Disease severity-based subgrouping of type 2 diabetes does not parallel differences in quality of life: the Maastricht Study.

AIMS/HYPOTHESIS: Type 2 diabetes is a highly heterogeneous disease for which new subgroups ('clusters') have been proposed based on disease severity: moderate age-related diabetes (MARD), moderate obesity-related diabetes (MOD), severe insulin-deficient diabetes (SIDD) and severe insulin-resistant diabetes (SIRD). It is unknown how disease severity is reflected in terms of quality of life in these clusters. Therefore, we aimed to investigate the cluster characteristics and cluster-wise evolution of quality of life in the previously defined clusters of type 2 diabetes. METHODS: We included individuals with type 2 diabetes from the Maastricht Study, who were allocated to clusters based on a nearest centroid approach. We used logistic regression to evaluate the cluster-wise association with diabetes-related complications. We plotted the evolution of HbA1c levels over time and used Kaplan-Meier curves and Cox regression to evaluate the cluster-wise time to reach adequate glycaemic control. Quality of life based on the Short Form 36 (SF-36) was also plotted over time and adjusted for age and sex using generalised estimating equations. The follow-up time was 7 years. Analyses were performed separately for people with newly diagnosed and already diagnosed type 2 diabetes. RESULTS: We included 127 newly diagnosed and 585 already diagnosed individuals. Already diagnosed people in the SIDD cluster were less likely to reach glycaemic control than people in the other clusters, with an HR compared with MARD of 0.31 (95% CI 0.22, 0.43). There were few differences in the mental component score of the SF-36 in both newly and already diagnosed individuals. In both groups, the MARD cluster had a higher physical component score of the SF-36 than the other clusters, and the MOD cluster scored similarly to the SIDD and SIRD clusters. CONCLUSIONS/INTERPRETATION: Disease severity suggested by the clusters of type 2 diabetes is not entirely reflected in quality of life. In particular, the MOD cluster does not appear to be moderate in terms of quality of life. Use of the suggested cluster names in practice should be carefully considered, as the non-neutral nomenclature may affect disease perception in individuals with type 2 diabetes and their healthcare providers.

The use of sodium-glucose co-transporter-2 inhibitors or glucagon-like peptide-1 receptor agonists versus sulfonylureas and the risk of lower limb amputations: a nation-wide cohort study.

BACKGROUND: Numerous studies have investigated the potential association of sodium-glucose co-transporter-2 inhibitors (SGLT2-Is) with an increased risk of lower limb amputations (LLAs), but have produced conflicting results. Particularly studies comparing SGLT2-Is to glucagon-like peptide-1 receptor agonists (GLP1-RAs) seem to find a higher LLA risk with SGLT2-I use. This raises the question whether the results are driven by a protective GLP1-RA-effect rather than a harmful SGLT2-I-effect. GLP1-RAs could promote wound healing and therefore reduce the risk of LLAs, but the associations between both drug classes and LLA remain uncertain. Therefore, the aim of the current study was to investigate the risk of LLA and diabetic foot ulcer (DFU) with SGLT2-I use and GLP1-RA use versus sulfonylurea use. METHODS: A retrospective population-based cohort study was conducted using data from the Danish National Health Service (2013-2018). The study population (N = 74,475) consisted of type 2 diabetes patients aged 18 + who received a first ever prescription of an SGLT2-I, GLP1-RA or sulfonylurea. The date of the first prescription defined the start of follow-up. Time-varying Cox proportional hazards models estimated the hazard ratios (HRs) of LLA and DFU with current SGLT2-I use and GLP1-RA use versus current SU use. The models were adjusted for age, sex, socio-economic variables, comorbidities and concomitant drug use. RESULTS: Current SGLT2-I use was not associated with a higher risk of LLA versus sulfonylureas {adjusted HR 1.10 [95% confidence interval (CI) 0.71-1.70]}. Current GLP1-RA use, on the other hand, was associated with a lower risk of LLA [adjusted HR 0.57 (95%CI 0.39-0.84)] compared to sulfonylureas. The risk of DFU was similar to that with sulfonylureas with both exposures of interest. CONCLUSION: SGLT2-I use was not associated with a higher risk of LLA, but GLP1-RAs with a lower risk of LLA. Previous studies reporting a higher risk of LLA with SGLT2-I use compared to GLP1-RA use might have been looking at a protective GLP1-RA effect, rather than a harmful SGLT2-I effect.

