Autoimmune comorbidity in type 1 diabetes and its association with metabolic control and mortality risk in young people: a population-based study.

AIMS/HYPOTHESIS: This register-based study aimed to describe autoimmune comorbidity in children and young adults from type 1 diabetes onset, and to investigate whether such comorbidity was associated with a difference in HbA1c or mortality risk compared with children/young adults with type 1 diabetes without autoimmune comorbidity. METHODS: A total of 15,188 individuals from the Swedish National Diabetes Register, registered with type 1 diabetes before 18 years of age between 2000 and 2019, were included. Five randomly selected control individuals from the Swedish population (Statistics Sweden) were matched to each individual with type 1 diabetes (n=74,210 [346 individuals with type 1 diabetes were not found in the Statistics Sweden register at the date of type 1 diabetes diagnosis, so could not be matched to control individuals]). The National Patient Register was used to attain ICD-10 codes on autoimmune diseases and the Cause of Death Register was used to identify deceased individuals. RESULTS: In the total type 1 diabetes cohort, mean±SD age at onset of type 1 diabetes was 9.5±4.4 years and mean disease duration at end of follow-up was 8.8±5.7 years. Of the individuals with type 1 diabetes, 19.2% were diagnosed with at least one autoimmune disease vs 4.0% of the control group. The HRs for comorbidities within 19 years from onset of type 1 diabetes were 11.6 (95% CI 10.6, 12.6) for coeliac disease, 10.6 (95% CI 9.6, 11.8) for thyroid disease, 1.3 (95% CI 1.1, 1.6) for psoriasis, 4.1 (95% CI 3.2, 5.3) for vitiligo, 1.7 (95% CI 1.4, 2.2) for rheumatic joint disease, 1.0 (95% CI 0.8, 1.3) for inflammatory bowel disease, 1.0 (95% CI 0.7, 1.2) for systemic connective tissue disorder, 1.4 (95% CI 1.1, 1.9) for uveitis, 18.3 (95% CI 8.4, 40.0) for Addison's disease, 1.8 (95% CI 0.9, 3.6) for multiple sclerosis, 3.7 (95% CI 1.6, 8.7) for inflammatory liver disease and 19.6 (95% CI 4.2, 92.3) for atrophic gastritis. Autoimmune disease in addition to type 1 diabetes had no statistically significant effect on HbA1c or mortality risk. CONCLUSIONS/INTERPRETATION: To our knowledge, this is the first comprehensive study where young individuals with type 1 diabetes were followed regarding development of a wide spectrum of autoimmune diseases, from onset of type 1 diabetes. In this nationwide and population-based study, there was already a high prevalence of autoimmune diseases in childhood, especially coeliac and thyroid disease. The presence of autoimmune comorbidity did not have a statistically significant effect on metabolic control or mortality risk.

Twenty Years of Cardiovascular Complications and Risk Factors in Patients With Type 2 Diabetes: A Nationwide Swedish Cohort Study.

BACKGROUND: The goal of this work was to investigate trends (2001-2019) for cardiovascular events and cardiometabolic risk factor levels in individuals with type 2 diabetes (T2D) and matched control subjects. METHODS: This study included 679 072 individuals with T2D from the Swedish National Diabetes Register and 2 643 800 matched control subjects. Incident outcomes comprised coronary artery disease, acute myocardial infarction, cerebrovascular disease, and heart failure (HF). Trends in time to first event for each outcome were analyzed with Cox regression and standardized incidence rates. In the group with T2D, Cox regression was also used to assess risk factor levels beyond target and outcomes, as well as the relative importance of each risk factor to each model. RESULTS: Among individuals with T2D, incidence rates per 10 000 person-years in 2001 and 2019 were as follows: acute myocardial infarction, 73.9 (95% CI, 65.4-86.8) and 41.0 (95% CI, 39.5-42.6); coronary artery disease, 205.1 (95% CI, 186.8-227.5) and 80.2 (95% CI, 78.2-82.3); cerebrovascular disease, 83.9 (95% CI, 73.6-98.5) and 46.2 (95% CI, 44.9-47.6); and HF, 98.3 (95% CI, 89.4-112.0) and 75.9 (95% CI, 74.4-77.5). The incidence for HF plateaued around 2013, a trend that then persisted. In individuals with T2D, glycated hemoglobin, systolic blood pressure, estimated glomerular filtration rate, and lipids were independently associated with outcomes. Body mass index alone potentially explained >30% of HF risk in T2D. For those with T2D with no risk factor beyond target, there was no excess cardiovascular risk compared with control subjects except for HF, with increased hazard with T2D even when no risk factor was above target (hazard ratio, 1.50 [95% CI, 1.35-1.67]). Risk for coronary artery disease and cerebrovascular disease increased in a stepwise fashion for each risk factor not within target. Glycated hemoglobin was most prognostically important for incident atherosclerotic events, as was body mass index for incident of HF. CONCLUSIONS: Risk and rates for atherosclerotic complications and HF are generally decreasing among individuals with T2D, although HF incidence has notably plateaued in recent years. Modifiable risk factors within target levels were associated with lower risks for outcomes. This was particularly notable for systolic blood pressure and glycated hemoglobin for atherosclerotic outcomes and body mass index for heart failure.

