Hoarding of insulin and oral antidiabetics in the first phase of the COVID-19 pandemic: Regulatory actions taken to avoid shortage.

OBJECTIVE: To report on hoarding of prescribed medicines, with focus on insulins, in the early phase of the COVID-19 pandemic and on regulatory actions taken to avoid shortage. MATERIALS AND METHODS: The National Prescribed Drug Register which utilizes the Anatomic Therapeutic Chemical (ATC) Classification System and covers the total Swedish population was used. We calculated the number of packages of insulins (ATC code A10A), oral anti-diabetics (A10B), and all medicines across all ATC codes combined (A-S) dispensed per week in 2019 and 2020. Correspondingly, the number of packages of glucose test strips dispensed was calculated using the data source Concise held by the Swedish eHealth Agency. RESULTS: Prompt increases in numbers of dispensed packages were observed in March, peaking at week 11/2020. The absolute numbers of packages dispensed in week 11/2019 and week 11/2020 were: insulin, 49,694 and 95,767, an increase by +92.7%; oral antidiabetics, 55,478 and 82,684, +47.1%; glucose test strips, 18,119 and 23,476, +29:6%; and all medicines across all ATC codes combined, 1,988,456 and 2,659,421, +33.7%. Voluntary restriction of dispensing and a rapid change to applicable regulation were implemented within 2 weeks. A steep decline occurred, which became more pronounced after temporary regulation came in force from April 1, then leveling out during the following months. CONCLUSION: A signal of insulin hoarding was detected early in the COVID-19 pandemic. A temporary regulation, reducing dispensing to a maximum supply of 3 months was rapidly implemented. A shortage of vitally important prescribed medicines was avoided.

Plasma proteomic signatures of a direct measure of insulin sensitivity in two population cohorts.

AIMS/HYPOTHESIS: The euglycaemic-hyperinsulinaemic clamp (EIC) is the reference standard for the measurement of whole-body insulin sensitivity but is laborious and expensive to perform. We aimed to assess the incremental value of high-throughput plasma proteomic profiling in developing signatures correlating with the M value derived from the EIC. METHODS: We measured 828 proteins in the fasting plasma of 966 participants from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study and 745 participants from the Uppsala Longitudinal Study of Adult Men (ULSAM) using a high-throughput proximity extension assay. We used the least absolute shrinkage and selection operator (LASSO) approach using clinical variables and protein measures as features. Models were tested within and across cohorts. Our primary model performance metric was the proportion of the M value variance explained (R2). RESULTS: A standard LASSO model incorporating 53 proteins in addition to routinely available clinical variables increased the M value R2 from 0.237 (95% CI 0.178, 0.303) to 0.456 (0.372, 0.536) in RISC. A similar pattern was observed in ULSAM, in which the M value R2 increased from 0.443 (0.360, 0.530) to 0.632 (0.569, 0.698) with the addition of 61 proteins. Models trained in one cohort and tested in the other also demonstrated significant improvements in R2 despite differences in baseline cohort characteristics and clamp methodology (RISC to ULSAM: 0.491 [0.433, 0.539] for 51 proteins; ULSAM to RISC: 0.369 [0.331, 0.416] for 67 proteins). A randomised LASSO and stability selection algorithm selected only two proteins per cohort (three unique proteins), which improved R2 but to a lesser degree than in standard LASSO models: 0.352 (0.266, 0.439) in RISC and 0.495 (0.404, 0.585) in ULSAM. Reductions in improvements of R2 with randomised LASSO and stability selection were less marked in cross-cohort analyses (RISC to ULSAM R2 0.444 [0.391, 0.497]; ULSAM to RISC R2 0.348 [0.300, 0.396]). Models of proteins alone were as effective as models that included both clinical variables and proteins using either standard or randomised LASSO. The single most consistently selected protein across all analyses and models was IGF-binding protein 2. CONCLUSIONS/INTERPRETATION: A plasma proteomic signature identified using a standard LASSO approach improves the cross-sectional estimation of the M value over routine clinical variables. However, a small subset of these proteins identified using a stability selection algorithm affords much of this improvement, especially when considering cross-cohort analyses. Our approach provides opportunities to improve the identification of insulin-resistant individuals at risk of insulin resistance-related adverse health consequences.

Validation of myocarditis diagnoses in the Swedish patient register for analyses of potential adverse reactions to COVID-19 vaccines.

