Bisphosphonates in Glucocorticoid-Treated Patients With Duchenne Muscular Dystrophy: A Systematic Review and Grading of the Evidence

BACKGROUND AND OBJECTIVES: Bisphosphonates are routinely used to treat osteoporosis in patients with Duchenne muscular dystrophy (DMD), a rare, severely debilitating neuromuscular disease. We sought to synthesize and grade benefits and harms evidence of bisphosphonates in glucocorticoid-treated patients with DMD. METHODS: In this systematic review (PROSPERO identifier: CRD42020157606), we searched MEDLINE, CINAHL, Embase, PsycINFO, Web of Science, and CENTRAL for articles published from inception up to and including March 31, 2023, reporting results in any language from any study type. Quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations framework. RESULTS: We identified 19 publications involving 1,010 children and adults from 12 countries across all inhabited continents except South America. We found high-quality evidence that bisphosphonates significantly increase the areal lumbar spine bone mineral density (BMD) Z score in glucocorticoid-treated patients with DMD. The greatest improvements were recorded in controlled settings among patients treated with intravenous zoledronate. Evidence of benefits to fracture risks was inconclusive and/or of low quality, primarily due to lack of controlled data and small samples. Bisphosphonates were generally well-tolerated, although adverse events related to the first infusion (i.e., "acute phase reaction") were frequently reported. DISCUSSION: There is high-quality evidence supporting the use of bisphosphonates to increase the areal lumbar spine BMD Z score in patients with DMD and glucocorticoid-induced osteoporosis. Our synthesis and grading affirm current recommendations put forward in the 2018 DMD Clinical Care Considerations and should be helpful in raising awareness about anticipated benefits of bisphosphonates, prevailing unmet needs, and potential safety issues in their use.

Effect of delay in treatment intensification in people with type 2 diabetes and suboptimal glycaemia after basal insulin initiation: A real-world observational study.

AIM: Despite global recommendations for type 2 diabetes mellitus treatment to maintain optimal glycaemic targets, a significant proportion of people remain in suboptimal glycaemic control. Our objective was to investigate the impact of intensification delay after basal insulin (BI) initiation on long-term complications in people with suboptimal glycaemia. MATERIALS AND METHODS: We conducted a retrospective cohort study in individuals with type 2 diabetes mellitus initiated on BI. Those with suboptimal glycaemia (glycated haemoglobin ≥7% or ≥53 mmol/mol) within 12 months of BI initiation were divided into early (treatment intensified within 5 years), or late (≥5 years) intensification groups. We estimated the age-stratified risks of micro- and macrovascular complications among these groups compared with those with optimal glycaemia (glycated haemoglobin <7%). RESULTS: Of the 13 916 people with suboptimal glycaemia, 52.5% (n = 7304) did not receive any treatment intensification. In those aged <65 years, compared with the optimal glycaemia group late intensification was associated with a 56% higher risk of macrovascular complications (adjusted hazard ratio 1.56; 95% confidence intervals 1.08, 2.26). In elderly people (≥65 years), late intensification was associated with a higher risk of cardiovascular-related death (1.62; 1.03, 2.54) and a lower risk of microvascular complications (0.26; 0.08, 0.83). CONCLUSIONS: Those who had late intensification were at an increased risk of cardiovascular death if they were ≥65 years and an increased risk of macrovascular complications if they were <65 years. These findings highlight the critical need for earlier intensification of treatment and adopting personalized treatment strategies to improve patient outcomes.

