Haptoglobin Phenotype and Intensive Glycemic Control for Coronary Artery Disease Risk Reduction in People With Type 2 Diabetes: The ADVANCE Study.

OBJECTIVE: Intensive glycemic control reduced coronary artery disease (CAD) events among the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study participants with the haptoglobin (Hp)2-2 phenotype but not in participants without the Hp2-2 phenotype. It is unknown whether and how these results translate across different demographic/clinical characteristics and treatment strategies. RESEARCH DESIGN AND METHODS: Haptoglobin phenotype was measured in available samples from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) biomarker case-cohort study. Weighted multivariable-adjusted Cox regression models were used to evaluate the association between intensive glycemic control (HbA1c target of ≤6.5%) versus standard therapy (based on local guidelines) and major CAD events among participants with (n = 1,327) and without (n = 2,077) the Hp2-2 phenotype separately and within prespecified stratifications by sex, race, previous cardiovascular disease (CVD), diabetes duration, and HDL-cholesterol. RESULTS: While the hazard ratios (HRs) were in the hypothesized differing directions, compared with standard therapy, intensive glycemic control was not significantly associated with risk of CAD events among participants without (1.04, 95% CI 0.82-1.32) or with (0.84, 0.63-1.14, Pinteraction = 0.27) the Hp2-2 phenotype overall. Intensive therapy was associated with lower CAD risk among participants with the Hp2-2 phenotype who had no previous CVD (0.47, 0.29-0.76, Pinteraction = 0.01). CONCLUSIONS: Our findings suggest that intensive glycemic control contributes to the prevention of major CAD events among ADVANCE participants with the Hp2-2 phenotype and no previous CVD and are in alignment with our hypothesis that intensive glycemic control may be beneficial in a subset of people with the Hp2-2 phenotype.

Intensive lifestyle intervention in type 2 diabetes and risk of incident coronary artery disease for the common haptoglobin phenotypes: the Look AHEAD study.

BACKGROUND: Intensive glycemic control reduced coronary artery disease (CAD) events among the Action to Control Cardiovascular Disease Risk in Diabetes (ACCORD) participants with the haptoglobin (Hp) 2-2 phenotype only. It remains unknown whether Hp phenotype modifies the effect of an intensive lifestyle intervention (ILI) on CAD in type 2 diabetes. METHODS: Haptoglobin phenotype was measured in 4542 samples from the Action for Health in Diabetes (Look AHEAD) study. Cox regression models assessed the effect of ILI (focused on weight loss from caloric restriction and physical activity) versus diabetes support and education (DSE) on CAD events in each phenotype group, and within pre-specified subgroups including race/ethnicity, sex, history of cardiovascular disease, diabetes medication use, and diabetes duration. RESULTS: 1590 (35%) participants had the Hp2-2 phenotype. The ILI did not lower glycated hemoglobin (%HbA1c) to < 6.5% in either phenotype, with a peak significant difference between treatment arms of 0.5% [non-Hp2-2] and 0.6% [Hp2-2]. The cumulative CAD incidence was 13.4% and 13.8% in the DSE arm and 12.2% and 13.6% in the ILI arm for non-Hp2-2 and Hp2-2 groups, respectively. Compared to DSE, the ILI was not associated with CAD among participants without (HR = 0.95, 95% CI 0.78-1.17) or with (0.89, 0.68-1.19) the Hp2-2 phenotype (p-interaction between Hp phenotype and ILI = 0.58). After Bonferroni correction, there were no significant results among any subgroups. CONCLUSIONS: Hp phenotype did not modify the effect of the weight loss ILI on risk of CAD in Look AHEAD, potentially because it did not substantially impact glycemic control among participants with or without the Hp2-2 phenotype. Further research is needed to determine if these results are conclusive.

Relationship Between Time-Varying Achieved High-Density Lipoprotein Cholesterol and Risk of Coronary Events Depends on Haptoglobin Phenotype Within the ACCORD Lipid Study.