Background: Coronavirus disease 2019 (COVID-19) mRNA vaccines are associated with an increased risk of myocarditis using hospital discharge diagnoses as an outcome. The validity of these register-based diagnoses is uncertain. Methods: Patient records for subjects < 40 years of age and a diagnosis of myocarditis in the Swedish National Patient Register were manually reviewed. Brighton Collaboration diagnosis criteria for myocarditis were applied based on patient history, clinical examination, laboratory data, electrocardiograms, echocardiography, magnetic resonance imaging and myocardial biopsy. Poisson regression was used to estimate incidence rate ratios, comparing the register-based outcome variable to validated outcomes. Interrater reliability was assessed by a blinded re-evaluation. Results: Overall, 95.6% (327/342) of cases registered as myocarditis were confirmed (definite, probable or possible myocarditis according to Brighton Collaboration diagnosis criteria, positive predictive value 0.96 [95% CI 0.93-0.98]). Of the 4.4% (15/342) cases reclassified as no myocarditis or as insufficient information, two cases had been exposed to the COVID-19 vaccine no more than 28 days before the myocarditis diagnosis, two cases were exposed >28 days before admission and 11 cases were unexposed to the vaccine. The reclassification had only minor impact on incidence rate ratios for myocarditis following COVID-19 vaccination. In total, 51 cases were sampled for a blinded re-evaluation. Of the 30 randomly sampled cases initially classified as either definite or probably myocarditis, none were re-classified after re-evaluation. Of the in all 15 cases initially classified as no myocarditis or insufficient information, 7 were after re-evaluation re-classified as probable or possible myocarditis. This re-classification was mostly due to substantial variability in electrocardiogram interpretation. Conclusion: This validation of register-based diagnoses of myocarditis by manual patient record review confirmed the register diagnosis in 96% of cases and had high interrater reliability. Reclassification had only a minor impact on the incidence rate ratios for myocarditis following COVID-19 vaccination.

Loci for insulin processing and secretion provide insight into type 2 diabetes risk.

Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.

Association between atherogenic lipids and GnRH agonists for prostate cancer in men with T2DM: a nationwide, population-based cohort study in Sweden.

BACKGROUND: Gonadotropin-releasing hormone agonists (GnRH) used in prostate cancer (PCa) are associated with atherogenic dyslipidaemia. It can be assumed that GnRH need to be used with greater caution in men with type 2 diabetes mellitus (T2DM). This study investigated association of GnRH with atherogenic lipids (AL) in PCa men with T2DM. METHODS: Two cohorts including 38,311 men with 11 years follow-up based on Swedish national registers were defined (PCa-Exposure cohort and GnRH-Exposure cohort). Based on European guidelines on cardiovascular diseases (CVD), primary outcomes were defined as: 1.0 mmol/L increase in AL and lipid-lowering therapy (LLT) intensification. We used Cox proportional-hazards models and Kaplan-Meier curves to assess the association. RESULTS: There was an association between GnRH and increased AL (i.e., triglyceride, PCa-Exposure cohort: HR 1.77, 95% CI 1.48-2.10; GnRH-Exposure cohort: HR 1.88, 95% CI 1.38-2.57). There was also an association between PCa diagnosis and increased AL. In contrast, no association between LLT intensification and GnRH was found. CONCLUSION: In this large population-based study, men with T2DM on GnRH for PCa had an increased risk of increased atherogenic lipids. These results highlight the need to closely monitor lipids and to be ready to intensify lipid-lowering therapy in men with T2DM on GnRH for PCa.

A temporary regulation to manage an impending shortage due to extraordinary prescribing patterns of chloroquines observed during early phase of COVID-19 epidemic.