Association of glucagon-like peptide-1 receptor agonists with serious liver events among patients with type 2 diabetes: A Scandinavian cohort study.

BACKGROUND AND AIMS: Clinical trials suggest that glucagon-like peptide-1 (GLP-1) receptor agonists may have beneficial effects on NAFLD, but the impact on hard hepatic end points is unknown. We assessed the association between the use of GLP-1 receptor agonists and the risk of serious liver events in routine clinical practice. APPROACH AND RESULTS: Cohort study using data from nationwide registers in Sweden, Denmark, and Norway, 2007-2020, including 91,479 initiators of GLP-1 receptor agonists and 244,004 initiators of the active comparator, dipeptidyl peptidase-4 inhibitors, without a history of chronic liver disease other than NAFLD/NASH. The primary outcome was serious liver events: a composite of incident compensated and decompensated cirrhosis and HCC. Secondary outcomes were the individual components of the primary outcome. Cox regression was used to estimate HRs, using propensity score weighting to control for confounding. Users of GLP-1 receptor agonists had 608 serious liver events (adjusted incidence rate: 16.9 events per 10,000 person-years), compared with 1770 events among users of dipeptidyl peptidase-4 inhibitors (19.2 events per 10,000 person-years). The adjusted HR was 0.85 (95% CI: 0.75 to 0.97), and the rate difference was -2.1 (-4.4 to 0.1) events per 10,000 person-years. In secondary outcome analyses, the adjusted HR was 0.85 (0.75 to 0.97) for compensated and decompensated cirrhosis and 1.05 (0.80 to 1.39) for HCC. CONCLUSIONS: The use of GLP-1 receptor agonists was associated with a significantly reduced risk of serious liver events, driven by a reduction of compensated and decompensated cirrhosis.

Risk factors for and risk of all-cause and atherosclerotic cardiovascular disease mortality in people with type 2 diabetes and peripheral artery disease: an observational, register-based cohort study.

BACKGROUND: Type 2 diabetes (T2D) and peripheral artery disease (PAD) are recognized as independent risk factors contributing to excess mortality. Contemporary observational studies exploring the associations of risk factors, and risk of all-cause and atherosclerotic cardiovascular disease mortality in persons with T2D following the onset of incident peripheral artery disease are limited. The objectives of this study were to investigate the associations of risk factors, and assess mortality risks in people with T2D compared with controls without T2D after the onset of PAD. METHODS: All persons with T2D (n = 150,215) registered in the Swedish National Diabetes Register between 2005 and 2009 were included, along with 346,423 controls without T2D matched for sex and age. Data were retrieved from several national registries, capturing information on risk factors, onset of incident peripheral artery disease, other comorbidities, socioeconomic factors, and outcomes. To compare persons with T2D and controls following the onset of peripheral artery disease regarding the risk of all-cause, and atherosclerotic cardiovascular disease mortality, Cox proportional hazard models and Kaplan-Meier curves were employed. A gradient-boosting model was utilized to estimate the relative statistical contribution of risk factors to the modeling of incident mortality risk in people with both T2D and peripheral artery disease. RESULTS: Crude rates of incident all-cause mortality were higher in individuals with T2D compared with controls, following the onset of PAD (600.4 (95% CI, 581.4-619.8) per 10,000 person-years versus 549.1 (95% CI, 532.1-566.5) per 10,000 person-years). Persons with T2D had an adjusted hazard ratio (HR) for all-cause mortality of 1.12 (95% CI, 1.05-1.19, P < 0.01) compared with controls after onset of incident PAD. The comparable adjusted HR for cardiovascular mortality was 1.13 (95% CI, 1.07-1.19, P < 0.01). High age and hyperglycemia at baseline played a significant role in contributing to the predictive models for incident all-cause and cardiovascular mortality among individuals with both T2D and PAD. CONCLUSIONS: The presence of T2D with concomitant PAD is related to an increased risk of both all-cause and cardiovascular mortality compared with individuals with only PAD. This argues for implementing optimized and intensive treatment strategies for individuals with both conditions.

Lifetime and 10-year cardiovascular risk prediction in individuals with type 1 diabetes: The LIFE-T1D model.

