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Articles by John R. Guyton
Total Records ( 10 ) for John R. Guyton
  John R. Guyton , Ronald B. Goldberg , Theodore Mazzone , Ruth S. Weinstock , Adam Polis , Elizabeth Rosenberg and Andrew M. Tershakovec
 

Background

Type 2 diabetes mellitus (T2DM) is associated with a high risk for coronary heart disease (CHD). A variety of lipoprotein and apolipoprotein (Apo) ratios have been proposed that may reflect the balance of cholesterol delivery and removal at the arterial wall and provide an assessment of CHD risk that is supplemental to low-density lipoprotein cholesterol (LDL-C), the primary guide for cholesterol-lowering therapy in patients at risk.

Objective

To examine changes in lipoprotein and apolipoprotein ratios in the VYTAL trial of hypercholesterolemic patients with T2DM.

Methods

Changes in the ratios LDL-C/high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC)/HDL-C, non-HDL-C/HDL-C, and ApoB/ApoA-I were assessed in this randomized, double-blind, parallel-group study that enrolled T2DM patients with LDL-C ≥100 mg/dL for 6-week treatments with either the usual daily starting doses of atorvastatin (ATORVA) 10 or 20 mg or ezetimibe/simvastatin (EZE/SIMVA) 10/20 mg, or the next highest doses (ATORVA 40 mg, EZE/SIMVA 10/40 mg). Changes in lipoprotein and apolipoprotein ratios, prespecified exploratory endpoints, were analyzed using analysis of variance.

Results

Efficacy results were based on 1198 patients with sufficient data among 1229 randomized patients. Baseline lipoproteins, apolipoproteins, and ratios were comparable among treatment groups. EZE/SIMVA produced significantly greater reductions compared with ATORVA in each lipoprotein or apolipoprotein ratio at each dose comparison (P < 0.001). For example, reductions from baseline in TC/HDL-C were ATORVA 10 mg, −30.2%; ATORVA 20 mg −34.9%; EZE/SIMVA 10/20 mg, −41.6%; ATORVA 40 mg, −37.9%; and EZE/SIMVA 10/40 mg, −43.5%. Tolerability of the two treatments was similar.

Conclusion

For the doses assessed, EZE/SIMVA was more effective compared with ATORVA in lowering the lipoprotein and apolipoprotein ratios that might be considered secondary measures of CHD risk.

  Ruth S. Weinstock , Ronald B. Goldberg , John R. Guyton , Theodore Mazzone , Adam Polis , Joanne E. Tomassini , Jianxin Lin , Arvind Shah and Andrew M. Tershakovec
 

Background

In addition to low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non–HDL-C), apolipoprotein B (ApoB), and high-sensitivity C-reactive protein (hs-CRP) are considered predictive for cardiovascular disease in type 2 diabetes mellitus (T2DM) patients.

Objective

To assess the proportion of T2DM patients with hypercholesterolemia who attained the optional target level of LDL-C (<70 mg/dL) and additionally non-HDL-C (<100 mg/dL), ApoB (<90 mg/dL), and hs-CRP (<2 mg/L), following treatment with ezetimibe/simvastatin (E/S) vs atorvastatin (A).

Methods

This post-hoc analysis of a multicenter, randomized, double-blind, 6-week parallel study assessed the proportion of T2DM patients who attained specified LDL-C levels and non-HDL-C, ApoB, and hs-CRP with usual, recommended starting doses of E/S (10/20 mg) vs A (10 or 20 mg) and next highest doses of E/S (10/40 mg) vs A (40 mg) by logistic regression. Baseline triglyceride and hs-CRP effects were also evaluated.

Results

Significantly higher percentages of patients treated with E/S compared to A achieved individual and concurrent target levels of LDL-C (<70 mg/dL), non-HDL-C (<100 mg/dL), and ApoB (<90 mg/dL) at all dose comparisons (P < 0.05 to P < 0.001). Baseline triglyceride levels had no effect on reaching LDL-C levels. Attainment of non-HDL-C (<100 mg/dL), and ApoB (<90 mg/dL) was lower at triglycerides ≥200 mg/dL than <200 mg/dL. Achievement of hs-CRP level (<2 mg/L) was comparable for both treatments. Significantly more patients attained both LDL-C (<70 mg/dL) and hs-CRP (<2 mg/L) at all E/S doses compared to A (P < 0.05 to P < 0.001), regardless of baseline CRP levels.