Background: Chloroquine and hydroxychloroquine (C/HC) received considerable international media attention due to anticipated treatment effect in COVID-19. This led to increased prescriptions threatening to generate product shortages for patients prescribed within approved indications.We evaluated effects of a temporary regulation mandating pharmacies to only dispense C/HC prescribed by physicians with defined specialties. Methods: Data from Region Stockholm, which include 2.4 out of 10 million Sweden's population, were used. Weekly time trends of prescriptions and requisitions of C/HC by prescriber's workplace during January to April 2020 were followed. Results: Numbers of unique individuals with filled prescriptions of chloroquine increased tenfold and of hydroxychloroquine more than threefold from January to March. In the first week of April, filled prescriptions of C/HC dropped. In the later weeks of April, the number of filled prescriptions was back at similar levels as before the SARS-CoV-2 outbreak.During January and February, specialists in rheumatology accounted for 686 out of all 979 prescriptions dispensed (70.1%) of C/HC. In March, a large proportion of prescriptions dispensed were from specialists not usually prescribing C/HC, and rheumatology accounted for 628 out of all 1,639 prescriptions (38.3%). In April, specialists in rheumatology accounted for 386 out of all 641 prescriptions dispensed (60.0%). Conclusion: After an observed increase in prescriptions of C/HC, a temporary regulation was introduced on 2nd April 2020 to reduce prescriptions from specialists not usually prescribing C/HC to avoid shortages for patients within approved indications. Subsequently, dispensed prescriptions decreased from April and remained at pre-COVID-19 levels thereafter.

Association of Gonadotropin-Releasing Hormone Agonists for Prostate Cancer With Cardiovascular Disease Risk and Hypertension in Men With Diabetes.

Importance: Men with type 2 diabetes have an increased risk of cardiovascular disease (CVD). Meanwhile, gonadotropin-releasing hormone (GnRH) agonists used in prostate cancer (PCa) are associated with increased risk of CVD. Objective: To evaluate the association between GnRH agonist use, PCa diagnosis per se, and CVD risk in men with type 2 diabetes. Design, Setting, and Participants: This nationwide population-based cohort study identified men with type 2 diabetes by use of data in the Prostate Cancer Data Base Sweden version 4.1 and the Swedish National Diabetes Register, with longitudinal data from 2006 to 2016. These data were used to create 2 cohorts, 1 including men with and without PCa and the other including men with PCa who received and did not receive GnRH agonists. Data analysis was conducted from January 2006 to December 2016. Exposures: Treatment with GnRH agonists and PCa diagnosis were the primary exposures. Main Outcomes and Measures: Primary outcome was a 10% increase in predicted 5-year CVD risk score. Secondary outcome was worsening hypertension as defined by the European Society of Hypertension Guidelines. Cox proportional hazards regression models were used to analyze the association. Results: The PCa exposure cohort included 5714 men (median [IQR] age, 72.0 [11.0]), and the non-PCa cohort included 28 445 men without PCa (median [IQR] age, 72.0 [11.0]). The GnRH agonist-exposure cohort included 692 men with PCa who received a GnRH agonist, compared with 3460 men with PCa who did not receive a GnRH agonist. Men with PCa receiving GnRH agonists had an increased estimated 5-year CVD risk score compared with men without PCa (hazard ratio [HR], 1.25; 95% CI, 1.16-1.36) and compared with men with PCa not receiving GnRH agonists (HR, 1.53; 95% CI, 1.35-1.74). Men receiving GnRH agonists had decreased blood pressure compared with men without PCa (HR, 0.70; 95% CI, 0.61-0.80) and compared with men with PCa not receiving GnRH agonists (HR, 0.68; 95% CI, 0.56-0.82). Conclusions and Relevance: In this population-based cohort study, there was an increased risk of CVD in men with type 2 diabetes who received a GnRH agonist for PCa. These findings highlight the need to closely control CVD risk factors in men with type 2 diabetes treated with GnRH agonists. The association between GnRH agonist use and decreased blood pressure levels warrants further study.

Comparison of years of life lost to 1,565 suicides versus 10,650 COVID-19 deaths in 2020 in Sweden: four times more years of life lost per suicide than per COVID-19 death.