AIMS: To develop and externally validate the LIFE-T1D model for the estimation of lifetime and 10-year risk of cardiovascular disease (CVD) in individuals with type 1 diabetes. MATERIALS AND METHODS: A sex-specific competing risk-adjusted Cox proportional hazards model was derived in individuals with type 1 diabetes without prior CVD from the Swedish National Diabetes Register (NDR), using age as the time axis. Predictors included age at diabetes onset, smoking status, body mass index, systolic blood pressure, glycated haemoglobin level, estimated glomerular filtration rate, non-high-density lipoprotein cholesterol, albuminuria and retinopathy. The model was externally validated in the Danish Funen Diabetes Database (FDDB) and the UK Biobank. RESULTS: During a median follow-up of 11.8 years (interquartile interval 6.1-17.1 years), 4608 CVD events and 1316 non-CVD deaths were observed in the NDR (n = 39 756). The internal validation c-statistic was 0.85 (95% confidence interval [CI] 0.84-0.85) and the external validation c-statistics were 0.77 (95% CI 0.74-0.81) for the FDDB (n = 2709) and 0.73 (95% CI 0.70-0.77) for the UK Biobank (n = 1022). Predicted risks were consistent with the observed incidence in the derivation and both validation cohorts. CONCLUSIONS: The LIFE-T1D model can estimate lifetime risk of CVD and CVD-free life expectancy in individuals with type 1 diabetes without previous CVD. This model can facilitate individualized CVD prevention among individuals with type 1 diabetes. Validation in additional cohorts will improve future clinical implementation.

Left-Sided Degenerative Valvular Heart Disease in Type 1 and Type 2 Diabetes.

BACKGROUND: The role of diabetes in the development of valvular heart disease, and, in particular, the relation with risk factor control, has not been extensively studied. METHODS: We included 715 143 patients with diabetes registered in the Swedish National Diabetes Register and compared them with 2 732 333 matched controls randomly selected from the general population. First, trends were analyzed with incidence rates and Cox regression, which was also used to assess diabetes as a risk factor compared with controls, and, second, separately in patients with diabetes according to the presence of 5 risk factors. RESULTS: The incidence of valvular outcomes is increasing among patients with diabetes and the general population. In type 2 diabetes, systolic blood pressure, body mass index, and renal function were associated with valvular lesions. Hazard ratios for patients with type 2 diabetes who had nearly all risk factors within target ranges, compared with controls, were as follows: aortic stenosis 1.34 (95% CI, 1.31-1.38), aortic regurgitation 0.67 (95% CI, 0.64-0.70), mitral stenosis 1.95 (95% CI, 1.76-2.20), and mitral regurgitation 0.82 (95% CI, 0.79-0.85). Hazard ratios for patients with type 1 diabetes and nearly optimal risk factor control were as follows: aortic stenosis 2.01 (95% CI, 1.58-2.56), aortic regurgitation 0.63 (95% CI, 0.43-0.94), and mitral stenosis 3.47 (95% CI, 1.37-8.84). Excess risk in patients with type 2 diabetes for stenotic lesions showed hazard ratios for aortic stenosis 1.62 (95% CI, 1.59-1.65), mitral stenosis 2.28 (95% CI, 2.08-2.50), and excess risk in patients with type 1 diabetes showed hazard ratios of 2.59 (95% CI, 2.21-3.05) and 11.43 (95% CI, 6.18-21.15), respectively. Risk for aortic and mitral regurgitation was lower in type 2 diabetes: 0.81 (95% CI, 0.78-0.84) and 0.95 (95% CI, 0.92-0.98), respectively. CONCLUSIONS: Individuals with type 1 and 2 diabetes have greater risk for stenotic lesions, whereas risk for valvular regurgitation was lower in patients with type 2 diabetes. Patients with well-controlled cardiovascular risk factors continued to display higher risk for valvular stenosis, without a clear stepwise decrease in risk between various degrees of risk factor control.

Risk of fracture in adults with type 2 diabetes in Sweden: A national cohort study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is considered a risk factor for fracture but the evidence regarding the impact of T2DM on fracture risk is conflicting. The objective of the study was to determine if patients with T2DM have increased fracture risk and if T2DM-related risk factors could be identified. METHODS AND FINDINGS: In this national cohort study in Sweden, we investigated the risk of fracture in 580,127 T2DM patients, identified through the national diabetes register including from both primary care and hospitals, and an equal number of population-based controls without diabetes matched for age, sex, and county from 2007 to 2017. The mean age at entry was 66.7 years and 43.6% were women. During a median follow-up time of 6.6 (interquartile range (IQR) 3.1 to 9.8) years, patients with T2DM had a marginally but significantly increased risk of major osteoporotic fracture (MOF) (hazard ratio (HR) 1.01 (95% confidence interval [CI] 1.00 to 1.03)) and hip fracture (HR 1.06 (95% CI 1.04 to 1.08)) compared to controls, associations that were only minimally affected (HR 1.05 (95% CI 1.03 to 1.06) and HR 1.11 (95% CI 1.09 to 1.14), respectively) by multivariable adjustment (age, sex, marital status, and an additional 20 variables related to general morbidity, cardiovascular status, risk of falls, and fracture). In a multivariable-adjusted Cox model, the proportion of the risk for all fracture outcomes (Heller's R2) explained by T2DM was below 0.1%. Among the T2DM patients, important risk factors for fracture were a low BMI (<25 kg/m2), long diabetes duration (≥15 years), insulin treatment, and low physical activity. In total, 55% of the T2DM patients had none of these risk factors and a significantly lower fracture risk than their respective controls. The relatively short mean duration of T2DM and lack of bone density data, constitute limitations of the analysis. CONCLUSION: In this study, we observed only a marginally increased fracture risk in T2DM, a condition that explained less than 0.1% of the fracture risk. Consideration of the herein identified T2DM-related risk factors could be used to stratify T2DM patients according to fracture risk.

