Klaas H. Groenier

Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16.

OBJECTIVE Several studies have suggested an association between specific diabetes treatment and cancer mortality. We studied the association between metformin use and cancer mortality in a prospectively followed cohort. RESEARCH DESIGN AND METHODS In 1998 and 1999, 1,353 patients with type 2 diabetes were enrolled in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) study in the Netherlands. Vital status was assessed in January 2009. Cancer mortality rate was evaluated using standardized mortality ratios (SMRs), and the association between metformin use and cancer mortality was evaluated with a Cox proportional hazards model, taking possible confounders into account. RESULTS Median follow-up time was 9.6 years, average age at baseline was 68 years, and average A1C was 7.5%. Of the patients, 570 died, of which 122 died of malignancies. The SMR for cancer mortality was 1.47 (95% CI 1.22–1.76). In patients taking metformin compared with patients not taking metformin at baseline, the adjusted hazard ratio (HR) for cancer mortality was 0.43 (95% CI 0.23–0.80), and the HR with every increase of 1 g of metformin was 0.58 (95% CI 0.36–0.93). CONCLUSIONS In general, patients with type 2 diabetes are at increased risk for cancer mortality. In our group, metformin use was associated with lower cancer mortality compared with nonuse of metformin. Although the design cannot provide a conclusion about causality, our results suggest a protective effect of metformin on cancer mortality.

The Frenchay Activities Index. Assessment of functional status in stroke patients.

Background and Purpose Assessment of functional status in stroke patients is of major importance in both clinical practice and outcome studies. The Frenchay Activities Index has been developed specifically for measuring disability and handicap in stroke patients. The purpose of the study was to evaluate the metric properties of this instrument and to obtain normal values in a group of unselected elderly subjects. Methods The Frenchay Activities Index was tested in a group of stroke patients and a group of unselected subjects aged 65 or older. The functional status of the stroke patients was measured 26 weeks after stroke. Their prestroke status was registered retrospectively. Reliability and validity of the instrument were assessed. Results The mean scores in the prestroke, poststroke, and control group demonstrated differences in functional status. The reliability of unweighted scores (range of Cronbachs α coefficients, 0.78 to 0.87) was sufficient. The construct validity was supported by meaningful correlations between the Frenchay Activities Index and scores on the Barthel Index and Sickness Impact Profile. Principal-components analysis indicated that the Frenchay Activities Index showed two traits: instrumental disability and some aspects of handicap. The reliability of the instrument could be improved by deleting two items and by creating two subscale scores: domestic and outdoors activities. Conclusions The Frenchay Activities Index is a useful stroke-specific instrument to assess functional status. Completion of the questionnaire is easy and takes only a few minutes. Currently, the instrument is suitable for use in patient care and cross-sectional, descriptive studies.

Skin Autofluorescence: A Tool to Identify Type 2 Diabetic Patients at Risk for Developing Microvascular Complications

OBJECTIVE—Skin autofluorescence is a noninvasive measure of the level of tissue accumulation of advanced glycation end products, representing cumulative glycemic and oxidative stress. Recent studies have already shown a relationship between skin autofluorescence and diabetes complications, as well as the predictive value of skin autofluorescence for total and cardiovascular mortality in type 2 diabetes. Our aim was to investigate the predictive value of skin autofluorescence for the development of microvascular complications in type 2 diabetes. RESEARCH DESIGN AND METHODS—At baseline, skin autofluorescence of 973 type 2 diabetic patients with well-controlled diabetes was noninvasively measured with an autofluorescence reader. The aggregate clinical outcome was defined as the development of any diabetes-associated microvascular complication of 881 surviving patients, which was assessed at baseline and at the end of follow-up. Single end points were the development of diabetes-associated retinopathy, neuropathy, and (micro)albuminuria. RESULTS—After a mean follow-up period of 3.1 years, baseline skin autofluorescence was significantly higher in patients who developed any microvascular complication, neuropathy, or (micro)albuminuria but not in those who developed retinopathy. Multivariate analyses showed skin autofluorescence as a predictor for development of any microvascular complication along with A1C, for development of neuropathy along with smoking, and for development of (micro)albuminuria together with sex, A1C, and diabetes duration. Skin autofluorescence did not have predictive value for the development of retinopathy, albeit diabetes duration did. CONCLUSIONS—Our study is the first observation of skin autofluorescence measurement as an independent predictor of development of microvascular complications in type 2 diabetes.