Background: The burden of disease from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is large; however, suicide affects the population year after year. From a public health perspective, it is important to not neglect contributors to the total burden of disease. The aim of this paper is to compare years of life lost (YLL) to suicide with those lost to coronavirus disease 2019 (COVID-19). Methods: A nationwide cohort study in 2020, in Sweden. YLL was measured as the sex- and age-specific remaining life expectancy at the time of the person's death based on the death risks that pertained to the Swedish population in 2019. YLL to suicide was compared to YLL to COVID-19 and presented by sex and age groups. Suicide deaths in 2020 were estimated as the annual average of suicides in 2015-2019. Results: Annual average of suicide was 1,565, whereof 1,076 (68.8%) men and 489 (31.2%) women. In 2020, 10,650 persons died of COVID-19, whereof 5,681 (53.3%) men and 4,969 (46.7%) women. Estimated total YLL to suicide and COVID-19 in 2020 was 53,237 and 90,116, respectively. The COVID-19 YLL to suicide YLL ratio in 2020 was 1.69 (90,116/53,237). Men accounted for 67.1% of suicide YLL and of 56.4% of COVID-19 YLL. Those 44 years or younger accounted for 60.3% of suicide YLL and 3.9% of COVID-19 YLL. Those 75 years and older accounted for 2.9% of suicide YLL and 60.9% of COVID-19 YLL. On average, each suicide generates 34 YLL (53,237/1,565), and each COVID-19 death generates 8.5 YLL (90,116/10,650). Conclusions: YLL to suicide affects Sweden year after year, foremost attributable to the younger age groups, whereas YLL to COVID-19 is foremost attributable to the elderly. On average, each suicide generates four times more YLL than a COVID-19 death. Enormous efforts and resources have been put on tackling the pandemic, and without these, the burden would probably have been much larger. However, from a public health perspective, it is important to not neglect other contributors to the total burden of disease where national efforts also may have an impact.

Self-reported physical activity and different cardiovascular diseases-Results from updated measurements over 40 years.

BACKGROUND: Self-reported leisure-time physical activity (PA) has previously been linked to risk of cardiovascular disease (CVD). We now aim to investigate the strength of associations between PA and different CVDs and how the risk varies with age. METHODS: PA and traditional CV risk factors assessed by a questionnaire on a four-level scale in 2,175 men at age 50 years in the ULSAM study. Examinations were thereafter repeated at ages 60, 70, and 77. RESULTS: During 40 years follow-up, 883 individuals experienced a CVD (myocardial infarction, stroke, or heart failure). Using data from all four examinations, a graded reduction in risk of incident CVD was seen with increasing PA (HR 0.84, 95%CI; 0.77-0.93, p = 0.001 for trend test). PA was related to myocardial infarction (HR 0.84, 95%CI; 0.74-0.95, 490 cases), heart failure (HR 0.79, 95%CI; 0.68-0.91, 356 cases), but only of borderline significance vs ischemic stroke (HR 0.85, 95%CI; 0.73-1.00, 315 cases) when the CVDs were analyzed separately. Adjusting for traditional CV risk factors attenuated all relationships between PA and incident CVD, and PA did not improve discrimination of CVD when added on top of risk factors. When 10-year risk was calculated from each examination, age 70 was the time-point when PA was most closely related to incident CVD. CONCLUSION: Leisure-time physical activity is related to future CVD. This was most evident at 70 years of age. If a causal relationship between self-reported PA and CVD exists, this relationship might to a major degree be mediated by traditional risk factors.

Exploring the association between use of gonadotropin releasing hormones agonists and prostate cancer diagnosis per se and diabetes control in men with type 2 diabetes mellitus: a nationwide, population-based cohort study.

BACKGROUND: Gonadotropin Releasing Hormones agonists (GnRH), which are first line treatment for metastatic prostate cancer (PCa), increase risk of type 2 diabetes mellitus (T2DM). This study aims to quantify the association of use of GnRH with diabetes control in PCa men with T2DM. METHODS: Nationwide population-based cohort study in the Swedish National Diabetes Register and Prostate Cancer data Base Sweden 4.1, on the association between GnRH and diabetes control in T2DM men with PCa by comparing T2DM men with PCa vs. without PCa, as well as comparing T2DM men with PCa on or not on GnRH. The primary exposure was use of GnRH. Worsening diabetes control was the primary outcome, defined as: 1) HbA1c rose to 58 mmol/mol or higher; 2) HbA1c increase by 10 mmol/mol or more; 3) Start of antidiabetic drugs or switch to insulin. We also combined all above definitions. Cox proportional hazards regression was used to analyze the association. RESULTS: There were 5714 T2DM men with PCa of whom 692 were on GnRH and 28,445 PCa-free men with T2DM with similar baseline characteristics. Diabetes control was worse in men with GnRH vs. PCa-free men (HR: 1.24, 95% CI: 1.13-1.34) as well as compared with PCa men without GnRH (HR:1.58, 95% CI: 1.39-1.80), when we defined the worsening control of diabetes by combining all definitions above. CONCLUSION: Use of GnRH in T2DM men with PCa was associated with worse glycemic control. The findings highlight the need to closely monitor diabetes control in men with T2DM and PCa starting GnRH.

Changes in leisure-time physical activity during the adult life span and relations to cardiovascular risk factors-Results from multiple Swedish studies.