Use of DPP4 Inhibitors and GLP-1 Receptor Agonists and Risk of Intestinal Obstruction: Scandinavian Cohort Study.

BACKGROUND & AIMS: Concerns have been raised that the incretin-based diabetes drugs dipeptidyl peptidase 4 (DPP4) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists may increase the risk of intestinal obstruction. We aimed to assess the association between use of DPP4 inhibitors and GLP-1 receptor agonists and the risk of intestinal obstruction. METHODS: Using data from nationwide registers in Sweden, Denmark, and Norway, 2013-2021, we conducted 2 cohort studies, one for DPP4 inhibitors and one for GLP-1 receptor agonists, to investigate the risk of intestinal obstruction as compared with an active comparator drug class (sodium-glucose co-transporter 2 [SGLT2] inhibitors). RESULTS: Among 19,0321 new users of DPP4 inhibitors (median (interquartile range [IQR]) follow-up time, 1.3 [0.6-2.6] years) and 139,315 new users of SGLT2 inhibitors (median [IQR] follow-up time, 0.8 [0.4-1.7] years), 919 intestinal obstruction events occurred. Use of DPP4 inhibitors, as compared with SGLT2 inhibitors, was not associated with a statistically significant increase in risk of intestinal obstruction (adjusted incidence rate, 2.0 vs 1.8 per 1000 person-years; hazard ratio, 1.13; 95% confidence interval, 0.96-1.34). Among 121,254 new users of GLP-1 receptor agonists (median [standard deviation] follow-up time, 0.9 [0.4-1.9] years) and 185,027 new users of SGLT2 inhibitors (median [IQR] follow-up time, 0.8 [0.4-1.8] years), 557 intestinal obstruction events occurred. Use of GLP-1 receptor agonists was not associated with a statistically significant increase in risk of intestinal obstruction (adjusted incidence rate, 1.3 vs 1.6 per 1000 person-years; hazard ratio, 0.83; 95% confidence interval, 0.69-1.01). CONCLUSIONS: In this analysis of nationwide data from 3 countries, previous safety signals indicating an increased risk of intestinal obstruction with use of DPP4 inhibitors and GLP-1 receptor agonists were not confirmed.

Glycaemic control and sepsis risk in adults with type 1 diabetes.

AIMS: To study the association between glycated haemoglobin (HbA1c) and sepsis in adults with type 1 diabetes, and to explore the relationship between HbA1c and mortality among individuals who developed sepsis. MATERIALS AND METHODS: We included 33 549 adult individuals with type 1 diabetes recorded in the Swedish National Diabetes Register between January 2005 and December 2015. We used multivariable Cox regression and restricted cubic spline analyses to study the relationship between HbA1c values and sepsis occurrence and association between HbA1c and mortality among those with sepsis. RESULTS: In total, 713 (2.1%) individuals developed sepsis during the study period. Compared with the HbA1c reference interval of 48-52 mmol/mol (6.5-6.9%), the adjusted hazard ratio for sepsis was: 2.50 [95% confidence interval (CI) 1.18-5.29] for HbA1c <43 mmol/mol; 1.88 (95% CI 0.96-3.67) for HbA1c 43-47 mmol/mol; 1.78 (95% CI 1.09-2.89) for HbA1c 53-62 mmol/mol; 1.86 (95% CI 1.14-3.03) for HbA1c 63-72 mmol/mol; 3.15 (95% CI 1.91-5.19) for HbA1c 73-82 mmol/mol; and 4.26 (95% CI 2.53-7.16) for HbA1c >82 mmol/mol. On multivariable restricted cubic spline analysis, we found a J-shaped association between HbA1c and sepsis risk, with the lowest risk observed at HbA1c of approximately 53 mmol/mol. We found no association between HbA1c and mortality among those individuals who developed sepsis. CONCLUSIONS: In our nationwide observational study of adult individuals with type 1 diabetes we found a J-shaped relationship between HbA1c and risk of sepsis, with the lowest risk at HbA1c levels about 53 mmol/mol (7.0%). HbA1c was not associated with mortality in individuals affected by sepsis.