Conclusion

E/S provides a therapeutic option to T2DM patients for lowering not only LDL-C, but also non-HDL-C, ApoB, and hs-CRP. These factors may help guide assessment and treatment of cardiovascular disease risk in these patients.

  W. Virgil Brown , Luther Clark , James M. Falko , John R. Guyton , Tomas J. Rees , Gustav Schonfeld and Maria F. Lopes-Virella
  Patients with diabetes or metabolic syndrome frequently have higher triglycerides, lower high-density lipoprotein (HDL) cholesterol, and more particles containing apolipoprotein B (ApoB); this combination contributes significantly to their cardiovascular risk. Optimal management of dyslipidemia and increased atherosclerotic risk requires a fundamental understanding of diabetic dyslipidemia, the clinical evidence for different interventional strategies, and the potential benefit of achieving therapeutic targets. For this review, we considered guidelines, recent reviews, and clinical trial results. The features of dyslipidemia in type 2 diabetes and the metabolic syndrome are linked metabolically and are related to central adiposity and insulin resistance. Levels of ApoB and HDL cholesterol are particularly important markers of risk. Guidelines broadly agree that low-density lipoprotein (LDL) cholesterol should be reduced below population average levels. Additional or secondary strategies in patients with diabetes or the metabolic syndrome are to decrease non-HDL cholesterol, ApoB and/or LDL particle concentration, to increase HDL cholesterol, and to reduce triglycerides. Lifestyle changes and statins are the bedrock of treatment, although second-line treatment using fibrates or niacin will likely benefit many patients with residual risk. Ezetimibe, too, has a favorable effect on lipid profile and inflammatory biomarkers of risk. Dyslipidemia in type 2 diabetes and metabolic syndrome has a distinct profile, suggesting the need for a tailored therapy that targets the key features of lowered HDL cholesterol and raised triglycerides, in addition to the primary antiatherogenic strategy of lowering ApoB-containing lipoproteins, such as LDL. With the prominent failure of some recent intervention trials, new therapeutic strategies-particularly safe and effective means to raise HDL-are needed to manage dyslipidemia in this high-risk population.
  W. Virgil Brown , Anne C. Goldberg , John R. Guyton and Robert H. Knopp
  Not available
  John R. Guyton and Phillip D. Simmons
 

Background

Niacin lowers levels of atherogenic apolipoprotein-B-containing lipoproteins, including lipoprotein(a), and raises levels of atheroprotective high-density lipoproteins. However, cutaneous flushing has been a major impediment to the clinical use of niacin.

Objective

Extended-release niacin (niacin ER) is a once-daily prescription niacin formulated to limit flushing. An analysis of flushing events with niacin ER should facilitate its clinical use.

Methods

The analysis pools previously unpublished data on flushing and related side effects from four randomized, double-blind studies of niacin ER, and also reviews long-term data on flushing from a 96-week open label, uncontrolled study.

Results

Among 333 patients treated with niacin ER (once daily at bedtime) for 3 to 6 months, 83% reported at least one flushing episode, compared to 18% of patients treated with placebo or gemfibrozil. Approximately 50% had ≤5 flushing events, and only 5% reported >20 flushing events. The majority (76%) of patients treated with niacin ER rated flushing events as mild to moderate in intensity; 6% of patients withdrew due to flushing. In an 8-week comparison of niacin ER once daily at bedtime with immediate-release niacin three times daily at equivalent total daily doses, the total number of flushing events was 76% lower in the niacin ER group.

Conclusion

Niacin ER can help control flushing events while providing favorable effects on lipids and lipoproteins. The generalizability of this analysis may be limited by self-selection and motivation of research subjects, and further studies of flushing in the clinical practice setting are warranted.

  Westly A. Bailey , Eric C. Westman , Megan L. Marquart and John R. Guyton
 

Purpose

To assess the effectiveness of low glycemic dietary counseling for weight loss among moderately hypertriglyceridemic patients in an academic referral lipid clinic.