OBJECTIVE: To evaluate how self-reported leisure-time physical activity (PA) changes during the adult life span, and to study how PA is related to cardiovascular risk factors using longitudinal studies. METHODS: Several Swedish population-based longitudinal studies were used in the present study (PIVUS, ULSAM, SHE, and SHM, ranging from hundreds to 30,000 participants) to represent information across the adult life span in both sexes. Also, two cross-sectional studies were used as comparison (EpiHealth, LifeGene). PA was assessed by questionnaires on a four or five-level scale. RESULTS: Taking results from several samples into account, an increase in PA from middle-age up to 70 years was found in males, but not in females. Following age 70, a decline in PA was seen. Young adults reported both a higher proportion of sedentary behavior and a higher proportion high PA than the elderly. Females generally reported a lower PA at all ages. PA was mainly associated with serum triglycerides and HDL-cholesterol, but also weaker relationships with fasting glucose, blood pressure and BMI were found. These relationships were generally less strong in elderly subjects. CONCLUSION: Using data from multiple longitudinal samples the development of PA over the adult life span could be described in detail and the relationships between PA and cardiovascular risk factors were portrayed. In general, a higher or increased physical activity over time was associated with a more beneficial cardiovascular risk factor profile, especially lipid levels.

The profile of the COvid-19 VACcination register SAFEty study in Sweden (CoVacSafe-SE).

BACKGROUND: The coronavirus disease 2019 (COVID-19) vaccines have been rapidly implemented in national vaccination programs world-wide after accelerated approval processes. The large population exposure achieved in very short time requires systematic monitoring of safety. The Swedish Medical Products Agency has launched a project platform for epidemiological surveillance to detect and characterise suspected adverse effects of COVID-19 vaccines in Sweden. METHODS: The platform includes all individuals 12 years or older in Sweden in 2021 and will be updated annually. Data, including vaccine and COVID-19 disease data, socioeconomic and demographic data, comorbidity, prescribed medicines and healthcare utilisation outcomes, are obtained from several national registers in collaboration with other Swedish Government agencies. Data from 2015 to 2019 are used as a historical comparison cohort unexposed to both the COVID-19 pandemic and to the COVID-19 vaccines. RESULTS: The primary study cohort includes 8,305,978 adults 18 years and older permanently residing in Sweden on 31 December 2020. The historical control cohort includes 8,679,641 subjects. By 31 July 2021, around 50% of those 18 years and older and two-thirds of those 50 years and older were vaccinated with at least one dose, 90% of those 70 years or older had two doses. CONCLUSIONS: The nationwide register-based study cohort created by the Swedish Medical Products Agency with regular updates of individual level linkage of COVID-19 vaccination exposure data to other health data registers will facilitate both safety signal detection and evaluation and other pharmacoepidemiological studies.

Association of type 2 diabetes mellitus and antidiabetic medication with risk of prostate cancer: a population-based case-control study.

BACKGROUND: Prostate cancer (PCa) and type 2 diabetes mellitus (T2DM) are prevalent conditions that often occur concomitantly. However, many aspects of the impact of T2DM, particularly the duration of T2DM and antidiabetic medications, on PCa risk are poorly understood. METHODS: To assess the association of duration of T2DM and antidiabetic medication with PCa risk, we designed a matched case-control study, including 31,415 men with PCa and 154,812 PCa-free men in Prostate Cancer data Base Sweden (PCBaSe) 4.1. RESULTS: Overall, a decreased risk of PCa was observed for men with T2DM (odds ratio (OR): 0.81, 95% confidence interval (CI): 0.78-0.84), as compared to men without T2DM. The decreased risk of PCa was consistently showed across duration of T2DM. With respect to use of antidiabetic drugs, this inverse association with duration was also found for all medications types, as compared to men without T2DM, including insulin, metformin and sulphonylurea (SU) (e.g. 3- < 5 yr insulin OR:0.69, 95%CI:0.60-0.80; 3- < 5 yr metformin OR: 0.82, 95%CI: 0.74-0.91; 3- < 5 yr SU OR: 0.72, 95%CI: 0.62-0.83). When stratifying by PCa risk categories, this decreased risk was most evident for diagnosis of low and intermediate-risk PCa (low-risk OR: 0.65, 95%CI: 0.66-0.70, intermediate-risk OR: 0.80, 95%CI: 0.75-0.85). CONCLUSIONS: The study showed an inverse association between pre-existing T2DM and PCa across different durations of T2DM and all types of T2DM medication received. This inverse association was most evident for low- and intermediate-risk PCa, suggesting that whilst T2DM and its medication may protect some men from developing PCa, the relationship warrants further study.