Anaemia in patients with self-reported use of iron supplements in the BAriatric surgery SUbstitution and nutrition study: A prospective cohort study.

BACKGROUND AND AIMS: After bariatric surgery, micronutrient deficiencies may lead to anaemia. To prevent post-operative deficiencies, patients are recommended lifelong micronutrient supplementation. Studies investigating the effectiveness of supplementation to prevent anaemia after bariatric surgery are scarce. This study aimed to investigate the relationship between nutritional deficiencies and anaemia in patients who report use of supplementation two years after bariatric surgery versus patients who do not. METHODS AND RESULTS: Obese (BMI≥35 kg/m2) individuals (n = 971) were recruited at Sahlgrenska University Hospital in Gothenburg, Sweden between 2015 and 2017. The interventions were Roux-en-Y gastric bypass (RYGB), n = 382, sleeve gastrectomy (SG), n = 201, or medical treatment (MT), n = 388. Blood samples and self-reported data on supplements were collected at baseline and two years post treatment. Anaemia was defined as haemoglobin <120 g/L for females and <130 g/L for males. Standard statistical methods, including a logistic regression model and a machine learning algorithm, were used to analyse data. The frequency of anaemia increased from baseline in patients treated with RYGB (3·0% vs 10·5%; p < 0·05). Neither iron-dependent biochemistry nor frequency of anaemia differed between participants who reported use of iron supplements and those who did not at the two-year follow-up. Low preoperative level of haemoglobin and high postoperative percent excessive BMI loss increased the predicted probability of anaemia two years after surgery. CONCLUSION: The results from this study indicate that iron deficiency or anaemia may not be prevented by substitutional treatment per current guidelines after bariatric surgery and highlights there is reason to ensure adequate preoperative micronutrient levels. TRIAL REGISTRATION: March 03, 2015; NCT03152617.

Registry-based randomised clinical trials: a remedy for evidence-based diabetes care?

This narrative review describes a new approach to navigation in a challenging landscape of clinical drug development in diabetes. Successful outcome studies in recent years have led to new indications and guidelines in type 2 diabetes, yet the number of clinical trials in diabetes is now declining. This is due to many environmental factors acting in concert, including the prioritisation of funding for other diseases, high costs of large randomised clinical trials, increase in regulatory requirements and limited entry of novel candidate drugs. There is a need for novel and cost-effective paradigms of clinical development to meet these and other challenges. The concept of registry-based randomised clinical trials (RRCTs) is an attractive option. In this review we focus on type 2 diabetes and the prevention of cardiovascular and microvascular comorbidities and mortality, using the Swedish SMARTEST trial as an example of an RRCT. We also give some examples from other disease areas. The RRCT concept is a novel, cost-effective and scientifically sound approach for conducting large-scale diabetes trials in a real-world setting.

HbA1c variability predicts cardiovascular complications in type 2 diabetes regardless of being at glycemic target.

BACKGROUND: HbA1c variability has emerged as risk factor for cardiovascular diseases in diabetes. However, the impact of HbA1c variability on cardiovascular diseases in subjects within the recommended HbA1c target has been relatively unexplored. METHODS: Using data from a large database, we studied 101,533 people with type 2 diabetes without cardiovascular diseases. HbA1c variability was expressed as quartiles of the standard deviation of HbA1c during three years (exposure phase). The primary composite outcome included non-fatal myocardial infarction, non-fatal stroke, all-cause mortality and was assessed during five years following the first three years of exposure to HbA1c variability (longitudinal phase). An expanded composite outcome including non-fatal myocardial infarction, non-fatal stroke, coronary revascularization/reperfusion procedures, peripheral revascularization procedures, and all-cause mortality was also considered, as well as a series of specific cardiovascular complications. Cox models were adjusted for a large range of risk factors and results were expressed as adjusted hazard ratios. RESULTS: An association between HbA1c variability and all the outcomes considered was found. The correlation between HbA1c variability and cardiovascular complications development was confirmed in both the subgroups of subjects with a mean HbA1c ≤ 53 mmol/mol (recommended HbA1c target) or > 53 mmol/mol during the exposure phase. The risk related to HbA1c variability was higher in people with mean HbA1c ≤ 53 mmol/mol for the primary outcome (p for interaction 0.004), for the expanded secondary outcome (p for interaction 0.001) and for the stroke (p for interaction 0.001), even though HbA1c remained at the target during the follow-up. CONCLUSIONS: These findings suggest that HbA1c variability may provide additional information for an optimized management of diabetes, particularly in people within the target of HbA1c.

The comparative cardiovascular and renal effectiveness of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists: A Scandinavian cohort study.