Manipulative Therapy in Addition to Usual Medical Care for Patients with Shoulder Dysfunction and Pain: A Randomized, Controlled Trial

Context Shoulder pain in the absence of trauma, fracture, rupture, or dislocation can lead to substantial functional limitations and can be a difficult condition to treat. Contribution In this randomized, controlled trial, patients with shoulder pain and shoulder girdle dysfunction assigned to receive manipulative therapy in addition to usual general practitioner care had more rapid improvement in symptoms and fewer shoulder symptoms at 12 weeks than patients assigned to usual care alone. Implications Manipulative therapy appears to be an effective treatment option for patients with shoulder pain and shoulder girdle dysfunction that are not due to trauma, fracture, rupture, or dislocation. The Editors Shoulder disorders are a widely recognized medical, social, and economic problem (1). They are characterized by functional disability due to pain in the shoulder at rest or during movement or by functional disability due to restricted range of motion. The annual incidence of shoulder symptoms in Dutch general medical practices is estimated to be 10 to 25 per 1000 enrolled patients (2-4). In the Netherlands, shoulder disorders are treated according to the Guidelines for Shoulder Complaints of the Dutch College of General Practitioners (5, 6). Initial treatment during the first 2 weeks includes informing patients about the nature and course of shoulder symptoms and advising them on how to use the affected shoulder during daily living. Patients can also be prescribed analgesics or nonsteroidal anti-inflammatory drugs if necessary. If this initial treatment is not effective, up to 3 corticosteroid injections (in the subacromial space or glenohumeral joint) can be given. Referral for physiotherapy is considered only for patients whose symptoms persist for 6 weeks or more. This treatment regimen, according to the guidelines, provides short-term benefit for many patients but cannot prevent the often unfavorable long-term course of the symptoms. Indeed, only 50% of all new episodes of shoulder disorders resolve within 6 months, while at 12 months more than 40% of all patients are still disabled during work and leisure time (4, 7). Pain or dysfunction of the cervicothoracic spine and the adjacent ribs (also called the shoulder girdle) often accompanies shoulder symptoms (8). A considerable proportion of patients with shoulder symptoms (approximately 20%) but no shoulder joint disorders may be found to have dysfunction of the shoulder girdle on further physical examination (9). Moreover, dysfunction of the shoulder girdle triples the risk for shoulder complications (10) and also predicts poor outcome of shoulder disorders (10-12). In clinical practice, dysfunction of the shoulder girdle can be treated with manipulative therapy, which aims to restore normal function. Winters and colleagues (13) found that manipulative therapy accelerated recovery and improved symptoms compared with physiotherapy in a relatively small subgroup of patients with both shoulder symptoms and shoulder girdle dysfunction. These effects were not sustained on long-term follow-up, possibly because of high attrition rates (14). Evidence showing that manipulative therapy for the shoulder girdle effectively treats shoulder symptoms is scarce; Winters and colleagues have performed the only randomized trial (13, 14) to date. Our objective was to study the effectiveness of manipulative therapy for the shoulder girdle in addition to usual medical care by a general practitioner. The study design has been described elsewhere (15), and the trial was designed and reported accord ing to the Consolidated Standards of Reporting Trials (CONSORT) statement (16). We report the effects of the use of additional manipulative therapy for the shoulder girdle to treat shoulder symptoms. Methods Participants Potential eligible participants with shoulder symptoms (pain and dysfunction) were recruited in 50 general practices in Groningen, the Netherlands. General practitioners started initial treatment (usual medical care) at presentation, assessed eligibility criteria, and told the conducting researcher about each eligible patient. The general practitioner used a standardized eligibility checklist and a physical examination as recommended by the Dutch College of General Practitioners (5, 6). A baseline assessment at the research center was scheduled within 2 weeks of presentation. Shoulder symptoms were defined as pain between the neck and the elbow at rest or during movement of the upper arm (Figure 1). Pain radiating to the neck region or to the lower part of the arm was not used as an exclusion criterion. The physical examination established the presence of both shoulder symptoms and dysfunction of the cervicothoracic spine and the adjacent ribs with accompanying pain or restricted movement. Eligible patients were 18 years of age or older and had had no consultation or treatment for shoulder symptoms in the past 3 months. No limits were placed on duration of symptoms before the first consultation. Figure 1. Location of shoulder symptoms. Reasons for exclusion were acute severe trauma, such as fractures, ruptures, or dislocation in the shoulder region; previous orthopedic surgery; clear treatment preference deviating