Self-Reported Health-Related Quality of Life of Children with Spinal Muscular Atrophy: Preliminary Insights from a Nationwide Patient Registry in Germany.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare, severely debilitating neuromuscular disease characterized by a wide spectrum of progressive muscular atrophy and weakness. OBJECTIVES: The objective of this pilot study was to estimate self-assessed health-related quality of life (HRQoL) of children with SMA. METHODS: Children with SMA were recruited via the German national TREAT-NMD SMA patient registry and asked to self-complete the following rating-scales: KIDSCREEN-27, KINDL, the PedsQL 3.0 Neuromuscular Module (PedsQL 3.0 NMM), EQ-5D-5L, and the Health Utilities Index (HUI). Estimates were stratified by current best motor function of the lower limb and trunk (i.e., non-sitter, sitter, and walker) and SMA type (i.e., type I, II, and III). RESULTS: In total, 17 children with SMA (mean age: 9.88 years, SD: 4.33 years, range: 5-16 years; 59% female) participated in the study. Across examined strata, the mean KIDSCREEN-27 total score was estimated at between 48.24 and 83.81; the mean KINDL total score at between 60.42 and 76.73; the mean PedsQL 3.0 NMM total score at between 58.00 and 83.83; the mean EQ-5D-5L utility at between 0.31 and 0.99; and the mean HUI-derived utility at between -0.02 and 0.96. CONCLUSIONS: The results from this pilot study show that German children with SMA, despite significant physical disability, have surprisingly good HRQoL as assessed using KIDSCREEN-27. Yet, many reside in health states associated with low utility. The disease burden was generally higher among non-sitters compared with walkers, and SMA type I compared with type III, but more research is needed to further delineate this variability. Our preliminary findings contribute to the understanding of HRQoL in pediatric patients with SMA and should be helpful to inform the design of future studies of this patient population.

Effect of more versus less intensive blood pressure control on cardiovascular, renal and mortality outcomes in people with type 2 diabetes: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Currently, there is uncertainty as to whether blood pressure control in patients with type 2 diabetes should be treated to standard recommended levels or more intensively. METHODS: Medline, EMBASE, CENTRAL, and Clinicaltrials.gov were searched between January 1, 2000 and April 20th, 2023. Outcomes considered were all-cause mortality, stroke, heart failure, cardiovascular disease, albuminuria, coronary heart disease, and renal outcomes. Random-effects meta-analyses estimated pooled relative risks and mean differences. RESULTS: Nine trials enrolling 11,005 participants with type 2 diabetes were included. The pooled mean difference between the intensive and standard treatment groups at follow-up were -7.98 mmHg (95% CI: 12.19 to -3.76) in systolic blood pressure, and -5.08 mmHg (-7.00 to -3.17) in diastolic blood pressure; although between study heterogeneity was high for both meta-analyses (I2>85%). Intensive blood pressure lowering resulted in a reduction in risk of stroke (risk ratio 0.64; 0.52 to 0.79), and macro-albuminuria (0.77; 0.63 to 0.93). More intensive blood pressure control did not result in a statistically significant reduction in risk of all-cause mortality, heart failure, cardiovascular death, cardiovascular events, renal outcomes, and micro-albuminuria; although the direction of estimated effect was beneficial for all outcomes. CONCLUSIONS: The use of intensive compared with standard blood pressure targets resulted in a significant reduction in blood pressure, stroke, and macro-albuminuria in patients with type 2 diabetes. The post-treatment blood pressure level in the intensive group was 125/73 mmHg, suggesting the current recommendations of 130/80 mmHg blood pressure or lower if tolerated, could be reduced further.

Areas of improvement in the medical care of SMA: evidence from a nationwide patient registry in Germany.