AIM: To assess the comparative cardiovascular and renal effectiveness of sodium-glucose co-transporter-2 (SGLT2) inhibitors versus glucagon-like peptide-1 (GLP-1) receptor agonists in routine clinical practice. MATERIALS AND METHODS: A cohort study of nationwide registers from Sweden, Denmark, and Norway, including 87 525 new users of SGLT2 inhibitors and 63 921 new users of GLP-1 receptor agonists, was conducted using data from 2013-2018. Co-primary outcomes, analysed using an intention-to-treat exposure definition, were major adverse cardiovascular events (MACE; myocardial infarction, stroke, and cardiovascular death), heart failure (hospitalization or death because of heart failure), and serious renal events (renal replacement therapy, hospitalization for renal events, and death from renal causes). RESULTS: Use of SGLT2 inhibitors versus GLP-1 receptor agonists was associated with a higher risk of MACE (adjusted incidence rate: 15.2 vs. 14.4 events per 1000 person-years; HR 1.07 [95% CI 1.01-1.15]), a similar risk of heart failure (6.0 vs. 6.0 events per 1000 person-years; HR 1.02 [0.92-1.12]), and a lower risk of serious renal events (2.9 vs. 4.0 events per 1000 person-years; HR 0.76 [0.66-0.87]). In as-treated analyses, the HR (95% CI) was 1.11 (1.00-1.24) for MACE, 0.88 (0.74-1.04) for heart failure, and 0.60 (0.47-0.77) for serious renal events. In secondary outcome analyses, use of SGLT2 inhibitors versus GLP-1 receptor agonists was not associated with statistically significant differences for the risk of myocardial infarction (HR 1.09 [95% CI 1.00-1.19]), cardiovascular death (HR 0.97 [95% CI 0.84-1.12]), death from renal causes (HR 0.75 [95% CI 0.41-1.35]), or any cause death (HR 1.01 [95% CI 0.94-1.09]), while the risk of stroke was higher (HR 1.14 [95% CI 1.03-1.26]), and the risk of renal replacement therapy (HR 0.74 [95% CI 0.56-0.97]) and hospitalization for renal events (HR 0.75 [95% CI 0.65-0.88]) were lower among users of SGLT2 inhibitors. CONCLUSIONS: Use of SGLT2 inhibitors versus GLP-1 receptor agonists was associated with a similar risk of heart failure and a lower risk of serious renal events, while use of GLP-1 receptor agonists versus SGLT2 inhibitors was associated with a slightly lower risk of MACE. In as-treated analyses, the associations with MACE and serious renal events increased in magnitude, and the HR for heart failure tended towards a protective association for SGLT2 inhibitors.

Oral health by obesity classification in young obese women - a cross-sectional study.

OBJECTIVE: To explore oral health by increasing degree of obesity and the influence of modifying factors. MATERIALS AND METHODS: A cross-sectional design was used. Swedish females (n = 118; 18-35 years) with morbid obesity were recruited from the BAriatric SUbstitution and Nutrition study (BASUN). Body mass index (BMI) was used as continuous and categorized into 35-39.9 kg/m2/40-44.9 kg/m2/≥45 kg/m2. Oral examinations assessed dental caries using the ICDAS system, periodontal status and saliva characteristics. Information on sociodemographics, oral health behaviour and symptoms was collected via a questionnaire. RESULTS: Mean BMI was 42.2 kg/m3 (SD 4.0; range 35.0-63.7). Significantly higher frequencies of dentine caries (p = .001) and total caries (p = .046) were found with higher BMI with an increase in total caries by 0.59 tooth surface (p = .025) for each increasing BMI degree. There were consistent associations between obesity and dentine caries for the group with the highest BMI (≥45), adjusted RR 2.08 (95% CI 1.20-3.61), and all stages of caries, adjusted RR 1.41 (95% CI 1.02-1.96). High scores were found for dental plaque (50.2%) and gingivitis (34.5%). CONCLUSION: Young obese women exhibited poor oral health with higher caries levels by higher BMI. Dental care should adapt the prevention efforts for obese individuals. Trial Registration: The trial was prospectively registered on March 03; 2015; NCT03152617.

Development of a life expectancy table for individuals with type 1 diabetes.