from the study protocol; contraindications to manipulative therapy (for example, hypermobility, instability, or severe arthrosis of the cervicothoracic spine); signs of cervical nerve root compression; presence of specific rheumatic disorders; presence of dementia or other severe psychiatric, emotional, or behavioral disorders; shoulder disorders due to general internal disease of thoracic and abdominal organs; and inability to complete Dutch-language written questionnaires. Eligibility and exclusion criteria were verified before randomization by using a structured medical history and physical assessment. Randomization Patients were evenly allocated to receive manipulative therapy plus usual medical care or usual medical care alone. An independent statistician not involved in recruitment of patients generated a random list that was stratified for general practitioner by permutation of randomized blocks, with a block size of 6. After eligibility was verified, written informed consent was obtained. A researcher opened preprepared numbered, opaque sealed envelopes containing the treatment allocation codes and made appointments with manual therapists when applicable. Interventions Usual Medical Care All patients received usual medical care from their general practitioners. Usual medical care was similar to that outlined by the Dutch College of General Practitioners (5, 6) and included information, advice, and therapy. During the first 2 weeks, patients were given information about the nature and course of shoulder symptoms, along with advice on daily use of the affected shoulder. Patients were prescribed oral analgesics or nonsteroidal anti-inflammatory drugs if necessary. The Dutch College of General Practitioners recommends 2 weeks of treatment with paracetamol, 4 times daily (maximum dosage, 4000 mg/d), or nonsteroidal anti-inflammatory drugs such as ibuprofen, 3 times daily (maximum dosage, 2400 mg/d); diclofenac, 3 times daily (maximum dosage, 150 mg/d); or naproxen, twice daily (maximum dosage, 1000 mg/d) (5, 6). If patients did improve, drug treatment could be extended for another 2 weeks. If this approach was ineffective, up to 3 corticosteroid injections could be given in either the subacromial space or the glenohumeral joint. For injections in either location, physicians used triamcinolone acetonide, 40 mg suspended in a 1-mL vehicle, if necessary, combined with lidocaine, 10 mg suspended in a 5- to 10-mL vehicle. If improvement remained insufficient 2 weeks after injections were given, injections could be repeated. Further corticosteroid treatment was not considered appropriate if patients did not improve after the second series of injections. For symptoms persisting at least 6 weeks, physiotherapy consisting of shoulder exercises, massage, and physical applications was considered. Other referrals during the intervention and follow-up periods (for example, to a rheumatology consultant or orthopedic surgeon) were discouraged but were documented if they occurred. Manipulative Therapy According to the International Federation of Orthopedic Manipulative Therapists, orthopedic manipulative (manual) therapy is a specialization within physical therapy and provides comprehensive conservative management for pain and other symptoms of neuro-musculo-articular dysfunction in the spine and extremities. Our approach to manipulative therapy focused on manual manipulation and mobilization techniques used in western Europe, North America, and Australia, including those described by Cyriax (17), Greenman (18), and Lewit (19). In our trial, manipulative therapy included specific manipulations (low-amplitude, high-velocity thrust techniques) and specific mobilizations (high-amplitude, low-velocity thrust techniques) to improve overall joint function and decrease any restrictions in movement at single or multiple segmental levels in the cervical spine and upper thoracic spine and adjacent ribs. The manual therapist chose the applied techniques on the basis of the location of the dysfunction and the therapists technique preferences. Within the boundaries of the protocol, treatment could be reassessed and adapted to the patients condition. A maximum of 6 treatment sessions could be given over a 12-week period. Eight experienced physiotherapists who were members of the Dutch Association of Manual Therapy and registered by the Royal Dutch Society for Physical Therapy (a member of the International Federation of Orthopedic Manipulative Therapists) provided the manual therapy. To minimize variations in manipulative therapy, therapists received a special training session to familiarize them with the protocols mobilization and manipulation techniques for treatment of the cervico

Longitudinal study on glycaemic control and quality of life in patients with Type 2 diabetes mellitus referred for intensified control

Aim The aim of our study was to describe investigate and association between improved glycaemic control on quality of life (QoL) during 1 year of treatment in a sample of 94 Type 2 diabetic patients referred for insulin therapy to an outpatient department (OPD). Treatment was aimed at achieving acceptable glycaemic control by means of maximizing oral therapy, if necessary switching over to insulin therapy, and information and education provided by a diabetes specialist nurse and dietitian.