Background The Hp (haptoglobin)2-2 phenotype (~40% of people) is associated with dysfunctional high-density lipoprotein (HDL) that is heavily oxidized in hyperglycemia, which may explain why raising HDL-cholesterol (HDL-C) does not reliably prevent coronary artery disease (CAD) in diabetes. Methods and Results In this observational study using longitudinal data from the ACCORD (Action to Control Cardiovascular Risk in Diabetes) lipid trial, time-varying (achieved) HDL-C updated at 4, 8, and 12 months, and annually thereafter over a mean of 4.7 years, was analyzed in relation to risk of CAD and secondary outcomes using Cox proportional hazards regression with time-varying covariables among participants with (n=1781) and without (n=3191) the Hp2-2 phenotype. HDL-C did not differ between the phenotypes throughout the study. Having low HDL-C (<40 mg/dL for male participants and <50 mg/dL for female participants) was associated with a greater risk of CAD compared with non-low HDL-C among participants with the non-Hp2-2 phenotype (hazard ratio [HR], 1.48 [95% CI, 1.18-1.87]) but not among the Hp2-2 phenotype (HR, 0.97 [95% CI, 0.70-1.35]; P interaction=0.03). Similarly, an inverse relationship was observed between HDL-C quintiles and CAD risk among participants without the Hp2-2 phenotype, whereas no significant inverse relationship was observed among participants with the Hp2-2 phenotype (P interaction=0.38). Among the Hp2-2 phenotype group, having low HDL-C was associated with higher risk of CVD mortality (HR, 2.09 [95% CI, 1.05-4.13]), and compared with the lowest HDL-C quintile, higher quintiles were associated with lower risk of CVD mortality and congestive heart failure. Conclusions Hp phenotype modified the association between HDL-C and risk of CAD in the ACCORD lipid study, suggesting that HDL dysfunction in the Hp2-2 phenotype may hinder CAD-protective properties of HDL-C.

The Relationship Between Time-Varying Achieved HbA1c and Risk of Coronary Events Depends on Haptoglobin Phenotype Among White and Black ACCORD Participants.

OBJECTIVE: Intensive glycemic therapy reduced coronary artery disease (CAD) events among White participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study with the haptoglobin (Hp)2-2 phenotype, while participants without the Hp2-2 phenotype had no CAD benefit. The association between achieved glycated hemoglobin (HbA1c) and CAD for each Hp phenotype remains unknown. RESEARCH DESIGN AND METHODS: Achieved HbA1c was similar in each phenotype throughout the study. Prospectively collected HbA1c data (categorized as <6.0%, 6.0-6.5%, 6.6-6.9%, or ≥8.0% compared with 7.0-7.9%) from the ACCORD study, updated every 4 months over a median of 4.7 years, were analyzed in relation to CAD in the Hp2-2 (n = 3,322) and non-Hp2-2 (n = 5,949) phenotypes separately overall, and within White (63%, 37% Hp2-2) and Black (19%, 26% Hp2-2) participants using Cox proportional hazards regression with time-varying covariables. RESULTS: Compared with HbA1c of 7.0-7.9%, having HbA1c ≥8.0% was associated with CAD risk among White (adjusted HR [aHR] 1.43, 95% CI 1.03-1.98) and Black (2.86, 1.09-7.51) participants with the Hp2-2 phenotype, but not when all Hp2-2 participants were combined overall (1.30, 0.99-1.70), and not among participants without the Hp2-2 phenotype. HbA1c <7.0% was not associated with a lower risk of CAD for any Hp phenotype. CONCLUSIONS: Achieving HbA1c >8.0% compared with 7.0-7.9% was consistently associated with incident CAD risk among White and Black ACCORD participants with the Hp2-2 phenotype, while no association was observed among participants without the Hp2-2 phenotype. We found no evidence that HbA1c concentration <7.0% prevents CAD in either Hp phenotype group.

Many authors of publicly available top-selling nutrition books in Canada are without clinical nutrition credentials, do not cite evidence, and promote their own services or products.

The accuracy of books as public nutrition resources varies substantially; whether authors of publicly available nutrition books possess related experience, cite scientific evidence, or have other financial incentives has not been assessed thoroughly. This study aimed to determine if publicly available top-selling nutrition books are written by authors who (1) have relevant expertise, (2) cite scientific evidence, and (3) benefit financially in other ways. Best-selling nutrition books were gathered from Amazon Canada. Differences in scientific citations and financial incentives were compared between authors with and without credentials. Authors who were Doctor of Medicine (MD), registered dietitians (RD), chiropractors, or naturopathic doctors had more in-text citations (56% versus 25%; p = 0.014) and cited more scientific articles (83% versus 50%; p = 0.0045) compared to all other authors. The majority of authors of publicly available top-selling nutrition books in Canada did not have MD/RD credentials. Many of the authors promoted their own services or products, regardless of credentials.