AIMS/HYPOTHESIS: Tables reporting life expectancies by common risk factors are available for individuals with type 2 diabetes; however, there is currently no published equivalent for individuals with type 1 diabetes. We aimed to develop a life expectancy table using a recently published simulation model for individuals with type 1 diabetes. METHODS: The simulation model was developed using data from a real-world population of patients with type 1 diabetes selected from the Swedish National Diabetes Register. The following six important risk factors were included in the life table: sex; age; current smoking status; BMI; eGFR; and HbA1c. For each of 1024 cells in the life expectancy table, a synthetic cohort containing 1000 individuals was created, with other risk factors assigned values representative of the real-world population. The simulations were executed for all synthetic cohorts and life expectancy for each cell was calculated as mean survival time of the individuals in the respective cohort. RESULTS: There was a substantial variation in life expectancy across patients with different risk factor levels. Life expectancy of 20-year-old men varied from 29.3 years to 50.6 years, constituting a gap of 21.3 years between those with worst and best risk factor levels. In 20-year-old women, this gap was 18.9 years (life expectancy range 35.0-53.9 years). The variation in life expectancy was a function of the combination of risk factor values, with HbA1c and eGFR consistently showing a negative and positive correlation, respectively, with life expectancy at any level combination of other risk factors. Individuals with the lowest level (20 kg/m2) and highest level of BMI (35 kg/m2) had a lower life expectancy compared with those with a BMI of 25 kg/m2. Non-smokers and women had a higher life expectancy than smokers and men, respectively, with the difference in life expectancy ranging from 0.4 years to 2.7 years between non-smokers and smokers, and from 1.9 years to 5.9 years between women and men, depending on levels of other risk factors. CONCLUSIONS/INTERPRETATION: The life expectancy table generated in this study shows a substantial variation in life expectancy across individuals with different modifiable risk factors. The table allows for rapid communications of risk in an easily understood format between healthcare professionals, health economists, researchers, policy makers and patients. Particularly, it supports clinicians in their discussion with patients about the benefits of improving risk factors.

Use of incretin-based drugs and risk of cholangiocarcinoma: Scandinavian cohort study.

AIMS/HYPOTHESIS: Concerns have been raised regarding a potential association of use of the incretin-based drugs dipeptidyl peptidase 4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP-1)-receptor agonists with risk of cholangiocarcinoma. We examined this association in nationwide data from three countries. METHODS: We used data from nationwide registers in Sweden, Denmark and Norway, 2007-2018, to conduct two cohort studies, one for DPP4 inhibitors and one for GLP-1-receptor agonists, to investigate the risk of incident cholangiocarcinoma compared with an active-comparator drug class (sulfonylureas). The cohorts included patients initiating treatment episodes with DPP4 inhibitors vs sulfonylureas, and GLP-1-receptor agonists vs sulfonylureas. We used Cox regression models, adjusted for potential confounders, to estimate hazard ratios from day 366 after treatment initiation to account for cancer latency. RESULTS: The main analyses of DPP4 inhibitors included 1,414,144 person-years of follow-up from 222,577 patients receiving DPP4 inhibitors (median [IQR] follow-up time, 4.5 [2.6-7.0] years) and 123,908 patients receiving sulfonylureas (median [IQR] follow-up time, 5.1 [2.9-7.8] years) during which 350 cholangiocarcinoma events occurred. Use of DPP4 inhibitors, compared with sulfonylureas, was not associated with a statistically significant increase in risk of cholangiocarcinoma (incidence rate 26 vs 23 per 100,000 person-years; adjusted HR, 1.15 [95% CI 0.90, 1.46]; absolute rate difference 3 [95% CI -3, 10] events per 100,000 person-years). The main analyses of GLP-1-receptor agonists included 1,036,587 person-years of follow-up from 96,813 patients receiving GLP-1-receptor agonists (median [IQR] follow-up time, 4.4 [2.4-6.9] years) and 142,578 patients receiving sulfonylureas (median [IQR] follow-up time, 5.5 [3.2-8.1] years) during which 249 cholangiocarcinoma events occurred. Use of GLP-1-receptor agonists was not associated with a statistically significant increase in risk of cholangiocarcinoma (incidence rate 26 vs 23 per 100,000 person-years; adjusted HR, 1.25 [95% CI 0.89, 1.76]; absolute rate difference 3 [95% CI -5, 13] events per 100,000 patient-years). CONCLUSIONS/INTERPRETATION: In this analysis using nationwide data from three countries, use of DPP4 inhibitors and GLP-1-receptor agonists, compared with sulfonylureas, was not associated with a significantly increased risk of cholangiocarcinoma.

Comparison between data-driven clusters and models based on clinical features to predict outcomes in type 2 diabetes: nationwide observational study.