BACKGROUND: Management and treatment of spinal muscular atrophy (SMA) has changed in recent years due to the introduction of novel transformative and potentially curative therapies resulting in the emergence of new disease phenotypes. Yet, little is known about the uptake and impact of these therapies in real-world clinical practice. The objective of this study was to describe current motor function, need of assistive devices, and therapeutic and supportive interventions provided by the healthcare system, as well as the socioeconomic situation of children and adults with different SMA phenotypes in Germany. We conducted a cross-sectional, observational study of German patients with genetically confirmed SMA identified and recruited via a nationwide SMA patient registry ( www.sma-register.de ) within the TREAT-NMD network. Study data was recorded directly from patient-caregiver pairs through a study questionnaire administered online via a dedicated study website. RESULTS: The final study cohort consisted of 107 patients with SMA. Of these, 24 were children and 83 adults. In total, about 78% of all participants were taking medication for SMA (predominantly nusinersen and risdiplam). All children with SMA1 were able to sit and 27% of children with SMA2 were able to stand or walk. Impaired upper limb function, scoliosis and bulbar dysfunction were observed more frequently in patients with reduced lower limb performance. Physiotherapy, occupational therapy, and speech therapy, as well as the use of cough assists were less common than indicated by care guidelines. Family planning and educational and employment status appear to be related to motor skill impairment. CONCLUSIONS: We show that the natural history of disease has changed in Germany following improvements in SMA care and the introduction of novel therapies. Yet, a non-trivial proportion of patients remain untreated. We also identified considerable limitations in rehabilitation and respiratory care, as well as low labour-market participation among adults with SMA, calling for action to improve the current situation.

Variations in documentation of atrial fibrillation predicted by population and service level characteristics in primary health care in England.

BACKGROUND: Identifying features associated with atrial fibrillation (AF) documentation could inform screening. This study used published data to describe differences in documented and estimated AF prevalence in general practices, and explored predictors of variations in AF prevalence. METHODS: Cross-sectional study of 7318 general practices in England. Descriptive and inferential statistics were undertaken. Multiple linear regression was used to model the difference between estimated AF and documented AF, adjusted for population, practice and practice performance variables. RESULTS: Documented AF prevalence was lower than estimated (- 0.55% 95% confidence intervals, -1.89, 2.99). The proportion of variability accounted for in the final regression model was 0.25. Factors positively associated with AF documentation (increase in difference between estimated and documented), were patients 65-74 years, 75 years +, Black or South Asian ethnicity, diabetes mellitus and practices in East and Midlands of England. Eight variables (female patients, deprivation score, heart failure and peripheral artery disease, total patients per practice, full-time GPs and nurses; and location in South of England) were negatively associated with AF documentation (reduction in difference). CONCLUSION: Variations in AF documentation were predicted by several practice and population characteristics. Screening could target these sources of variation to decrease variation and improve AF documentation.

Caregiver Burden of Spinal Muscular Atrophy: A Systematic Review.

OBJECTIVE: The objective of our study was to review, synthesize, and grade published evidence of caregiver burden of spinal muscular atrophy (SMA), a rare autosomal-recessive neuromuscular disease. METHODS: We searched Embase and PubMed for full-text articles published from inception up until 28 February, 2022, reporting results from studies of caregiver burden (i.e., negative aspects of providing informal care) in SMA. Two investigators independently screened article titles and abstracts for eligibility, reviewed full-text versions of selected records, extracted the data, and assessed risk of bias using the Newcastle-Ottawa Scale. The evidence was synthesized to answer the following questions: (1) In which geographical settings have the caregiver burden of SMA been studied? (2) What aspects of the caregiver burden of SMA have been investigated? (3) What instruments have been used to measure the caregiver burden of SMA? (4) What is known of the caregiver burden of SMA? (5) How is the caregiver burden of SMA impacted by available disease-modifying drugs? RESULTS: We identified 15 publications, covering samples from a total of ten countries (i.e., Australia, Canada, China, France, Germany, Romania, Spain, Turkey, the UK, and the USA), reporting estimates of caregiver burden derived using data recorded via surveys or interviews. The most common instruments used to measure caregiver burden were the Zarit Caregiver Burden Interview, the EQ-5D-5L, and the PedsQL Family Impact Model. Caregiving in SMA was found to be associated with reduced health-related quality of life, impaired family function, depression and anxiety, strain, and stress, as well as a substantial impact on work life and productivity. Evidence of the impact of disease-modifying drugs on caregiver burden in SMA was scarce. CONCLUSIONS: Caregivers to patients with SMA were found to be subject to a significant burden, including impaired health-related quality of life, reduced work ability and productivity, and financial stress, and many devote a substantial proportion of their time to provide informal care. Yet, the current body of literature is relatively scarce and more research is needed to better understand the clinical implications of informal caregiving in SMA and the relationship between caregiver burden and SMA types, as well as the impact of new disease-modifying treatments. Our synthesis will be helpful in informing clinical and social support programs (e.g., the routine screening of depression among caregivers, as well as financial support schemes to help manage the long-term day-to-day care) directed towards families caring for patients with SMA.