Eating Timing and Frequency as a Predictor of Hospitalization and/or Mortality From Coronary Artery Disease: The Linked CCHS-DAD-CMDB 2004-2013 Study.

Background: Coronary artery disease (CAD) is a major overlapping challenge in both clinical and public health realms due to high rates of hospitalization and mortality. Despite nutrition being a key risk factor for CAD, little is known about eating timing and frequency in Canadians or their relation to risk of hospitalization and/or mortality from CAD. Methods: Breakfast consumption, between-meal consumption, eating frequency, and established CAD risk factors were assessed at baseline in 13,328 adults free of cancer and CAD from the 2004 Canadian Community Health Survey, Cycle 2.2, Nutrition Focus and were linked to administrative health databases to determine incidence of hospitalization and/or mortality from CAD in the following 9 years. Multivariable-adjusted hazard ratios with 95% confidence intervals estimated from Cox proportional hazards models were computed to test for associations between eating timing/frequency and hospitalization and/or mortality from CAD (n = 746 cases). Results: Skipping breakfast (12.0% of participants) and engaging in between-meal consumption (90.2%) were common practices, as was eating 4-5 times per day (55.2%). Skipping breakfast, between-meal consumption, and eating more or less than 4-5 times/day were strongly and bi-directionally associated with many sociodemographic, lifestyle, and metabolic risk factors at baseline. No associations were observed between skipping breakfast, between-meal consumption, or eating frequency and risk of hospitalization and/or mortality from CAD. Conclusions: Skipping breakfast, between-meal consumption, and eating frequency were associated with numerous established risk and preventative factors for CAD at baseline but were not directly associated with the risk of hospitalization and/or mortality from CAD in this cohort of Canadian adults.

Introduction: La maladie coronarienne (MC) est un enjeu majeur chevauchant les domaines clinique et de santé publique en raison des taux élevés d'hospitalisation et de mortalité. Bien que la nutrition soit un facteur de risque fondamental de la MC, on en connaît peu sur le moment et la fréquence de la consommation d'aliments chez les Canadiens ou sur leur relation au risque d'hospitalisation et/ou de mortalité en raison de la MC. Méthodes: Nous avons initialement évalué la prise du déjeuner, la consommation entre les repas, la fréquence de la consommation d'aliments et les facteurs de risque établis de MC de 13 328 adultes indemnes de cancer et de MC de l'Enquête sur la santé dans les collectivités canadiennes de 2004, cycle 2.2, volet nutrition, et avons lié les bases de données administratives en santé pour déterminer la fréquence d'hospitalisation et/ou de mortalité en raison de la MC dans les neuf années subséquentes. Nous avons calculé les rapports de risque ajustés à plusieurs variables à intervalles de confiance à 95 % estimés à partir des modèles à risques proportionnels de Cox pour vérifier les associations entre le moment et la fréquence de la consommation d'aliments et l'hospitalisation et/ou la mortalité en raison de la MC (n = 746 cas). Résultats: L'absence du déjeuner (12,0 % des participants), la consommation d'aliments entre les repas (90,2 %) et la consommation d'aliments de 4 à 5 fois par jour (55,2 %) étaient des pratiques courantes. L'absence du déjeuner, la consommation d'aliments entre les repas et la consommation d'aliments plus ou moins 4-5 fois/jour étaient fortement et bidirectionnellement associées aux facteurs de risque sociodémographiques, liés au mode de vie et métaboliques initiaux. Nous n'avons observé aucune association entre l'absence du déjeuner, la consommation d'aliments entre les repas ou la fréquence de la consommation d'aliments, et le risque d'hospitalisation et/ou de mortalité en raison de la MC. Conclusions: L'absence du déjeuner, la consommation d'aliments entre les repas et la fréquence de la consommation d'aliments étaient associées à de nombreux risques établis et de facteurs préventifs initiaux de la MC, mais n'étaient pas directement associées au risque d'hospitalisation et/ou de mortalité en raison de la MC dans cette cohorte d'adultes canadiens.

