Acarbose for the prevention of Type 2 diabetes,hypertension and cardiovascular disease in subjects with impaired glucose tolerance: facts and interpretations concerning the critical analysis of the STOP-NIDDM Trial data

The STOP-NIDDM Trial has shown that acarbose treatment in subjects with impaired glucose tolerance is associated with a significant risk reduction in the development of diabetes, hypertension and cardiovascular complications. Kaiser and Sawicki have accused the investigators of the STOP-NIDDM Trial of major biases in the conduct of the study, of manipulating the data and of conflict of interest. The aim of this paper is to present data and explanations refuting these allegations.In the STOP-NIDDM Trial, 61 subjects were excluded from the efficacy analysis before unblinding for legitimate reasons: failure to satisfy major entry criteria (n=17) and lack of post-randomisation data (n=44). Blinding and randomisation were carried out by an independent biostatistician. Titration of placebo/acarbose is well described in the protocol and in the study design paper.Of the study population, 9.3% had a fasting plasma glucose of 7.0 mmol/l at screening and could have been diabetic according to the new diagnostic criteria. However, even if these subjects are excluded, patients having acarbose treatment still saw a significant risk reduction in the development of diabetes (p=0.0027). The changes in weight are consistent in different publications and are related to different times of follow-up and assessment. Weight change does have an effect on the development of diabetes, but acarbose treatment is still effective even after adjusting for this (p=0.0063). The cardiovascular endpoints were a clearly designated assessment in the original protocol, and only those defined in the protocol and ascertained by the independent Cardiovascular Event Adjudication Committee were used in the analysis. Hypertension was defined according to the most recent diagnostic criteria.The STOP-NIDDM Trial results are scientifically sound and credible. The investigators stand strongly behind these results demonstrating that acarbose treatment is associated with a delay in the development of diabetes, hypertension and cardiovascular complications in a high-risk population with IGT.Abbreviations BID two times a day - FPG fasting plasma glucose - OD once a day - STOP-NIDDM Study to Prevent Non-Insulin-Dependent Diabetes Mellitus - TID three times a day     

Effect of plant sterols in combination with other cholesterol-lowering foods

The National Cholesterol Education Program Adult Treatment Panel III guidelines advocate effective combinations of cholesterol-lowering dietary components. This approach (dietary portfolio) produces large reductions in serum cholesterol, but the contribution of individual components remains to be established. We therefore assessed the effect of eliminating one out of the 4 dietary portfolio components. Plant sterols were selected because at 2 g/d, they have been reported to reduce low-density lipoprotein cholesterol (LDL-C) by 9% to 14%. Forty-two hyperlipidemic subjects were prescribed diets high in soy protein (22.5 g/1000 kcal), viscous fibers (10 g/1000 kcal), and almonds (23 g/1000 kcal) for 80 weeks. Subjects were instructed to take these together with plant sterols (1.0 g/1000 kcal) except between weeks 52 and 62. While taking the full dietary portfolio, including plant sterols, mean LDL-C reduction from baseline was 15.4% +/- 1.6% (P < .001). After sterol elimination, mean LDL-C reduction was 9.0% +/- 1.5% (P < .001). Comparable LDL-C reductions were also seen for the 18 subjects with a complete data set: on plant sterols, 16.7% +/- 3.1% (P < .001) and off plant sterols, 10.3% +/- 2.6% (P < .001), resulting in a 6.3% +/- 2.0% (P = .005) difference attributable to plant sterols. Compliance in this group of 18 was 67.0% +/- 5.9% for plant sterols and 61.9% +/- 4.8% for the other components. In combination with other cholesterol-lowering foods and against the background of a low-saturated fat diet, plant sterols contributed over one third of the LDL-C reduction seen with the dietary portfolio after 1 year of following dietary advice.     