Ethnicity and prognosis following a cardiovascular event in people with and without type 2 diabetes: Observational analysis in over 5 million subjects in England.

AIMS: To quantify ethnic differences in the risk of all-cause mortality and cardiovascular disease (CVD) events following a first CVD event in people with and without type 2 diabetes. METHODS: We identified 5,349,271 subjects with a first CVD between 1 January 2002 and 31 May 2020 in England; CVD included aortic aneurism, cerebrovascular accident, heart failure, myocardial infarction, peripheral vascular disease, and other cardiovascular diseases. We estimated adjusted hazard ratios (HRs) for type 2 diabetes and ethnicity of three outcomes: fatal and nonfatal second CVD event (different phenotype compared to the first) and all-cause mortality. RESULTS: Relative to White, HRs indicated lower rates in all ethnicities and for all outcomes in both men (from 0.64 to 0.79 for all-cause death; 0.78-0.79 for CVD-related death; and 0.85-0.98 for a second CVD event) and women (0.69-0.77; 0.77-0.83; 0.83-0.95, respectively). Irrespective of ethnicity and sex, type 2 diabetes increased rates of all outcomes by around a third. CONCLUSIONS: Prognosis following a CVD event was consistently worse in subjects with type 2 diabetes while varied across ethnicities, suggesting the implementation of different strategies for the secondary prevention of CVD in different ethnic groups.

Consultation rates in people with type 2 diabetes with and without vascular complications: a retrospective analysis of 141,328 adults in England.

OBJECTIVE: To assess trends in primary and specialist care consultation rates and average length of consultation by cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), or cardiometabolic multimorbidity exposure status. METHODS: Observational, retrospective cohort study used linked Clinical Practice Research Datalink primary care data from 01/01/2000 to 31/12/2018 to assess consultation rates in 141,328 adults with newly diagnosed T2DM, with or without CVD. Patients who entered the study with either a diagnosis of T2DM or CVD and later developed the second condition during the study are classified as the cardiometabolic multimorbidity group. Face to face primary and specialist care consultations, with either a nurse or general practitioner, were assessed over time in subjects with T2DM, CVD, or cardiometabolic multimorbidity. Changes in the average length of consultation in each group were investigated. RESULTS: 696,255 (mean 4.9 years [95% CI, 2.02-7.66]) person years of follow up time, there were 10,221,798 primary and specialist care consultations. The crude rate of primary and specialist care consultations in patients with cardiometabolic multimorbidity (N = 11,881) was 18.5 (95% CI, 18.47-18.55) per person years, 13.5 (13.50, 13.52) in patients with T2DM only (N = 83,094) and 13.2 (13.18, 13.21) in those with CVD (N = 57,974). Patients with cardiometabolic multimorbidity had 28% (IRR 1.28; 95% CI: 1.27, 1.31) more consultations than those with only T2DM. Patients with cardiometabolic multimorbidity had primary care consultation rates decrease by 50.1% compared to a 45.0% decrease in consultations for those with T2DM from 2000 to 2018. Specialist care consultation rates in both groups increased from 2003 to 2018 by 33.3% and 54.4% in patients with cardiometabolic multimorbidity and T2DM, respectively. For patients with T2DM the average consultation duration increased by 36.0%, in patients with CVD it increased by 74.3%, and in those with cardiometabolic multimorbidity it increased by 37.3%. CONCLUSIONS: Annual primary care consultation rates for individuals with T2DM, CVD, or cardiometabolic multimorbidity have fallen since 2000, while specialist care consultations and average consultation length have both increased. Individuals with cardiometabolic multimorbidity have significantly more consultations than individuals with T2DM or CVD alone. Service redesign of health care delivery needs to be considered for people with cardiometabolic multimorbidity to reduce the burden and health care costs.