Prospective study of breakfast frequency and timing and the risk of incident type 2 diabetes in community-dwelling older adults: the Cardiovascular Health Study.

BACKGROUND: No evidence-based recommendations regarding optimal breakfast frequency and timing and type 2 diabetes mellitus (T2DM) exist for older adults because of limited studies. OBJECTIVES: We sought to prospectively assess relations between breakfast frequency and timing and T2DM risk among older adults and determine whether these depended on sex or cardiometabolic risk factors. METHODS: Weekly breakfast frequency and usual daily breakfast time were assessed by questionnaire at baseline in 3747 older adults (aged ≥ 65 y) from the Cardiovascular Health Study (CHS) who were free of cancer and T2DM and followed for 17.6 y. Multivariable-adjusted hazard ratios (aHRs) with 95% CIs estimated from Cox proportional hazards models were used to quantify associations with T2DM. RESULTS: Most CHS participants (median age: 74 y; IQR: 71-78 y) consumed breakfast daily (85.5%), and 73% had their first daily eating occasion between 07:00 and 09:00, both of which were associated with higher socioeconomic status, factors that are indicative of a healthier lifestyle, and lower levels of cardiometabolic risk indicators at baseline. During follow-up, 547 T2DM cases were documented. No strong evidence was observed linking breakfast frequency and risk of T2DM. Compared with participants whose breakfast timing (first eating occasion of the day) was 07:00-09:00, those who broke fast after 09:00 had an aHR for T2DM of 0.71 (95% CI: 0.51, 0.99). This association was present in participants with impaired fasting glucose at baseline (aHR: 0.61; 95% CI: 0.39, 0.95) but not in those without (aHR: 0.83; 95% CI: 0.50, 1.38). No associations between eating frequency or timing and T2DM were observed within other prespecified subgroups. CONCLUSIONS: Eating breakfast daily was not associated with either higher or lower risk of T2DM in this cohort of older adults, whereas a later (after 09:00) daily first eating occasion time was associated with lower T2DM risk in participants with impaired fasting glucose at baseline.This trial was registered at clinicaltrials.gov as NCT00005133.

Haptoglobin Phenotype Modifies the Effect of Fenofibrate on Risk of Coronary Event: ACCORD Lipid Trial.

OBJECTIVE: The haptoglobin (Hp)2-2 phenotype (∼35-40% of people) is associated with increased oxidation and dysfunctional HDL in hyperglycemia and may explain why drugs designed to pharmacologically raise HDL cholesterol and lower triglycerides have not reliably prevented cardiovascular disease in diabetes. We aimed to determine whether the effect of adding fenofibrate versus placebo to simvastatin on the risk of coronary artery disease (CAD) events depends on Hp phenotype in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial. RESEARCH DESIGN AND METHODS: Cox proportional hazards regression models quantified the relationship between fenofibrate therapy and CAD events in the ACCORD lipid trial in participants with the Hp2-2 phenotype (n = 1,795) separately from those without (n = 3,201). RESULTS: Fenofibrate therapy successfully lowered the risk of CAD events in participants without the Hp2-2 phenotype (multivariable adjusted hazard ratio 0.74 [95% CI 0.60-0.90] compared with no fenofibrate therapy) but not in participants with the Hp2-2 phenotype (1.16 [0.87-1.56]; P interaction = 0.009). Subgroup analyses revealed that this protective effect of fenofibrate against CAD events among the non-Hp2-2 phenotype group was pronounced in participants with severe dyslipidemia (P interaction = 0.01) and in males (P interaction = 0.02) with an increased CAD risk from fenofibrate treatment observed in females with the Hp2-2 phenotype (P interaction = 0.002). CONCLUSIONS: The effect of fenofibrate added to simvastatin on risk of CAD events depends on Hp phenotype in the ACCORD lipid trial.

Prospective Study of Skipping Meals to Lose Weight as a Predictor of Incident Type 2 Diabetes With Potential Modification by Cardiometabolic Risk Factors: The Canadian 1995 Nova Scotia Health Survey.

