber intake, through consumption of food sources such as legumes, whole fruits (e.g., apples and pears) and whole grain oats and barley, as well as dietary supplementation with products such as psyllium (e.g., Metamucil®), methylcellulose (e.g., Citrucel®) or konjac (e.g., Lipozene®), appears to have several benefits regarding cardiometabolic health.  For those with T2D, this meta-analysis shows evidence to support favorable effects on glycemic control and insulin sensitivity.  More research is needed to establish more clearly whether all viscous fibers enhance insulin sensitivity, or whether this property is limited to those with certain characteristics, such colonic fermentability or content of specific bioactive compounds3,4.  Evidence from other sources also shows that viscous fiber lowers the circulating cholesterol level, likely by trapping cholesterol and bile acids, thus preventing their absorption/reabsorption3.  In addition, viscous fibers appear to play a role in appetite regulation, enhancing satiety after meal5.

 

The meta-analysis by Jovanovski and colleagues shows that inclusion of viscous fiber in the diet produces clinically meaningful improvements in glycemic control for patients with T2D.  Based on this, as well as evidence for other benefits (cholesterol lowering and enhanced satiety), inclusion of viscous fiber from foods and/or supplements should be considered an important component of the management plan for patients with T2D.

 

References

  1. American Diabetes Association. 10. Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes—2019. Diabetes Care. 2019;42(Supplement 1): S103-S123.

 

  1. Jovanovski E, Khayyat R,  Zurbau A,  et al. Should viscous fiber supplements be considered in diabetes control? Results from a systematic review and meta-analysis of randomized controlled trials. Diabetes Care. 2019 Jan; doi:10.2337 [Epub ahead of print].

 

  1. Weickert MO, Pfeiffer AFH. Impact of dietary fiber consumption on insulin resistance and the prevention of type 2 diabetes. J Nutr. 2018;148:7-12.

 

  1. Kärkkäninen O, Lankinen MA, Vitale M, et al. Diets rich in whole grains increase betainized compounds associated with glucose metabolism. Am J Clin Nutr. 2018;108:971-979.

 

  1. Rebello CJ, Chu YF, Johnson WD, et al. The role of meal viscosity and oat ß–glucan characteristics in human appetite control: a randomized crossover trial. Nutr J. 2014;13:49.

 

 

Photo by Sara Dubler

Potential Cognitive Benefits of Intensive Blood Pressure Lowering

Potential Cognitive Benefits of Intensive Blood Pressure Lowering

By Heather Nelson Cortes, PhD and Kevin C Maki, PhD

Currently there are no well-established clinical interventions for the prevention of mild cognitive impairment (MCI) or dementia.  Alzheimer’s disease and dementia are expected to affect 115 million people worldwide by the year 20501.  More than 75% of people over the age of 65 have hypertension, a modifiable risk factor that has been associated with the risk for developing MCI and dementia2-4.  Vascular damage is commonly found in Alzheimer’s disease, along with the β-amyloid and tau pathology5-7, yet research has been inconclusive on the role of blood pressure (BP) reduction and risk for MCI and dementia.

 

Recently, results from the Systolic Blood Pressure Intervention Trial (SPRINT) Memory and Cognition in Decreased Hypertension (MIND) study were published from the parent SPRINT study8.  SPRINT-MIND was designed to assess the effect of intensive blood pressure treatment/control on the risk for dementia.  The primary outcome was the occurrence of adjudicated probable dementia.  Secondary outcomes included adjudicated MCI and a composite outcome of MCI or probable dementia.

 

The parent SPRINT study was designed to test the effect of more intensive BP control on cardiovascular (primary end point), renal and cognitive outcomes in subjects with systolic blood pressure (SBP) greater than 130 mm Hg who had an increased cardiovascular risk but did not have diabetes or preexisting stroke9.  In SPRINT, 9361 persons were randomized to either a standard treatment (SBP goal, <140 mm Hg; n = 4683) or to an intensive treatment (SBP goal, <120 mm Hg; n = 4678).  After a median follow up of 3.26 years, SPRINT was stopped early because of the observed benefits in the primary outcome of cardiovascular disease events as well as reduced all-cause mortality9.

