Bernd Richter

Intensified glucose lowering in type 2 diabetes: time for a reappraisal

Obesity, urbanisation and an ageing population combine to drive a dramatic increase in the global prevalence of type 2 diabetes [1], a condition in which the morbidity and mortality from cardiovascular disease substantially outweigh the risk of microvascular complications such as renal disease [2]. Statins and antihypertensive agents lower cardiovascular risk in type 2 diabetes, but the benefits of intensified glucose-lowering remain controversial in this context— management recommendations tend to be based on extrapolation from surrogate endpoints. Recent studies have shown that intensified glycaemic control has limited impact on cardiovascular disease, but there is little indication that entrenched positions in the debate have been affected. Intensified glucose-lowering is more difficult to achieve, and has a greater negative impact on quality of life, than lowering cholesterol or blood pressure [3]. Nonetheless, and despite questionable benefits to the individual, substantial pressure has been exerted on patients and practitioners to achieve rigorous glycaemic targets. This article examines the evidence for and against intensified glucoselowering therapy in type 2 diabetes.

Emerging role of dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes

Background: In type 2 diabetes mellitus (T2DM) there is a progressive loss of β-cell function. One new approach yielding promising results is the use of the orally active dipeptidyl peptidase-4 (DPP-4) inhibitors. However, every new compound for T2DM has to prove long-term safety especially on cardiovascular outcomes. Objectives: Systematic review and meta-analysis of the effects of sitagliptin and vildagliptin therapy on main efficacy parameters and safety. Selection criteria, data collection, and analysis: Randomized controlled clinical studies of at least 12 weeks’ duration in T2DM. Results: DPP-4 inhibitors versus placebo showed glycosylated hemoglobin A1c(A1c) improvements of 0.7% versus placebo but not compared to monotherapy with other hypoglycemic agents (0.3% in favor of controls). The overall risk profile of DPP-4 inhibitors was low, however a 34% relative risk increase (95% confidence interval 10% to 64%, P = 0.004) was noted for all cause infection associated with sitagliptin use. No data on immune function, health-related quality of life and diabetic complications could be extracted. Conclusions: DPP-4 inhibitors have some theoretical advantages over existing therapies with oral antidiabetic compounds but should currently be restricted to individual patients. Long-term data on cardiovascular outcomes and safety are needed before widespread use of these new agents.

Meta-analysis does not allow appraisal of complex interventions in diabetes and hypertension self-management: a methodological review

Common methodologies used in systematic reviews do not allow adequate appraisal of complex interventions. The aim of the present study was to describe and critically appraise current methods of systematic reviews on complex interventions, using diabetes and hypertension patient education as examples. PubMed, the Cumulative Index to Nursing and Allied Health (CINAHL), the Cochrane Library and Health Technology Assessment databases were searched. Systematic reviews focusing on diabetes or hypertension patient education were included. Authors were contacted. Two investigators independently evaluated the reviews. The available evidence of three patient education programmes of diabetes and hypertension self-management implemented in Germany was used as a reference. We included 14 reviews; 12 reviews mentioned that the included education programmes were multidimensional. Reviews on comparable topics identified different publications of the same programme. Identical programmes were classified differently within and between reviews. Education programmes were dissected to analyse effects of single components. Different components of identical programmes were used. Interdependencies between components were not explored. Six reviews performed meta-analysis across programmes with heterogeneous educational or organisational approaches. The complexity of efficacy measures was disregarded: e.g. HbA1c was used as an isolated outcome variable without considering treatment goals, effects on hypoglycaemia, body weight or quality of life. Our results indicate that methods of current systematic reviews are not fully equipped to appraise patient education and self-management programmes. Since these are complex and heterogeneous interventions, consideration of aggregated evidence is necessary.

Intensified glucose control in type 2 diabetes--whose agenda?