Incidence, hospitalization and mortality and their changes over time in people with a first ever diabetic foot ulcer.

AIMS: A diabetic foot ulcer (DFU) is a severe condition associated with morbidity and mortality. Population-based studies are rare and limited by access to reliable data. Without this data, efforts in primary prevention cannot be evaluated. Therefore, we examined the incidence and changes over time for the first DFU in people with diabetes. We also examined hospitalization and all-cause mortality and their changes over time. METHODS: From the UK primary care CPRD GOLD database (2007-2017), we identified 129,624 people with diabetes by a prescription for insulin or a non-insulin anti-diabetic drug. DFUs were identified using Read codes and expressed as incidence rates (IRs). Changes over time were described using Poisson and logistic regression and expressed as incidence rate ratios (IRRs) and odds ratios (ORs) respectively. RESULTS: The mean IR of first registered DFUs was 2.5 [95% CI: 2.1-2.9] per 1000 person-years for people with type 2 diabetes and 1.6 [1.3-1.9] per 1000 person-years for people with type 1. The IRs declined for people with type 2 diabetes (IRR per year: 0.97 [0.96-0.99]), while no changes were observed for people with type 1 diabetes (IRR per year: 0.96 [0.89-1.04]). Average hospitalization and 1-year mortality risk for people with type 2 diabetes were 8.2% [SD: 4.7] and 11.7% [SD: 2.2] respectively. Both declined over time (OR: 0.89 [0.84, 0.94] and 0.94 [0.89, 0.99]). CONCLUSION: The decline in all IRs, hospitalizations and mortality in people with type 2 diabetes suggests that prevention and care of the first DFU has improved for this group in primary care in the UK.

Use of Sodium-Glucose Co-Transporter-2-Inhibitors (SGLT2-Is) and Risk of Lower Limb Amputation.

BACKGROUND: Treatment with sodium-glucose co-transporter-2-inhibitors (SGLT2-Is), such as canagliflozin, has been associated with an increased risk of lower limb amputations (LLAs) in type 2 diabetes mellitus (T2DM). However, conflicting results have been reported for different SGLT2-Is and the underlying mechanism is unclear. OBJECTIVE: To investigate the risk of LLA and diabetic foot ulcer with SGLT2-I use compared to other anti-diabetic drugs and to explore hypovolemia as a potential underlying mechanism. METHODS: A cohort study was conducted using data from the Clinical Practice Research Datalink GOLD (2013-2019). The study population (N=51,847) consisted of T2DM patients over 18 years of age with at least one prescription of a non-insulin anti-diabetic drug. Concomitant diuretic use and the presence of signs of hypovolemia were determined to assess the potential underlying mechanism. Cox proportional hazard models were used to estimate the hazard ratio (HR) for LLA in current SGLT2-I use versus current sulphonylurea (SU) use. Analyses were adjusted for lifestyle variables, comorbidities, and concomitant drug use. RESULTS: Current SGLT2-I use was not associated with an increased risk of LLA compared to current SU use (fully adjusted HR 0.70; 95% confidence interval 0.38-1.29). Concomitant use of diuretics and the presence of signs of hypovolemia were not associated with an increased risk of LLA. CONCLUSION: Use of SGLT2-Is, with or without signs of hypovolemia, was not associated with an increased risk of LLA or DFU versus current SU use. Future studies powered to detect potential differences between individual SGLT2-Is are required to rule out a canagliflozin-specific effect.

Drug utilization in the Maastricht Study: A comparison with nationwide data.

Within the southern region of the Netherlands, the Maastricht Study is an on-going observational prospective population-based cohort study that focuses on the etiology of Type 2 diabetes mellitus (T2DM). Representativeness of the participating population is a crucial but often an unknown factor in population-based cohort studies such as the Maastricht Study. We therefore aimed to assess the representativeness of the study population by comparing drug utilization of the participants of the Maastricht Study with the general population of the Netherlands.Since T2DM patients were oversampled in this study, a sampling method was applied in order to ensure a similar distribution of T2DM over the study population. Drug use in the study population was compared with drug use in the population of the Netherlands, using a Z-test to compare 2 independent proportions.In general, drug use in the study was similar compared with national data. However, in the age group 65 to 74 years total drug use was lower in the study population (833/1000 persons) versus nationwide data (882/1000 persons). The use of pulmonary medications was lower (104/1000 persons vs 141/1000 persons) and the use of hypnotics/anxiolytics was higher (90/1000 persons vs 36/1000 persons) in the Maastricht Study as compared with national data.Drug use in the Maastricht Study population is largely comparable to that in the total Dutch population aged 45 to 74. Therefore, data on drug use by participants in the Maastricht Study can be used to perform studies assessing outcomes associated with drug use.