A systematic review and meta-analysis to compare the prevalence of depression between people with and without Type 1 and Type 2 diabetes.

AIMS: Diabetes can significantly impact quality of life and mental health. However, inconsistencies have been reported in the prevalence of depression in those with Type 1 and Type 2 diabetes, and those without. Systematic reviews also included studies without adequate control subjects. We update existing literature, by comparing depression prevalence between individuals with and without Type 1 and Type 2 diabetes. METHODS: A systematic review and meta-analysis. We searched MEDLINE, EMBASE and PSYCHINFO, from January 1985 to August 2021. Studies were excluded if they failed to have an adequate control group, specified type of diabetes, or reported depression prevalence by type of diabetes. RESULTS: 44 studies were selected for inclusion. The prevalence of depression was significantly higher in people with Type 1 (22% vs 13%, OR = 2.10 (95% CI: 1.23, 3.52)), or Type 2 diabetes (19% vs 11%, OR = 1.76 (1.55, 2.01)) compared to those without diabetes. There was no association between study effect size and mean age or gender. Findings did not significantly differ between methods of depression assessment. Prevalence of depression in people with diabetes was higher in studies carried out in specialist care (36%, OR = 3.14 (2.12, 4.63)) compared to those in community or primary care (12%, OR = 1.51 (1.35, 1.70) and in low- and middle-income countries (OR = 2.58 (1.91, 3.50) compared to countries with high income economies (OR = 1.59 (1.39, 1.82)). CONCLUSIONS: Depression prevalence remains significant in those with type 1 and type 2 diabetes. Effective chronic disease management in people with diabetes is important, particularly screening and managing depression and diabetes distress in specialist care settings.

Progression to type 2 diabetes in women with a known history of gestational diabetes: systematic review and meta-analysis.

OBJECTIVE: To estimate and compare progression rates to type 2 diabetes mellitus (T2DM) in women with gestational diabetes mellitus (GDM) and healthy controls. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline and Embase between January 2000 and December 2019, studies published in English and conducted on humans. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Observational studies investigating progression to T2DM. Inclusion criteria were postpartum follow-up for at least 12 months, incident physician based diagnosis of diabetes, T2DM reported as a separate outcome rather than combined with impaired fasting glucose or impaired glucose tolerance, and studies with both a group of patients with GDM and a control group. RESULTS: This meta-analysis of 20 studies assessed a total of 1 332 373 individuals (67 956 women with GDM and 1 264 417 controls). Data were pooled by random effects meta-analysis models, and heterogeneity was assessed by use of the I2 statistic. The pooled relative risk for the incidence of T2DM between participants with GDM and controls was estimated. Reasons for heterogeneity between studies were investigated by prespecified subgroup and meta-regression analyses. Publication bias was assessed by funnel plots and, overall, studies were deemed to have a low risk of bias (P=0.58 and P=0.90). The overall relative risk for T2DM was almost 10 times higher in women with previous GDM than in healthy controls (9.51, 95% confidence interval 7.14 to 12.67, P<0.001). In populations of women with previous GDM, the cumulative incidence of T2DM was 16.46% (95% confidence interval 16.16% to 16.77%) in women of mixed ethnicity, 15.58% (13.30% to 17.86%) in a predominantly non-white population, and 9.91% (9.39% to 10.42%) in a white population. These differences were not statistically significant between subgroups (white v mixed populations, P=0.26; white v non-white populations, P=0.54). Meta-regression analyses showed that the study effect size was not significantly associated with mean study age, body mass index, publication year, and length of follow-up. CONCLUSIONS: Women with a history of GDM appear to have a nearly 10-fold higher risk of developing T2DM than those with a normoglycaemic pregnancy. The magnitude of this risk highlights the importance of intervening to prevent the onset of T2DM, particularly in the early years after pregnancy. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019123079.