How solid is the evidence for glucose lowering in people with diabetes? The Diabetes Control and Complications Trial showed that glucose control slows progression of microvascular complications in type 1 diabetes, and the UK Prospective Diabetes Study (UKPDS) showed the same for type 2 diabetes. The main diff erence between the studies was the high incidence of arterial disease in type 2 diabetes (22% of UKPDS participants had a coronary or stroke event within 10 years of enrolment). What was needed, therefore, was an unequivocal demonstration that macrovascular disease would respond to tight glucose control in type 2 diabetes. But combined analysis of four major trials (some 27 000 patients) suggested that lowering glycosylated haemoglobin (HbA1C) by around 1% had a minor eff ect on heart disease (6·3 coronary heart events prevented for every 1000 individuals treated for a mean of 4·4 years), and no eff ect on stroke, cardiovascular mortality, total mortality, blindness, or renal failure. The onlooker might imagine that a relatively minor benefi t such as this would have prompted policy makers to reconsider the role of aggressive blood-glucose lowering in type 2 diabetes. Not so. If the benefi ts of intensive glucose lowering in type 2 diabetes are only minor, what are the merits of population screening? A recent analysis from the American Diabetes Association (ADA), supported by an educational grant from three drug companies involved in diabetes care, modelled gains in quality-adjusted lifeyears (QALYs) with diff erent approaches to screening in the USA. The optimum model estimated that between 138 and 208 people would need screening to prevent one myocardial infarction over 50 years of follow-up, with similar numbers to prevent one person becoming blind. It was concluded that screening would be cost eff ective when started between 30 and 45 years of age, and repeated every 3–5 years, assuming that all those diagnosed would be treated to a target HbA1C below 7%. One additional result would be a diagnosis of diabetes for an additional 10–12% of the senior US population. The model assumes that pharmacological glucose lowering fully reverses the impact of hyperglycaemia on complications, and has no eff ect on quality of life (disutility). The fi rst assumption has been challenged in both observational and interventional studies. The second seems optimistic, because at least two-thirds of those diagnosed are likely to require multiple injection regimens plus blood-glucose monitoring within 15 years 3 Ministry of Health. 2007 China tobacco control report. May, 2007. http:// tobaccofreecenter.org/fi les/pdfs/reports_articles/2007%20China% 20MOH%20Tobacco%20Control%20Report.pdf (accessed June 2, 2010). 4 Yang GH, Ma JM, Liu N, Zhou LN. Smoking and passive smoking in Chinese, 2002. Chin J Epidemiol 2005; 26: 77–83 (in Chinese). 5 Shi Y, Yu C, Luo A, Huang Y, Warner DO. Perioperative tobacco interventions by Chinese anesthesiologists: practices and attitudes. Anesthesiology 2010; 112: 338–46. 6 Ceraso M, McElroy JA, Kuang X, et al. Smoking, barriers to quitting, and smoking-related knowledge, attitudes, and patient practices among male physicians in China. Prev Chronic Dis 2009; 6: A06. 7 Zhou J, Abdullah AS, Pun VC, Huang D, Lu S, Luo S. Smoking status and cessation counseling practices among physicians, Guangxi, China, 2007. Prev Chronic Dis 2010; 7: A15. 8 Bland B. China tells doctors to quit smoking to set example to patients. BMJ 2009; 338: b993. 9 Chinese Ministry of Health. Decision on banning smoking in all health facilities by 2011. May 22, 2009. http://www.moh.gov.cn/publicfi les/ business/htmlfi les/mohbgt/s9510/200905/40804.htm (accessed June 1, 2010) (in Chinese). 10 The Chinese Ministry of Health. Health statistical digest. 2009. http://www.moh.gov.cn/publicfi les/business/htmlfi les/mohwsbwstjxxzx/ s8208/ 201001/45652.htm (accessed June 3, 2010) (in Chinese). 11 Gonhuan Y. China wrestles with tobacco control: interview by Weiyuan Cui. Bull World Health Organ 2010; 88: 251–52. 12 Yan J, Xiao S, Ouyang D, Jiang D, He C, Yi S. Smoking behavior, knowledge, attitudes and practice among health care providers in Changsha city, China. Nicotine Tob Res 2008; 10: 737–44. 13 Chinese Ministry of Health. Press conference on China’s nursing and smoke free health facilities. May 10, 2010. http://www.moh.gov.cn/publicfi les/ business/htmlfi les/wsb/pxwfb /index.htm (accessed Sept 15, 2010) (in Chinese).

Aspirin in diabetic retinopathy: A systematic review

Diabetes mellitus is a risk factor for eye disease that can lead to blindness. There have been both concerns that aspirin use might worsen diabetic retinopathy, as well as hopes that aspirin might be beneficial in treating it. We investigated whether there are beneficial effects of aspirin alone and in combination with other antiplatelet agents in the treatment of diabetic retinopathy, and the relative hazards for the development of high-risk proliferative retinopathy following aspirin treatment. We conducted a sensitive search for randomized controlled trials combined with index terms for identifying studies on aspirin treatment in diabetic retinopathy in the Cochrane Library (issue 4, 2001) and Medline (1966 to October, 2001). We examined randomized controlled clinical trials in diabetic patients with (non) proliferative diabetic retinopathy and aspirin treatment alone or in combination with dipyramidole versus placebo administration. Two independent reviewers judged trial eligibility, collected details of study population, interventions, and outcomes using a standard data extraction form. One reviewer assessed the quality of trial reporting. We identified six publications pertinent to our objective. Aspirin dosages ranged from 650 mg to 990 mg daily, the dose of dipyridamole, used in only one trial, was 225 mg per day. Studies lasted 8 weeks to 5 years. All trials showed that aspirin alone or in combination with dipyridamole neither lowered nor increased the risk of the development of diabetic retinopathy. The results suggest that there are no ocular contraindications to taking aspirin if required as part of a treatment for cardiovascular diseases or other medical indications.