Impact of the definition of osteoarthritis and of the timing of its onset on the association between type 2 diabetes mellitus and osteoarthritis: Clinical Practice Research Datalink.

AIMS: In a previous case-control study in a large primary care database, the Clinical Practice Research Datalink (CPRD), type 2 diabetes mellitus (T2DM) was associated with a decreased rate of total joint replacement (TJR). As this was in contrast to the hypothesis, selection bias due to the used definition of osteoarthritis (OA) or misclassification of the onset of OA were raised as possible explanations. We therefore aimed to explore the effect of the definition of OA, and hypothesized timing of its onset on the association between T2DM and OA. METHODS: All patients using a non-insulin anti-hyperglycaemic drug (NIAD) between 1989 and 2012 in the CPRD were included and matched to unexposed patients. Cox proportional hazard models were fitted estimating the risk of TJR or OA in T2DM patients compared to patients without T2DM. These analyses were repeated in sensitivity scenarios and joint-specific analyses. To assess whether misclassification of onset of OA may affect the association, analyses were repeated with addition of a latency period of up to 10 years after start of follow-up. RESULTS: The use of TJR as a proxy for OA (hazard ratio (HR) = 0.74; 95% Confidence Interval (CI) = 0.70-0.78) resulted in a HR that was approximately 0.2 lower than when OA diagnostic codes were used (HR = 0.93; 95% CI = 0.90-0.95). The joint-specific subgroup analyses, sensitivity scenarios, and latency analyses showed similar results. CONCLUSION: When examining the association between T2DM and OA, the use of TJR as a proxy for OA resulted in a 20% lower estimate than the OA diagnosis.

The Association Between ß-Blocker Use and Cardiorespiratory Fitness: The Maastricht Study.

PURPOSE: ß-Blockers (BBs) have been associated with a reduced cardiorespiratory fitness (CRF). This is possibly caused by inhibition of ß2-receptors in the airways. However, there are limited data available on ß-receptor selectivity and CRF. We therefore aimed to assess the association between BB use and CRF and to assess the association between ß-receptor selectivity and CRF. METHODS: Participants in the Maastricht Study were aged between 40 and 75 years. Exposure to BB use was determined by use of pharmacy records. General linear models were used to obtain adjusted means of 2 proxies for CRF: covered distance during the 6-minute walk test (6MWT) and estimated maximum power output adjusted for body mass ( Wmax kg-1) during the submaximal cycle ergometer test. Adjusted means were compared between current, past, and never BB users. Current users were subsequently stratified by ß-receptor selectivity and dose. RESULTS: Compared to never use, current use was associated with a lower CRF, based on the 6MWT (current use: 569.7 m; never use: 580.4 m [ P = .010]), but not based on the cycling test (current use: 2.14 W kg-1; never use: 2.13 W kg-1 [ P = .690]). There was no difference between current selective and current nonselective BB use. CONCLUSION: ß-Blockers use was associated with CRF based on the 6MWT but not the cycling test. There was no difference between current selective and nonselective BB users, possibly due to the small number of nonselective BB users, differential underlying diseases, other pharmacological properties, and limitations related to the proxies of the outcome.

Consumption of dairy products in relation to the presence of clinical knee osteoarthritis: The Maastricht Study.

PURPOSE: Observational studies showed inverse associations between milk consumption and knee osteoarthritis (knee OA). There is lack of information on the role of specific dairy product categories. We explored the association between dairy consumption and the presence of knee osteoarthritis in 3010 individuals aged 40-75 years participating in The Maastricht Study. METHODS: The presence of knee OA was defined according to a slightly modified version of the American College of Rheumatology (ACR) clinical classification criteria. Data on dairy consumption were appraised by a 253-item FFQ covering 47 dairy products with categorization on fat content, fermentation or dairy type. Multivariable logistic regression analyses were performed to estimate odd ratios (ORs) and 95% confidence intervals (95%CI), while correcting for relevant factors. RESULTS: 427 (14%) participants were classified as having knee OA. Significant inverse associations were observed between the presence of knee OA and intake of full-fat dairy and Dutch, primarily semi-hard, cheese, with OR for the highest compared to the lowest tertile of intake of 0.68 (95%CI 0.50-0.92) for full-fat dairy, and 0.75 (95%CI 0.56-0.99) for Dutch cheese. No significant associations were found for other dairy product categories. CONCLUSION: In this Dutch population, higher intake of full-fat dairy and Dutch cheese, but not milk, was cross-sectionally associated with the lower presence of knee OA. Prospective studies need to assess the relationship between dairy consumption, and in particular semi-hard cheeses, with incident knee OA.