Methods

During 1998 to 2000, weight loss advice followed traditional guidelines. Beginning in 2001, hypertriglyceridemic patients were advised to greatly reduce intake of high glycemic carbohydrates. The clinic database was queried for all patients initiating consultative treatment from 1998 through 2004. Subjects were included if initial fasting triglyceride was 200 to 800 mg/dL and if at least two follow-up visits were made during a period of 365 days or more. Mean percent changes from baseline in weight and lipid/lipoproteins beyond 1 year were calculated. Macronutrient composition was determined 3- to 5-day food diaries submitted by subjects from the highest quartile of weight loss.

Results

Patients (n = 56) first seen in 1998-2000 had 0.2 ± 0.7% mean weight gain beyond one year compared with 3.0 ± 0.5% weight loss for patients (n = 141) initially seen in 2001 to 2004 (P < .001 comparing groups). Weight loss correlated with triglyceride reduction (−2.6 mg/dL per kilogram body weight, r = 0.29, P < .001) and with HDL-C increase (0.22 mg/dL per kilogram body weight, r = 0.16; P = .038). Highest quartile weight losers in the low glycemic group (n = 15) reported consuming 44% carbohydrate calories, 32% fat, 22% protein, and 2% alcohol.

Conclusion

Hypertriglyceridemic patients who received low glycemic dietary counseling and maintained clinic attendance more than 1 year achieved mean 3.0% weight loss. This was improved compared with historical controls with traditional dietary counseling. Food diaries from successful weight losers suggested compliance with a low glycemic, moderately reduced carbohydrate diet plan.

  Veena Rajanna , Kristen B. Campbell , Jeffrey Leimberger , Bibhu D. Mohanty and John R. Guyton
 

Background

Niacin increases fasting glucose levels, and statins modestly increase the rate of new-onset diabetes. The clinical importance and mechanisms of these effects are not fully explored.

Objective

On the basis of anecdotal observations, we hypothesized that elevated morning fasting glucose may be accompanied by relatively normal hemoglobin A1c (HbA1c) in patients treated with niacin and other lipid-modifying drugs. We conducted a retrospective cohort analysis to test this hypothesis.

Methods

The Duke Lipid Clinic database (1994-2007) was screened for simultaneous determinations of fasting morning glucose and HbA1c, yielding 1483 data pairs among 554 subjects. Subjects with diabetes, by clinical diagnosis, medication, or any HbA1c ≥6.5%, or nondiabetes were analyzed separately. Repeated-measures linear regression featured glucose as dependent variable and included terms for HbA1c, drug(s), and their interaction.

Results

Regression lines for glucose on HbA1c had altered slopes in the presence of niacin and/or statin use in normoglycemic subjects. The corresponding interaction terms (drug and HbA1c) were significant (niacin P = .026, statin P = .013). Fibrate use had no effect (interaction P = .49). When modeled together, niacin and statin effects were independent. Regression curves in diabetic patients were not affected by lipid medications.

Conclusion

Elevated fasting glucose may be accompanied by relatively normal HbA1c in niacin- and statin-treated patients. HbA1c reflects average daily glucose levels and is likely a better measure of the glycemic effect of lipid medications. Because our data were retrospective, confirmation from randomized trials is needed.

  Mark J. Cziraky , Vincent J. Willey , James M. McKenney , Siddhesh A. Kamat , Maxine D. Fisher , John R. Guyton , Terry A. Jacobson and Michael H. Davidson
 

Background

The occurrence of low rates of rhabdomyolysis among patients receiving lipid-lowering drugs (LLDs) in randomized clinical trials may be elucidated with population-based studies.

Objective

To determine the risk of hospitalized rhabdomyolysis associated with LLD therapy.

Methods

This observational study used claims data from 9 million members of five United States health plans to identify patients (≥18 years) who received >2 statin and nonstatin LLDs during July 2000 to December 2004. Inpatient International Classification of Diseases, Ninth Revision, Clinical Modification, codes for rhabdomyolysis (791.3, 728.89, and 728.88) were observed during the follow-up period; cases were confirmed with patients' medical records. Rhabdomyolysis events were reported per 10,000 person-years of LLD exposure; multivariate analysis was conducted.