 

Of the 9361 subjects randomized in SPRINT, 91.5% (n = 8562) completed at least 1 follow-up cognitive assessment as part of SPRINT-MIND.  The median intervention period was 3.34 years with a total median follow-up of 5.11 years, including time after the intervention ended.  In the intensive treatment group, the primary outcome, adjudicated probable dementia, occurred in 149 subjects compared to 176 subjects in the standard treatment group (7.2 vs. 8.6 cases per 1000 person-years; hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.67-1.04, p = 0.10).  Intensive BP control did significantly reduce the risk of MCI (14.6 vs. 18.3 cases per 1000 person-years; HR, 0.81; 95% CI, 0.69-0.95, p = 0.007) and the combined rate of MCI or probable dementia (20.2 vs. 24.1 cases per 1000 person-years; HR, 0.85; 95% CI, 0.74-0.97, p = 0.01)8.

 

Comment. SPRINT-MIND did not demonstrate a statistically significant effect on the primary outcome of adjudicated probable dementia, possibly due to the early termination of SPRINT and the resulting loss of statistical power.  The study did, however, show reductions in the secondary outcomes of incident MCI (19% lower risk) and the combined outcome of MCI or probable dementia (15% lower risk).  While it is disappointing that the primary outcome showed no significant benefit (a non-significant 17% lower incidence in the intensive BP control group), the reduction in risk for the secondary outcomes is encouraging and suggests a plausible link between intensive BP treatment and prevention of MCI and dementia.  These results support the need for additional research to confirm and extend the SPRINT-MIND findings.  Because dementia and MCI have several risk factors in common with cardiometabolic diseases such as heart disease, stroke and type 2 diabetes, the SPRINT-MIND findings also suggest that there might be potential for reductions in cardiometabolic risk factors beyond BP to play a role in maintaining optimal brain health10

 

References

  1. Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia:
a systematic review and meta-analysis. Alzheimers Dement. 2013;9(1):63-75.
  2. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/ NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71(6):1269-1324.
  3. Kivipelto M, Helkala EL, Hänninen T, et al. Midlife vascular risk factors and late-life mild cognitive impairment: a population-based study. Neurology. 2001;56(12):1683-1689.
  4. Qiu C, Winblad B, Fratiglioni L. The age-dependent relation of blood pressure to cognitive function and dementia. Lancet Neurol. 2005;4(8):487-499.
  5. Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology. 2007;69(24):2197-2204.
  6. HaroutunianV, Schnaider-Beeri M, Schmeidler J, et al. Role of the neuropathology of Alzheimer disease in dementia in the oldest-old. Arch Neurol. 2008;65(9):1211-1217.
  7. Savva GM, Wharton SB, Ince PG, Forster G, Matthews FE, Brayne C; Medical Research Council Cognitive Function and Ageing Study. Age, neuropathology, and dementia. N Engl J Med. 2009;360(22):2302-2309.
  8. SPRINT MIND Investigators for the SPRINT Research Group, Williamson JD, Pajewski NM, et al. Effect of intensive vs. standard blood pressure control on probable dementia: a randomized clinical trial. 2019; doi:10.1001/jama.2018.21442.
  9. Wright JT Jr, Williamson JD, Whelton PK, et al; SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2103-2116.
  10. Santos CY, Snyder PJ, Wu WC, Zhang M, Ecehverria A, Alber J. Pathophysiologic relationship between Alzheimer’s disease, cerebrovascular disease, and cardiovascular risk: a review and synthesis. Alzheimers Dement (Amst). 2017;7:69-87.

 

Nurse measuring patient blood pressure