Use of parenteral glucocorticoids and the risk of new onset type 2 diabetes mellitus: A case-control study.

BACKGROUND: Use of oral glucocorticoids (GCs) has been associated with hyperglycaemia and type 2 diabetes mellitus (T2DM). However, unlike oral GCs, there is minimal or no data on the effect of parenteral GC use on T2DM. OBJECTIVE: To assess the association between use of parenteral GCs and the risk of receiving a first prescription of a non-insulin antidiabetic drug (NIAD) as a proxy for new onset of T2DM. METHODS: A population based case-control study was performed using the Clinical Practice Research Datalink (CPRD). Cases (n = 177,154) were defined as patients >18 years of age who had their first ever NIAD prescription between January 1987 and October 2013. Controls were matched by age, gender and general practitioner practice. Conditional logistic regression analyses were used to estimate the risk of NIAD prescription and use of parenteral GCs. Our analyses were statistically adjusted for lifestyle factors, comorbidities and concomitant drug use. RESULTS: Although this study confirmed that oral GCs increases the risk of receiving a first prescription of a NIAD (OR 2.63 [95% CI 2.53-2.73]), there was no association between the use of parenterally administered GCs and the risk of receiving a first prescription of a NIAD (OR 0.88 [95% CI 0.76-1.02]). The number of GC prescriptions was not associated with risk of new onset T2DM compared to no parenteral GCs use; neither the type of GC. CONCLUSION: Our study does not demonstrate an association between the use of parenteral GCs and the risk of new onset of T2DM.

Safety and efficacy of new oral anticoagulants and low-molecular-weight heparins compared with aspirin in patients undergoing total knee and hip replacements.

BACKGROUND: There has been much debate recently on the best type of thromboprophylaxis following elective total joint replacement surgery. OBJECTIVE: This study aims to compare rates of venous thromboembolism (VTE), gastro-intestinal (GI) bleeding and mortality events, with use of new oral anticoagulants (NOAC) or low-molecular-weight heparins (LMWHs) compared with aspirin in patients undergoing total joint replacement. METHODS: A population-based retrospective cohort study was performed using the Clinical Practice Research Datalink. Patients ≥18 years of age who had undergone total knee (n = 3261) or hip replacement (THR (n = 4016)) between 2008 and 2012 were included. Within this population, three cohorts were selected, based on their first prescription within the 35-day period after surgery: use of NOACs only, LMWHs only and aspirin only. Incidence rates were calculated, and Cox proportional hazard models were fitted to estimate the risk of VTE, GI bleeding and all-cause mortality with the use of NOACs and LMWHs compared with aspirin use after total knee replacement and THR. We statistically adjusted our analyses for lifestyle factors, comorbidities and concomitant drug use. RESULTS: Total knee replacement and THR patients currently on LMWHs had higher risk of VTE (HR = 17.2 (6.9-43.0) and HR = 39.5 (18.0-87.0), respectively), GI bleeding (HR = 20.9 (1.9-232.3) and HR = 2.0 (0.2-17.2), respectively) and all-cause mortality (HR = 4.3 (1.7-12.4) and HR = 4.0 (2.4-6.7), respectively). NOAC use was associated with an increased risk of GI bleeding in patients undergoing THR surgery. CONCLUSIONS: In contrast to previous studies, we found an increased risk of VTE, GI bleeding and all-cause mortality with the use of LMWHs compared with aspirin. Risk of GI bleeding was increased with the use of NOACs compared with aspirin use after THR surgery. Copyright © 2016 John Wiley & Sons, Ltd.

Severity of Diabetes Mellitus and Total Hip or Knee Replacement: A Population-Based Case-Control Study.