SPISE and other fasting indexes of insulin resistance: risks of coronary heart disease or type 2 diabetes. Comparative cross-sectional and longitudinal aspects.

Background: Fasting insulin resistance indexes are used extensively nowadays. We intended to analyze a new recently presented fasting index, SPISE (sensitivity formula: 600 × HDL-cholesterol0.185/triglycerides0.2/BMI1.338), in comparison with three previously known fasting indexes, regarding correlation with the insulin clamp index, and for the predictive effects of future long-term risks of coronary heart disease (CHD) or manifest type 2 diabetes.Methods: A total of 1049 71-year-old male subjects from the Swedish ULSAM study, median follow-up 8 years, were included. All subjects performed the euglycemic insulin clamp, and analyses of four fasting insulin resistance indexes: SPISE-IR (= 10/SPISE), QUICKI-IR, Log HOMA-IR, and Revised QUICKI-IR.Results: Spearman correlation coefficients with the insulin clamp were 0.60-0.62 for all indexes. Area under curve at ROC analysis was 0.80 for SPISE-IR, and 0.84 for QUICKI-IR, Log HOMA-IR, and Rev QUICKI-IR. Adjusted hazard ratios per 1 SD index increase for long-term risk CHD were similar in all patients: 1.20-1.24 (p = 0.02-0.03). However, comparing the highest quartile (recommended to define insulin resistance) with the lower quartiles, SPISE-IR was the strongest and the only statistically significant insulin resistance index: HR 1.53 (p = 0.02). Adjusted odds ratios per 1 SD index increase for long-term risk of type 2 diabetes were fairly similar (p < 0.001) in all patients: 1.62 for SPISE-IR, 1.97 for QUICKI-IR and Log HOMA-IR, and 2.04 for Rev QUICKI-IR, and also when comparing the highest versus the lower quartiles: 2.8-3.1 (p < 0.001).Conclusion: SPISE, easily applicable, performed equally well as other fasting insulin indexes previously recommended for clinical use, regarding correlation with the insulin clamp, and as predictor for future long-term risks of CHD or type 2 diabetes.

The impact of muscle function, muscle mass and sarcopenia on independent ageing in very old Swedish men.

BACKGROUND: Preserved functions of daily life and cognition are cornerstones of independent aging, which is crucial for maintaining a high quality of life. The aim of this study was to examine the impact of sarcopenia, and its underlying components, on independent ageing in a cohort study of very old men. METHODS: The presence of sarcopenia and independent ageing at a mean age of 87 was investigated in 287 men from the Uppsala Longitudinal Study of Adult Men. Five years later 127 men were re-evaluated for independent ageing. Sarcopenia was defined by two different definitions from the European Working Group on Sarcopenia in Older People. In the first definition sarcopenia was defined as skeletal muscle index < 7.26 kg/m2 and either gait speed ≤0.8 m/s or hand grip strength < 30 kg. In the later up-dated definition, HGS < 27 kg and/or chair stand test > 15 s defines probable sarcopenia, which is confirmed by SMI < 7.0 kg/m2. Independent ageing was defined as a Mini-Mental State Examination score of ≥25 points, absence of diagnosed dementia, community-dwelling, independency in personal care and ability to walk outdoors alone. RESULTS: Sarcopenia at baseline was observed in 21% (60/287) and 20% (58/287), respectively, due to definition. The prevalence of independent ageing was 83% (239/288) at baseline and 69% (87/127) five years later. None of the sarcopenia diagnoses were associated with independent ageing. In contrast, gait speed was both in cross-sectional (odds ratio (OR) per one standard deviation increase 2.15, 95% confidence interval (CI) 1.47-3.15), and in longitudinal multivariate analyses (OR 1.84, 95% CI 1.19-2.82). In the cross-sectional analysis also higher hand grip strength was associated with independent ageing (OR 1.58, 95% CI 1.12-2.22), while a slower chair stand test was inversely associated (OR 0.61, 95% CI 0.43-0.86). Muscle mass; i.e. skeletal muscle index, was not associated with independent ageing. CONCLUSIONS: For very old men, especially a higher gait speed, but also a higher hand grip strength and a faster chair stand test, were associated with independent ageing, while skeletal muscle index alone, and the composite sarcopenia phenotype measured with two different definitions, were not.