Detection of silent myocardial ischemia in diabetes mellitus

The prevalence of silent myocardial ischemia and its relation to autonomic dysfunction and pain threshold was studied in 58 men with diabetes mellitus and without cardiac symptoms. All patients underwent 48-hour ambulatory electrocardiographic monitoring and exercise testing after assessment of their autonomic function and pain threshold. Silent myocardial ischemia, defined as greater than or equal to 1 mm of ST-segment depression on either exercise testing or ambulatory electrocardiographic monitoring, was corroborated by exercise-induced reversible defect(s) on tomographic thallium scintigraphy. Autonomic function was assessed by heart rate response to: (1) Valsalva maneuver, (2) deep breathing, and (3) upright posture, as well as by diastolic blood pressure response to sustained handgrip and systolic blood pressure response to upright posture. Autonomic dysfunction was defined as greater than or equal to 2 abnormal responses. Pain threshold measurements were performed using electrical cutaneous stimulation of both forearms. Of the 58 diabetic patients, 21 were found to have autonomic dysfunction (36%). Silent myocardial ischemia was detected in 10 patients (17%), and was significantly more frequent in patients with than without autonomic dysfunction (38 vs 5%, p = 0.003). There was no difference in the electrical pain threshold or tolerance in subjects with and without silent myocardial ischemia. It is concluded that silent myocardial ischemia in asymptomatic diabetic men occurs frequently and in association with autonomic dysfunction, suggesting that diabetic neuropathy may be implicated in the mechanism of silent myocardial ischemia.     

Bisphosphonates for treatment of osteoporosis: Expected benefits,potential harms,and drug holidays

Objective

To outline the efficacy and risks of bisphosphonate therapy for the management of osteoporosis and describe which patients might be eligible for bisphosphonate “drug holiday.”

Quality of evidence

MEDLINE (PubMed, through December 31, 2012) was used to identify relevant publications for inclusion. Most of the evidence cited is level II evidence (non-randomized, cohort, and other comparisons trials).

Main message

The antifracture efficacy of approved first-line bisphosphonates has been proven in randomized controlled clinical trials. However, with more extensive and prolonged clinical use of bisphosphonates, associations have been reported between their administration and the occurrence of rare, but serious, adverse events. Osteonecrosis of the jaw and atypical subtrochanteric and diaphyseal femur fractures might be related to the use of bisphosphonates in osteoporosis, but they are exceedingly rare and they often occur with other comorbidities or concomitant medication use. Drug holidays should only be considered in low-risk patients and in select patients at moderate risk of fracture after 3 to 5 years of therapy.

Conclusion

When bisphosphonates are prescribed to patients at high risk of fracture, their antifracture benefits considerably outweigh their potential for harm. For patients taking bisphosphonates for 3 to 5 years, reassess the need for ongoing therapy.Postmenopausal osteoporosis is characterized by accelerated loss of bone mass and deterioration of bone architecture, leading to increased fracture risk.¹ Osteoporotic fractures decrease personal independence,² increase morbidity,^3–5 and shorten life^6,7; thus, their prevention is paramount.Aminobisphosphonates (alendronate, risedronate, and zoledronic acid) are first-line therapies for the prevention of fracture in high-risk individuals.⁸ Aminobisphosphonates might also increase survival in ways at least partially independent of their contribution to decrease in fracture incidence.^9–11 While the antifracture efficacy and relative safety of the aminobisphosphonates have been well established in clinical trials,^12–16 there have been concerns that prolonged use of these drugs might increase the risk of rare, but serious, adverse events.^17–21     