Risks and causes of death in a community-based stroke population : 1 month and 3 years after stroke

We performed a community-based study on a cohort of 221 stroke patients followed for 3 years. In this paper, we tried to answer the following questions: Is the risk of dying increased throughout the first 3 years after stroke? What are the causes of death after the 1st month? What factors at stroke onset are independent predictors of early and late mortality? The relative risk of death was estimated using age- and sex-specific mortality rates for the Netherlands. Causes of death were registered by the attending physicians, mostly general practitioners. During the 1st month 26% of the patients died. At 1, 2 and 3 years, the cumulative mortality rates were 37, 46 and 54%, respectively. Stroke patients had an increased risk of dying, approximately twice that of the general population, during the 3 years of follow-up. In women, this increased risk was more pronounced than in men. After 1 month, cardiovascular pathology, stroke and diseases resulting from stroke were the causes of death in 70% of the patients, i.e. substantially higher than in the general population, matched for age and sex. Factors predicting mortality after stroke varied over time. Severity of the stroke, preexisting atrial fibrillation and congestive heart failure were associated with early mortality (within 30 days). For 1-month survivors, incontinence and preexisting atrial fibrillation were associated with mortality in the 1st year after stroke. After 1 year, only age was associated with mortality.

Health-Related Quality of Life and Mortality in a General and Elderly Population of Patients With Type 2 Diabetes (ZODIAC-18)

OBJECTIVE Diabetes negatively impacts the health-related quality of life (HRQOL) of patients with type 2 diabetes. An earlier analysis showed HRQOL to be associated with mortality, which suggests that measuring HRQOL could have clinical implications. We studied the association between HRQOL and total and cardiovascular mortality in patients with type 2 diabetes during long-term follow-up and specifically focused on old age and sex differences. RESEARCH DESIGN AND METHODS HRQOL was measured in a prospectively followed cohort of 1,353 patients with type 2 diabetes using the RAND-36. Cox proportional hazard models were used to measure the independent effect of baseline HRQOL on mortality. RESULTS During a mean follow-up of 9.6 years, 570 (42%) patients died, 280 of whom died of cardiovascular disease (49%). The Physical Component Score (PCS) and the Mental Component Score (MCS) were inversely associated with total mortality, with hazard ratios of 0.988 (95% CI 0.983–0.993) and 0.990 (95% CI 0.985–0.995), respectively. A 10-point-higher score on the PCS and MCS decreased the risk for total mortality by 11 and 10%, respectively. An inverse relationship with mortality was also seen for men, women, and for patients aged >75 years. Mental health was significantly related to mortality in men but not in women. CONCLUSIONS Lower physical and mental HRQOL was associated with a higher total mortality and cardiovascular mortality in patients with type 2 diabetes; this is also the case when studying men and women and the elderly separately. The dimension mental health, related to depression and anxiety, was only associated with mortality in men, not in women.

Lower blood pressure associated with higher mortality in elderly diabetic patients (ZODIAC-12)

OBJECTIVE to investigate the relationship between blood pressure over time and mortality in elderly patients with type 2 diabetes mellitus (T2DM). DESIGN prospective observational cohort study. SETTING primary care, Zwolle, The Netherlands. SUBJECTS patients with T2DM aged 60 years and older (n = 881). The cohort was divided into two age categories: 60-75 years and older than 75 years. METHODS updated means for systolic, diastolic and pulse pressures were calculated after a median follow-up time of 9.8 years. These values were used as time-dependent covariates in a Cox proportional hazard model. Main outcome measures were all-cause and cardiovascular mortality. RESULTS all of the blood pressure measures were inversely related to all-cause mortality in elderly diabetic patients (>75 years). Furthermore, these relationships were specifically found in elderly patients treated with antihypertensive medication at baseline. A decrease of 10 mm Hg in systolic blood pressure, diastolic blood pressure and pulse pressure led to a mortality increase of 22% [95% confidence interval (95% CI): 13-31%], 30% [95% CI: 13%-46%] and 22% [95% CI: 11%-33%], respectively. In the low age group (60-75 years), no relationship was found between blood pressure and mortality. CONCLUSIONS blood pressure is a marker for mortality in elderly T2DM patients; however, the relationship is inverse.