Pharmacotherapy for thyroid nodules: A systematic review and meta-analysis

The review highlights the uncertainty in the management of nodular thyroid disease. Thyroxine suppressive treatment is given in the hope that nodules might decrease in size, sometimes assuming that dependency on TSH is different in benign and malignant nodular disease. Follow-up of benign nodules over 10 years suggested that most remain the same, shrink, or disappear [14]. TSH suppression may lead to hyperthyroidism, reduced bone density [37.39], and atrial fibrilation; however, apart from reduction of nodule size or arrest in nodule growth, thyroxine therapy may benefit patients by reducing perinodular volume. Consequently, both pressure symptoms and cosmetic complaints could improve. Unfortunately, no information concerning symptoms or well-being is available from published randomized trials. In conclusion, more high quality studies of sufficient duration with adequate power estimation are needed. Uncertainty about predictors of response or the impact on outcomes that are important to patients leaves considerable doubt about the wisdom of applying suppressive therapy. Future studies shoudl include patient-important outcomes including thyroid cancer incidence, health-related quality of life and costs.

Effects of on-demand beta2-agonist inhalation in moderate-to-severe asthma. A randomized controlled trial.

Abstract. Richter B, Bender R, Berger M (Heinrich‐Heine‐University of Duesseldorf and University of Bielefeld, Germany). Effects of on‐demand β2‐agonist inhalation in moderate‐to‐severe asthma. A randomized controlled trial. J Intern Med 2000; 247: 657–666.

Unrelated and alternative donor allogeneic stem cell transplant in patients with relapsed or refractory Hodgkin lymphoma: a systematic review

Abstract Allogeneic stem cell transplant (allo-SCT) is considered a clinical option for patients with Hodgkin lymphoma (HL) who have experienced at least two chemosensitive relapses. The aim of this systematic review was to determine the benefits and harms of allo-SCT with an unrelated donor (UD) versus related donor (RD) allo-SCT for adult patients with HL. Alternative donor sources such as haploidentical donor cells (Haplo) and umbilical cord blood (UCB) were also included. The available evidence was limited. Ten studies were included in this assessment. Four studies provided sufficient data to compare UD with RD allo-SCT. None of these studies was a randomized controlled trial. Additionally, three non-comparative studies, such as registry analyses, which considered patients with UD transplants were included. The risk of bias in the studies was high. Results on overall and progression-free survival (PFS) showed no consistent tendency in favor of a donor type. Results on therapy-associated mortality and acute (grade II–IV) and chronic graft-versus-host disease were also inconsistent. The study comparing UCB with RD transplants and two non-comparative studies with UCB transplants showed similar results. One of the studies comparing additionally Haplo with RD transplants indicated a benefit in PFS for the Haplo transplant group. In summary, our findings do not indicate a substantial outcome disadvantage of UD and alternative donor sources versus RD allo-SCT for adult patients with advanced HL.

Criteria for decision-making – what makes sense?

Rational medical decision-making increasingly demands the acquisition of critical appraisal skills through application of the principles of evidence-based medicine and clinical epidemiology. Moreover, mastery of information technology to reduce time constraints and data overload is necessary. Ultimately, decision-making has to take into account patient preferences in order to establish real communication to optimise shared decision endeavours.

All That Glitters Isn't Gold: A Survey on Acknowledgment of Limitations in Biomedical Studies

Background Acknowledgment of all serious limitations to research evidence is important for patient care and scientific progress. Formal research on how biomedical authors acknowledge limitations is scarce. Objectives To assess the extent to which limitations are acknowledged in biomedical publications explicitly, and implicitly by investigating the use of phrases that express uncertainty, so-called hedges; to assess the association between industry support and the extent of hedging. Design We analyzed reporting of limitations and use of hedges in 300 biomedical publications published in 30 high and medium -ranked journals in 2007. Hedges were assessed using linguistic software that assigned weights between 1 and 5 to each expression of uncertainty. Results Twenty-seven percent of publications (81/300) did not mention any limitations, while 73% acknowledged a median of 3 (range 1–8) limitations. Five percent mentioned a limitation in the abstract. After controlling for confounders, publications on industry-supported studies used significantly fewer hedges than publications not so supported (p = 0.028). Limitations Detection and classification of limitations was – to some extent – subjective. The weighting scheme used by the hedging detection software has subjective elements. Conclusions Reporting of limitations in biomedical publications is probably very incomplete. Transparent reporting of limitations may protect clinicians and guideline committees against overly confident beliefs and decisions and support scientific progress through better design, conduct or analysis of new studies.