Complementary and alternative medicine use by osteoporosis clinic patients

Summary We describe complementary and alternative medicine use (CAM) in 360 patients attending osteoporosis clinics. Of these patients, 57% were CAM users. Predictors of CAM use included lower mental quality of life, younger age and higher education. Less than half of CAM use was disclosed to physicians, despite potential adverse interactions. Introduction The prevalence of complementary and alternative medicine (CAM) use in osteoporosis clinics is not known. The objective of this study was to describe the pattern of CAM use in this population. Methods We performed a cross-sectional study of 360 patients attending academic osteoporosis clinics in Toronto, Canada in 2001. Subjects completed a self-administered questionnaire on CAM use. Health-related quality of life (HQL) was measured with the Short-Form 36v2. Comparative statistics and logistic regression were performed to identify sociodemographic, HQL and clinical correlates of CAM use. Results More than 80% of participants were women, Caucasian and had at least a high school education. Of subjects, 57% used CAM in the previous year. Only 44% of CAM use was disclosed to a medical doctor. CAM users and non-users did not differ in clinical characteristics such as bone mineral density, level of comorbidity and fracture history. In univariate analysis, CAM users were less satisfied with conventional medicine. However, when we explored patient satisfaction, comorbidities and sociodemographic as predictors for CAM use, the multivariable analyses showed that lower mental HQL, younger age, and post-secondary education were the only significant predictors. We identified 35 cases in which the utilization of CAM supplements could possibly exacerbate existing medical conditions. Conclusion Patients attending osteoporosis clinics frequently use CAM. Conceptually, the predictors of use identified in this study may fit into a socio-behavioral model that helps explain why people turn to CAM. Physicians may need to elicit a history of CAM use more vigilantly so as to better screen for possible adverse clinical interactions. Funding: Dr. A. M. Cheung is supported by a career award from the Canadian Institute of Health Research and an Ontario Premier’s Research Excellence Award, Dr. S. Jamal is supported by a career award from the Canadian Institute of Health Research, and Dr. G. A. Hawker receives support as the FM Hill Chair in Academic Women’s Medicine at Women’s College Hospital and the University of Toronto and as the recipient of a Senior Distinguished Research Investigator Award from The Arthritis Society of Canada.     

In vitro study of osteoblastic cells from patients with idiopathic osteoporosis and comparison with cells from non-osteoporotic controls [1]

We have examined bone cells derived from iliac crest trabecular explants of 30 patients with idiopathic osteoporosis and 45 control subjects in order to determine whether intrinsic abnormalities in osteoblast function may contribute to the decreased bone formation observed in this disease. Bone cells isolated from all subjects expressed several in vitro characteristics of the osteoblast phenotype including adenylate cyclase responsiveness to parathyroid hormone (PTH) and prostaglandin E₁ (PGE₁), basal and 1,25(OH)₂D₃-stimulated alkaline phosphatase activity and osteocalcin production. Results were compared amongst three subject groups: young controls less than 40 years old, older controls over 40 years old, and osteoporotics. Osteoporotic cells were found in general to be fully active in vitro. There were no differences between osteoporotic and control cells in their basal levels of adenylate cyclase, or alkaline phosphatase, in their growth rates, or cell morphology. The cyclic AMP (cAMP) response to PTH was significantly lower in osteoporotic cells (71%,p<0.01) and older control cells (64% ,p<0.005) relative to the response in cells from younger controls, suggesting that the decreased responsiveness in osteoporotic cells was due to subject age rather than the osteoporotic state. At the same time, the cAMP responses to PGE₁ and cholera toxin were similar in cells from all three subject groups. The response to forskolin was reduced to about 40% in osteoporotic cells compared with controls, but this was not mirrored by similar differences in the responses to PTH, PGE₁ or cholera toxin, suggesting that the availability of catalytic subunits is not rate-limiting in these cells. l,25 (OH)₂D₃-stimulated osteocalcin production was 220% higher in osteoporotics than in older controls, but the numbers tested were small and the difference did not reach significance. The one significant abnormality we observed in osteoporotic cells was in alkaline phosphatase activity: 1,25(OH)₂D₃-stimulated alkaline phosphatase activity was twofold higher in osteoporotics than in younger (p<0.05), older (p<0.05) and pooled controls (p<0.025). The significance of this finding is unknown, but we postulate that it may reflect an intrinsic abnormality in osteoblast function in patients with idiopathic osteoporosis.