Relative Prognostic Importance and Optimal Levels of Risk Factors for Mortality and Cardiovascular Outcomes in Type 1 Diabetes Mellitus.

BACKGROUND: The strength of association and optimal levels for risk factors related to excess risk of death and cardiovascular outcomes in type 1 diabetes mellitus have been sparsely studied. METHODS: In a national observational cohort study from the Swedish National Diabetes Register from 1998 to 2014, we assessed relative prognostic importance of 17 risk factors for death and cardiovascular outcomes in individuals with type 1 diabetes mellitus. We used Cox regression and machine learning analyses. In addition, we examined optimal cut point levels for glycohemoglobin, systolic blood pressure, and low-density lipoprotein cholesterol. Patients with type 1 diabetes mellitus were followed up until death or study end on December 31, 2013. The primary outcomes were death resulting from all causes, fatal/nonfatal acute myocardial infarction, fatal/nonfatal stroke, and hospitalization for heart failure. RESULTS: Of 32 611 patients with type 1 diabetes mellitus, 1809 (5.5%) died during follow-up over 10.4 years. The strongest predictors for death and cardiovascular outcomes were glycohemoglobin, albuminuria, duration of diabetes mellitus, systolic blood pressure, and low-density lipoprotein cholesterol. Glycohemoglobin displayed ≈2% higher risk for each 1-mmol/mol increase (equating to ≈22% per 1% glycohemoglobin difference), whereas low-density lipoprotein cholesterol was associated with 35% to 50% greater risk for each 1-mmol/L increase. Microalbuminuria or macroalbuminuria was associated with 2 to 4 times greater risk for cardiovascular complications and death. Glycohemoglobin <53 mmol/mol (7.0%), systolic blood pressure <140 mm Hg, and low-density lipoprotein cholesterol <2.5 mmol/L were associated with significantly lower risk for outcomes observed. CONCLUSIONS: Glycohemoglobin, albuminuria, duration of diabetes mellitus, systolic blood pressure, and low-density lipoprotein cholesterol appear to be the most important predictors for mortality and cardiovascular outcomes in patients with type 1 diabetes mellitus. Lower levels for glycohemoglobin, systolic blood pressure, and low-density lipoprotein cholesterol than contemporary guideline target levels appear to be associated with significantly lower risk for outcomes.

ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations.

The ADAMTS9 rs4607103 C allele is one of the few gene variants proposed to increase the risk of type 2 diabetes through an impairment of insulin sensitivity. We show that the variant is associated with increased expression of the secreted ADAMTS9 and decreased insulin sensitivity and signaling in human skeletal muscle. In line with this, mice lacking Adamts9 selectively in skeletal muscle have improved insulin sensitivity. The molecular link between ADAMTS9 and insulin signaling was characterized further in a model where ADAMTS9 was overexpressed in skeletal muscle. This selective overexpression resulted in decreased insulin signaling presumably mediated through alterations of the integrin ß1 signaling pathway and disruption of the intracellular cytoskeletal organization. Furthermore, this led to impaired mitochondrial function in mouse muscle-an observation found to be of translational character because humans carrying the ADAMTS9 risk allele have decreased expression of mitochondrial markers. Finally, we found that the link between ADAMTS9 overexpression and impaired insulin signaling could be due to accumulation of harmful lipid intermediates. Our findings contribute to the understanding of the molecular mechanisms underlying insulin resistance and type 2 diabetes and point to inhibition of ADAMTS9 as a potential novel mode of treating insulin resistance.

Pragmatic clinical trials in the context of regulation of medicines.

The pragmatic clinical trial addresses scientific questions in a setting close to routine clinical practice and sometimes using routinely collected data. From a regulatory perspective, when evaluating a new medicine before approving marketing authorization, there will never be enough patients studied in all subgroups that may potentially be at higher risk for adverse outcomes, or sufficient patients to detect rare adverse events, or sufficient follow-up time to detect late adverse events that require long exposure times to develop. It may therefore be relevant that post-marketing trials sometimes have more pragmatic characteristics, if there is a need for further efficacy and safety information. A pragmatic study design may reflect a situation close to clinical practice, but may also have greater potential methodological concerns, e.g. regarding the validity and completeness of data when using routinely collected information from registries and health records, the handling of intercurrent events, and misclassification of outcomes. In a regulatory evaluation it is important to be able to isolate the effect of a specific product or substance, and to have a defined population that the results can be referred to. A study feature such as having a wide and permissive inclusion of patients might therefore actually hamper the utility of the results for regulatory purposes. Randomization in a registry-based setting addresses confounding that could otherwise complicate a corresponding non-interventional design, but not any other methodological issues. Attention to methodological basics can help generate reliable study results, and is more important than labelling studies as 'pragmatic'.