It is generally thought that people with diabetes mellitus (DM) are more likely to suffer from osteoarthritis (OA) due to an increased body mass index (BMI), resulting in mechanical destruction of cartilage. However, previous studies have suggested a coexisting metabolic causality.To evaluate the risk of hip or knee replacement, as a proxy for severe OA, in patients with DM. We additionally evaluated the risk of total joint replacement (TJR) with various proxies for increased DM severity.A population-based case-control study was performed, using the Clinical Practice Research Datalink (CPRD). Cases (n = 94,609) were defined as patients >18 years who had undergone TJR between 2000 and 2012. Controls were matched by age, gender, and general practice. Conditional logistic regression was used to estimate the risk of total knee (TKR) and total hip replacement (THR) surgery associated with use of antidiabetic drugs (ADs). We additionally stratified current AD users by proxies for DM severity.Current AD use was significantly associated with a lower risk of TKR (OR = 0.86 (95% CI = 0.78-0.94)) and THR (OR = 0.90 (95% CI = 0.82-0.99)) compared to patients not using ADs. Moreover, risk of TKR and THR was decreased with increasing HbA1c.This study does not support the theory that DM patients are more likely to suffer from severe OA as compared to patients without diabetes. Moreover, risk of severe OA necessitating TJR decreases with increasing DM severity. This is possibly due to dissimilarities in methodology, a decrease in eligibility for surgery, or variability of OA phenotypes.

Use of thiazolidinediones and the risk of elective hip or knee replacement: a population based case-control study.

AIMS: Osteoarthritis (OA) is the most common musculoskeletal condition in the elderly population. However, no disease modifying drug exists for this disease. In vivo animal studies have suggested that thiazolidinediones (TZD) may be used as disease modifying osteoarthritis drugs (DMOADs). To our knowledge, this has not yet been examined in humans before. The aim was to determine the risk of total joint replacement (TJR) in patients using TZDs compared with diabetic patients using other antidiabetic drugs. METHODS: A population based case-control study was performed using the Clinical Practice Research Datalink (CPRD). Cases (n = 94 609) were defined as patients >18 years of age who had undergone total knee (TKR) or hip replacement (THR) between 2000 and 2012. Controls were matched by age, gender and practice/surgery. Conditional logistic regression analyses were used to estimate the risk of TKR and THR with the use of TZDs in patients currently using one or more antidiabetic drugs. In order to determine effect with prolonged use, we also stratified TZD users by total number of prescriptions prior to surgery. We statistically adjusted our analyses for lifestyle factory, comorbidities and concomitant drug use. RESULTS: There was no difference in risk of TKR (OR 1.09, 95% CI 0.93, 1.27) and THR (OR 0.92, 95% CI 0.76, 1.10) when TZD users were compared with other AD users. Furthermore, we did not find an association with prolonged use of TZDs and TJR. CONCLUSION: Despite promising results from animal in vivo studies, this study did not find any evidence for a disease modifying osteoarthritic effect of TZDs.

Measuring anticholinergic drug exposure in older community-dwelling Australian men: a comparison of four different measures.

AIMS: Anticholinergic drug exposure is associated with adverse outcomes in older people. While a number of tools have been developed to measure anticholinergic drug exposure, there is limited information about the agreement and overlap between the various scales. The aim of this study was to investigate the agreement and overlap between different measures of anticholinergic drug exposure in a cohort of community-dwelling older men. METHODS: A cross-sectional study was used to compare anticholinergic drug exposure calculated using the Anticholinergic Risk Scale (ARS), the Anticholinergic Drug Scale (ADS), the Anticholinergic Cognitive Burden (ACB) and the Drug Burden Index anticholinergic subscale (DBI-ACH) in a cohort of community-dwelling men aged 70 years and older (n = 1696). Statistical agreement, expressed as Cohen's kappa (κ), between these measurements was calculated. RESULTS: Differences were found between the tools regarding the classification of anticholinergic drug exposure for individual participants. Thirteen percent of the population used a drug listed as anticholinergic on the ARS, 39% used a drug listed on the ADS and the ACB, and 18% of the population used one or more anticholinergic drugs listed on the DBI-ACH. While agreement was good between the ACB and ADS (κ = 0.628, 95% CI 0.593, 0.664), little agreement was found between remaining tools (κ = 0.091-0.264). CONCLUSIONS: With the exception of the ACB and ADS, there was poor agreement regarding anticholinergic drug exposure among the four tools compared in this study. Great care should be taken when interpreting anticholinergic drug exposure using existing scales due to the wide variability between the different scales.