Randomised controlled trial of local corticosteroid injections for de Quervain's tenosynovitis in general practice

BackgroundDe Quervains tenosynovitis is a stenosing tenosynovitis of the first dorsal compartment of the wrist and leads to wrist pain and to impaired function of the wrist and hand. It can be treated by splinting, local corticosteroid injection and operation. In this study effectiveness of local corticosteroid injections for de Quervains tenosynovitis provided by general practitioners was assessed.MethodsParticipants with de Quervains tenosynovitis were recruited by general practitioners. Short-term outcomes (one week after injections) were assessed in a randomised, placebo-controlled trial. Long-term effectiveness was evaluated in an open prospective cohort-study of steroid responders during a follow-up period of 12 months. Participants were randomised to one or two local injections of 1 ml of triamcinolonacetonide (TCA) or 1 ml of NaCl 0.9% (placebo). Non-responders to NaCl were treated with additional TCA injections. Main outcomes were immediate treatment response, severity of pain, improvement as perceived by participant and functional disability using sub items hand and finger function of the Dutch Arthritis Impact Measurement Scale (Dutch AIMS-2-HFF).Results11 general practitioners included 21 wrists in 21 patients. The TCA-group had better results for short-term outcomes treatment response (78% vs. 25%; p = 0.015), perceived improvement (78% vs. 33%; p = 0.047) and severity of pain (4.27 vs. 1.33; p = 0.031) but not for the Dutch-AIMS-HFF (2.71 vs. 1.92; p = 0.112). Absolute risk reduction for the main outcome short-term treatment response was 0.55 (95% CI: 0.34, 0.76) with a number needed to treat of 2 (95% CI: 1, 3). In the cohort of steroid responders (n = 12) the beneficial effects of steroid injections were sustained during the follow-up of 12 months regarding severity of pain (p = 0.67) and scores of Dutch AIMS-2-HFF (p = 0.36), but not for patient perceived improvement (p = 0.02). No adverse events were observed during the 12 months of follow-up.ConclusionOne or two local injections of 1 ml triamcinolonacetonide 10 mg/ml provided by general practitioners leads to improvement in the short term in participants with de Quervains tenosynovitis when compared to placebo. The short-term beneficial effects of steroid injections for symptoms were maintained during the follow-up after 12 months.Trial registrationCurrent Controlled Trials ISRCTN53171398

Can diabetes management be safely transferred to practice nurses in a primary care setting? A randomised controlled trial

AIMS AND OBJECTIVES To determine whether the management of type 2 diabetes mellitus in a primary care setting can be safely transferred to practice nurses. BACKGROUND Because of the increasing prevalence of type 2 diabetes mellitus and the burden of caring for individual patients, the demand type 2 diabetes mellitus patients place on primary health care resources has become overwhelming. DESIGN Randomised controlled trial. METHODS The patients in the intervention group were cared for by practice nurses who treated glucose levels, blood pressure and lipid profile according to a specified protocol. The control group received conventional care from a general practitioner. The primary outcome measure was the mean decrease seen in glycated haemoglobin (HbA1c) levels at the end of the follow-up period (14 months). RESULTS A total of 230 patients was randomised with 206 completing the study. The between-group differences with respect to reduction in HbA1c, blood pressure and lipid profile were not significant. Blood pressure decreased significantly in both groups; 7.4/3.2 mm Hg in the intervention group and 5.6/1.0 mm Hg in the control group. In both groups, more patients met the target values goals for lipid profile compared to baseline. In the intervention group, there was some deterioration in the health-related quality of life and an increase in diabetes-related symptoms. Patients being treated by a practice nurse were more satisfied with their treatment than those being treated by a general practitioner. CONCLUSION Practice nurses achieved results, which were comparable to those achieved by a general practitioner with respect to clinical parameters with better patient satisfaction. RELEVANCE TO CLINICAL PRACTICE This study shows that diabetes management in primary care can be safely transferred to practice nurses.