BACKGROUND: Skipping meals is an increasingly common practice to lose weight among North American adults. However, the long-term effect of this practice on incident type 2 diabetes mellitus (T2DM) remains unknown. We assessed whether skipping meals to lose weight is associated with T2DM risk and whether this association is modified by cardiometabolic risk factors. METHODS: Skipping meals to lose weight was assessed by questionnaire in 2,288 adults from the 1995 Nova Scotia Health Survey and was linked to administrative health databases to determine T2DM incidence in the following 23 years. Multivariable-adjusted Cox proportional hazards models estimated hazard ratios (aHRs) and 95% confidence intervals (CIs) for T2DM. RESULTS: During follow up, 378 T2DM cases were diagnosed. Compared with participants who did not skip meals to lose weight, those who did (2.2%) had a 125% higher risk of T2DM (aHR, 2.25; 95% CI, 1.31 to 3.86). This association was no longer present after further adjustment for baseline body mass index (BMI) (aHR, 1.66; 95% CI, 0.96 to 2.85). Skipping meals to lose weight was associated with T2DM among participants who were men (n=1,135; aHR, 2.09; 95% CI, 1.09 to 4.02) or had a BMI <30 kg/m2 (n=1,676; aHR, 2.64, 95% CI, 1.15 to 6.06), elevated cholesterol (n=1,146; aHR, 2.11; 95% CI, 1.06 to 4.22), high blood pressure (n=1,133; aHR, 2.10; 95% CI, 1.10 to 4.01) and restless sleep (n=1,186; aHR, 2.19; 95% CI, 1.13 to 4.25), but not among women, those with a BMI of ≥30 kg/m2 and those without elevated cholesterol, high blood pressure or restless sleep. CONCLUSIONS: Skipping meals to lose weight may be a predictive modifiable risk factor for developing T2DM over time, potentially working in connection with other T2DM risk factors.

Haptoglobin Phenotype Modifies the Influence of Intensive Glycemic Control on Cardiovascular Outcomes.

BACKGROUND: Whereas there exists a direct relationship between glycated hemoglobin and cardiovascular disease (CVD), clinical trials targeting glycated hemoglobin to near-normal levels using intensive therapy have failed to prevent CVD and have even increased mortality, making clinical decision making difficult. A common polymorphism at the haptoglobin (Hp) genetic locus is associated with CVD, especially coronary heart disease, in the setting of hyperglycemia. OBJECTIVES: This study sought to determine whether the treatment difference of intensive versus standard glucose-lowering therapy on risk of CVD events in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study depended on Hp phenotype. METHODS: Hp phenotype was measured within 5,806 non-Hispanic white ACCORD participants using a validated assay. Adjusted hazard ratios (aHR) with 95% confidence intervals (CI) estimated from stratified Cox regression models were used to quantify the association between intensive therapy and incident CVD for the 2 different Hp phenotype groups (Hp2-2, Hp1 carriers). RESULTS: Compared with standard therapy, intensive therapy was associated with a lower risk of incident coronary heart disease among participants with the Hp2-2 phenotype (n = 2,133; aHR: 0.71; 95% CI: 0.55 to 0.91; p = 0.006), but not among the other 2 phenotypes (Hp1 allele carriers) (n = 3,673; aHR: 0.95; 95% CI: 0.79 to 1.13; p = 0.550). The same pattern was observed for CVD. Conversely, intensive therapy was associated with an increased risk of fatal CVD (aHR: 1.50; 95% CI: 1.00 to 2.25; p = 0.049) and total mortality (aHR: 1.40; 95% CI: 1.08 to 1.81; p = 0.011) among the Hp1 carriers, whereas this risk was not increased in the Hp2-2 phenotype (fatal CVD: aHR: 1.02; 95% CI: 0.59 to 1.77; p = 0.931; total mortality: aHR: 0.98; 95% CI: 0.68 to 1.41; p = 0.908). CONCLUSIONS: Intensive glucose-lowering therapy was effective at preventing incident coronary heart disease and CVD events in ACCORD study participants with the Hp2-2 phenotype but not in Hp1 carriers, who had increased mortality risk from intensive therapy.