AIMS/HYPOTHESIS: Research using data-driven cluster analysis has proposed five novel subgroups of diabetes based on six measured variables in individuals with newly diagnosed diabetes. Our aim was (1) to validate the existence of differing clusters within type 2 diabetes, and (2) to compare the cluster method with an alternative strategy based on traditional methods to predict diabetes outcomes. METHODS: We used data from the Swedish National Diabetes Register and included 114,231 individuals with newly diagnosed type 2 diabetes. k-means clustering was used to identify clusters based on nine continuous variables (age at diagnosis, HbA1c, BMI, systolic and diastolic BP, LDL- and HDL-cholesterol, triacylglycerol and eGFR). The elbow method was used to determine the optimal number of clusters and Cox regression models were used to evaluate mortality risk and risk of CVD events. The prediction models were compared using concordance statistics. RESULTS: The elbow plot, with values of k ranging from 1 to 10, showed a smooth curve without any clear cut-off points, making the optimal value of k unclear. The appearance of the plot was very similar to the elbow plot made from a simulated dataset consisting only of one cluster. In prediction models for mortality, concordance was 0.63 (95% CI 0.63, 0.64) for two clusters, 0.66 (95% CI 0.65, 0.66) for four clusters, 0.77 (95% CI 0.76, 0.77) for the ordinary Cox model and 0.78 (95% CI 0.77, 0.78) for the Cox model with smoothing splines. In prediction models for CVD events, the concordance was 0.64 (95% CI 0.63, 0.65) for two clusters, 0.66 (95% CI 0.65, 0.67) for four clusters, 0.77 (95% CI 0.77, 0.78) for the ordinary Cox model and 0.78 (95% CI 0.77, 0.78) for the Cox model with splines for all variables. CONCLUSIONS/INTERPRETATION: This nationwide observational study found no evidence supporting the existence of a specific number of distinct clusters within type 2 diabetes. The results from this study suggest that a prediction model approach using simple clinical features to predict risk of diabetes complications would be more useful than a cluster sub-stratification.

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.).

Cardiorenal and other diabetes related outcomes with SGLT-2 inhibitors compared to GLP-1 receptor agonists in type 2 diabetes: nationwide observational study.

BACKGROUND: Major prospective randomized clinical safety trials have demonstrated beneficial effects of treatment with glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose co-transporter-2 inhibitors (SGLT-2i) in people with type 2 diabetes and elevated cardiovascular risk, and recent clinical treatment guidelines therefore promote early use of these classes of pharmacological agents. In this Swedish nationwide observational study, we compared cardiorenal outcomes and safety of new treatment with GLP-1RA and SGLT-2i in people with type 2 diabetes. METHODS: We linked data from national Swedish databases to capture patient characteristics and outcomes and used propensity-score based matching to account for differences between the two groups. The treatments were compared using Cox regression models. RESULTS: We identified 9648 participants starting GLP-1RA and 12,097 starting SGLT-2i with median follow-up times 1.7 and 1.1 years, respectively. The proportion of patients with a history of MACE were 15.8%, and 17.0% in patients treated with GLP-1RA and SGLT-2i, respectively. The mean age was 61 years with 7.6 years duration of diabetes. Mean HbA1c were 8.3% (67.6 mmol/mol) and 8.3% (67.2 mmol/mol), and mean BMI 33.3 and 32.5 kg/m2 in patients treated with GLP-1RA or SGLT-2i, respectively. The cumulative mortality risk was non-significantly lower in the group treated with SGLT-2i, HR 0.78 (95% CI 0.61-1.01), as were incident heart failure outcomes, but the risks of cardiovascular or renal outcomes did not differ. The risks of stroke and peripheral artery disease were higher in the SGLT-2i group relative to GLP-1RA, with HR 1.44 (95% CI 0.99-2.08) and 1.68 (95% CI 1.04-2.72), respectively. CONCLUSIONS: This observational study suggests that treatment with GLP-1RA and SGLT-2i result in very similar cardiorenal outcomes. In the short term, treatment with GLP-1RA seem to be associated with lower risks of stroke and peripheral artery disease, whereas SGLT-2i seem to be nominally associated with lower risk of heart failure and total mortality.

Variability in body weight and the risk of cardiovascular complications in type 2 diabetes: results from the Swedish National Diabetes Register.

BACKGROUND: There is a high incidence of cardiovascular disease in diabetes. Weight variability has been reported as independent risk factor for cardiovascular disease in the general population and preliminarily also in people with type 2 diabetes. METHODS: Using data from the Swedish National Diabetes Register the possible link between visit-to-visit body weight variability and the risk of cardiovascular complications among people with type 2 diabetes and without prevalent cardiovascular diseases at baseline has been evaluated. Overall, 100,576 people with type 2 diabetes, with at least five measurements of body weight taken over three consecutive years, were included. Variability was expressed as quartiles of the standard deviation of the measures during the three years. The primary composite outcome included non-fatal myocardial infarction, non-fatal stroke, and all-cause mortality and was assessed during five years following the first 3 years of exposure to weight variability. RESULTS: After adjusting for known cardiovascular risk factors, the risk of the primary composite outcome significantly increased with increasing body weight variability [upper quartile HR = 1.45; 95% confidence interval 1.39-1.52]. Furthermore, elevated body weight variability was associated with almost all the other cardiovascular complications considered (non-fatal myocardial infarction, non-fatal stroke, all-cause mortality, peripheral arterial disease, peripheral vascular angioplasty, hospitalization for heart failure, foot ulcer, and all-cause mortality). CONCLUSIONS: High body weight variability predicts the development of cardiovascular complications in type 2 diabetes. These data suggest that any strategy to reduce the body weight in these subjects should be aimed at maintaining the reduction in the long-term, avoiding oscillations.