Can the Plasma Concentration Ratio of Triglyceride/High-Density Lipoprotein Cholesterol Identify Individuals at High Risk of Cardiovascular Disease During 40-Year Follow-Up?

BACKGROUND: The plasma concentration ratio of triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) is a simple way to estimate insulin resistance. We aimed to evaluate the TG/HDL-C ratio as a simple clinical way to identify apparently healthy individuals with insulin resistance and enhanced risk of future cardiovascular disease (CVD). METHODS: One thousand seven hundred twenty men, aged 50 years, free from diabetes and CVD when evaluated at baseline in 1970-1974 were followed for 40 years regarding incident CVD (myocardial infarction and/or ischemic stroke, n = 576). RESULTS: Participants with a high TG/HDL-C ratio (highest quartile >1.8) at baseline were more insulin resistant, with a significantly more adverse cardiometabolic risk profile (P < 0.001) at baseline, compared with those with a lower ratio. This group also showed an increased risk of CVD [hazard ratio, HR 1.47 (95% confidence interval 1.26-1.93) P < 0.001]. Fourteen percent of subjects with metabolic syndrome, in whom insulin resistance is increased, were also at enhanced CVD risk [HR 1.75 (1.42-2.16) P < 0.001]. CONCLUSIONS: Twenty-five percent of apparently healthy 50-year-old men with the highest TG/HDL-C plasma concentration ratio had a significantly more adverse cardiometabolic profile at baseline, and developed more CVD over the next 40 years, compared with those not meeting this cut point. Determining the TG/HDL-C ratio in middle-aged men provided a simple and potentially clinically useful way to identify increased risk of developing CVD in persons free of diabetes or manifest CVD.

Risk Factors, Mortality, and Cardiovascular Outcomes in Patients with Type 2 Diabetes.

BACKGROUND: Patients with diabetes are at higher risk for death and cardiovascular outcomes than the general population. We investigated whether the excess risk of death and cardiovascular events among patients with type 2 diabetes could be reduced or eliminated. METHODS: In a cohort study, we included 271,174 patients with type 2 diabetes who were registered in the Swedish National Diabetes Register and matched them with 1,355,870 controls on the basis of age, sex, and county. We assessed patients with diabetes according to age categories and according to the presence of five risk factors (elevated glycated hemoglobin level, elevated low-density lipoprotein cholesterol level, albuminuria, smoking, and elevated blood pressure). Cox regression was used to study the excess risk of outcomes (death, acute myocardial infarction, stroke, and hospitalization for heart failure) associated with smoking and the number of variables outside target ranges. We also examined the relationship between various risk factors and cardiovascular outcomes. RESULTS: The median follow-up among all the study participants was 5.7 years, during which 175,345 deaths occurred. Among patients with type 2 diabetes, the excess risk of outcomes decreased stepwise for each risk-factor variable within the target range. Among patients with diabetes who had all five variables within target ranges, the hazard ratio for death from any cause, as compared with controls, was 1.06 (95% confidence interval [CI], 1.00 to 1.12), the hazard ratio for acute myocardial infarction was 0.84 (95% CI, 0.75 to 0.93), and the hazard ratio for stroke was 0.95 (95% CI, 0.84 to 1.07). The risk of hospitalization for heart failure was consistently higher among patients with diabetes than among controls (hazard ratio, 1.45; 95% CI, 1.34 to 1.57). In patients with type 2 diabetes, a glycated hemoglobin level outside the target range was the strongest predictor of stroke and acute myocardial infarction; smoking was the strongest predictor of death. CONCLUSIONS: Patients with type 2 diabetes who had five risk-factor variables within the target ranges appeared to have little or no excess risk of death, myocardial infarction, or stroke, as compared with the general population. (Funded by the Swedish Association of Local Authorities and Regions and others.).