Results

The study cohort (N = 473,343) received 490,988 and 11,624 person-years of LLD, and combination therapy, respectively. Medical charts were obtained for 104 of 144 eligible patients with rhabdomyolysis claims; 42 cases were confirmed. With atorvastatin as reference, rhabdomyolysis rates (95% confidence interval) were greatest for cerivastatin, 8.4 (2.3-21.7); no difference among available statins was observed. Rates for other LLD monotherapies were: niacin, 2.1 (0.3−7.7), ezetimibe, 2.1 (0.3−7.8), fenofibrate, 0 (0−1.7), and gemfibrozil, 2.0 (0.5−5.2). Multivariate analysis showed only cerivastatin with a significantly greater risk of rhabdomyolysis (odds ratio 4.74, 95% confidence interval 1.1-21.2, P = .041) versus atorvastatin among the statins. Combination therapies had increased rhabdomyolysis risk (OR 7.1, 1.6-31.6, P = .010) versus LLDs alone.

Conclusion

The risk of habdomyolysis among hospitalized patients receiving statins was low; no difference among the available statins was evident. Further data are needed to establish the risk profile but current findings already offer guidance to physicians.

  Wanda C. Lakey , Nicole Greyshock and John R. Guyton
  Multiple cholesterol-reducing therapies have been shown to induce the regression of tendon xanthoma in patients with familial hypercholesterolemia. We present 3 cases of adverse reactions in Achilles tendon xanthomas after the addition of niacin and bile acid sequestrants to ongoing statin therapy. Reduction in tendon dimensions and marked softening of xanthomas were interpreted as cholesterol removal from heavily infiltrated tissue sites. In 2 cases, changes in the xanthomas occurred despite only minor lipoprotein improvements, raising the possibility of direct drug effects in cholesterol-infiltrated tissue. Intriguingly, recent studies have described niacin receptor-mediated effects in macrophages. In summary, although adverse reactions in Achilles tendon xanthomas appear to be infrequent, clinicians should be aware of this phenomenon in their patients after intensifying lipid treatments, especially with the use of niacin in patients with familial hypercholesterolemia. Xanthoma responses may provide clues to new pharmacologic effects in cholesterol-infiltrated tissues.
  Daniel E. Okorodudu , Matthew J. Crowley , Siby Sebastian , Jennifer V. Rowell and John R. Guyton
 

Objective

We review disorders associated with splenomegaly and dyslipidemia with an emphasis on the APOE p.Leu167del mutation. Recent studies suggest that this rare mutation may present more often without splenomegaly in patients with familial combined hyperlipidemia or autosomal dominant hypercholesterolemia. We supplement the literature review by reporting a new kindred.

Methods

We reviewed our 3405-patient lipid clinic database to identify persons with dyslipidemia and splenomegaly. Identified patients were evaluated for relevant disorders, including genetic testing for a 3-base pair deletion in APOE that causes deletion of leucine at position 167 of apolipoprotein E.

Results

We identified 4 patients with splenomegaly and dyslipidemia, one of whom had a heterozygous APOE p.Leu167del mutation. This proband is a 76-year-old man with a history of splenomegaly first noted at age 13 and subsequent diagnosis of hypertriglyceridemia, low high-density lipoprotein cholesterol, leukopenia, and thrombocytopenia in his third decade. He never required splenectomy, and his splenic enlargement regressed over time with medical management of his hypertriglyceridemia. The APOE p.Leu167del mutation was also found in the proband's son and granddaughter, neither of whom has splenomegaly or marked dyslipidemia.

Conclusion

Splenomegaly in association with dyslipidemia may indicate the presence of an underlying disorder. We discuss possible causes, review the literature relating to the rare APOE p.Leu167del mutation, and present a 3-generation kindred with variable phenotypic expression of this mutation. Severity of expression may depend on genotype, sex, or effective medical management of dyslipidemia or a combination of these factors. Aggressive lipid treatment may improve or prevent splenomegaly among patients with this disorder.

 
 
 
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