Longitudinal HbA1c patterns before the first treatment of diabetes in routine clinical practice: A latent class trajectory analysis.

AIMS: To examine the longitudinal heterogeneity of HbA1c preceding the initiation of diabetes treatment in clinical practice. METHODS: In this population-based study, we used HbA1c from routine laboratory and healthcare databases. Latent class trajectory analysis was used to classify individuals according to their longitudinal HbA1c patterns before first glucose-lowering drug prescription irrespective of type of diabetes. RESULTS: Among 21,556 individuals initiating diabetes treatment during 2017-2018, 20,733 (96 %) had HbA1c measured (median 4 measurements [IQR 2-7]) in the 5 years preceding treatment initiation. Four classes with distinct HbA1c trajectories were identified, with varying steepness of increase in HbA1c. The largest class (74 % of the individuals) had mean HbA1c above the 48 mmol/mol threshold 9 months before treatment initiation. Mean HbA1c was 52 mmol/mol (95 % CI 52-52) at treatment initiation. In the remaining three classes, mean HbA1c exceeded 48 mmol/mol almost 1.5 years before treatment initiation and reached 79 mmol/mol (95 % CI 78-80), 105 mmol/mol (95 % CI 104-106), and 137 mmol/mol (95 % CI 135-140) before treatment initiation. CONCLUSION: We identified four distinct longitudinal HbA1c patterns before initiation of diabetes treatment in clinical practice. All had mean HbA1c levels exceeding the diagnostic threshold many months before treatment initiation, indicating therapeutic inertia.

HbA1c-defined prediabetes and progression to type 2 diabetes in Denmark: A population-based study based on routine clinical care laboratory data.

AIMS: To estimate the prevalence, incidence, mortality, and risk of progression to type 2 diabetes for individuals with HbA1c-defined prediabetes based on Danish nationwide population-based laboratory databases. METHODS: We included all HbA1c measurements from general practice and hospitals during 2012 to 2018. We estimated the cumulative incidence of having at least one HbA1c measurement. The prevalence and incidence rates of prediabetes (HbA1c 42-47 mmol/mol) were examined in the adult Danish population. The 5-year cumulative incidence of progression to type 2 diabetes was estimated with death as competing event. RESULTS: Among 4,979,590 adult Danes, 70.8% (95% CI 70.8-70.9) had at least one HbA1c measurement during 2012 to 2018. The prevalence of prediabetes was 7.1% (95% CI 7.1-7.1) in 2018. The incidence rate was 14.2 (95% CI 14.1-14.3) per 1,000 person-years, with median age 66.9 years (IQR 56.7-75.7) and median HbA1c 43 mmol/mol (IQR 42-44) at prediabetes diagnosis. Within five years, 17.5% (95% CI 17.3-17.7) died and the 5-year cumulative incidence of type 2 diabetes was 21.3% (95% CI 21.1-21.5). CONCLUSIONS: Out of 100 Danish adults, 1.4 develop prediabetes each year and they can be identified at an early stage in laboratory databases. Within five years, one in five individuals with prediabetes progresses to diabetes and one in six dies.

Clinical and biochemical characteristics of postpancreatitis diabetes mellitus: A cross-sectional study from the Danish nationwide DD2 cohort.

BACKGROUND: Postpancreatitis diabetes mellitus (PPDM) is a common metabolic sequalae of acute and chronic pancreatitis. We conducted a cross-sectional study to examine the proportion of PPDM among patients clinically diagnosed with type 2 diabetes (T2D) in Denmark and their clinical and biochemical characteristics. METHODS: We identified all past diagnoses of pancreatitis among patients in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) cohort through linkage with national health registries. Using International Classification of Diseases, Tenth Revision codes we categorized patients as PPDM and further divided them into acute/chronic subtypes (PPDM-A and PPDM-C). We assessed PPDM prevalence and examined associations with clinical and biochemical parameters using log binomial or Poisson regression to calculate age-/sex-adjusted prevalence ratios (aPRs). RESULTS: Among 5564 patients with a clinical diagnosis of T2D, 78 (1.4%) had PPDM. Compared to T2D, PPDM patients were more often underweight or normal weight (body mass index ≤25.0 kg/m2 : aPR 2.3; 95% confidence interval [CI]: 1.6-3.2) and had lower waist-to-hip ratio (≤0.95/≤0.80 in men/women: aPRs 1.8; 95% CI: 1.2-2.7). PPDM patients had lower plasma amylase levels (<17 U/L: aPRs 2.2; 95% CI: 1.1-4.3), higher insulin sensitivity (homeostatic model assessment 2S [HOMA2S] >63: aPR 2.0; 95% CI: 1.2-3.2) and tended to have worse glycaemic control (HbA1c ≥8.0%: aPRs 1.4; 95% CI: 0.8-2.4). PPDM-A was largely indistinguishable from T2D, whereas PPDM-C had impaired insulin secretion, higher insulin sensitivity, and worse glycemic control. CONCLUSIONS: The proportion of PPDM among patients with clinically diagnosed T2D is ~1.5% in an everyday clinical care setting. Glucose metabolism of PPDM-A is largely indistinguishable from T2D, whereas PPDM-C differs in relation to insulin secretion and sensitivity.

Falls and fractures associated with type 2 diabetic polyneuropathy: A cross-sectional nationwide questionnaire study.

AIMS/INTRODUCTION: To examine the prevalence of falls and fractures, and the association with symptoms of diabetic polyneuropathy (DPN) in patients with recently diagnosed type 2 diabetes. MATERIALS AND METHODS: A detailed questionnaire on neuropathy symptoms and falls was sent to 6,726 patients enrolled in the Danish Center for Strategic Research in Type 2 Diabetes cohort (median age 65 years, diabetes duration 4.6 years). Complete data on fractures and patient characteristics were ascertained from population-based health registries. We defined possible DPN as a score ≥4 on the Michigan Neuropathy Screening Instruments questionnaire. Using Poisson regression analyses, we estimated the adjusted prevalence ratio (aPR) of falls and fractures, comparing patients with and without DPN. RESULTS: In total, 5,359 patients (80%) answered the questions on the Michigan Neuropathy Screening Instruments questionnaire and falls. Within the year preceding the questionnaire response, 17% (n = 933) reported at least one fall and 1.4% (n = 76) suffered from a fracture. The prevalence ratio of falls was substantially increased in patients with possible DPN compared with those without (aPR 2.33, 95% confidence interval [CI] 2.06-2.63). The prevalence ratio increased with the number of falls from aPR 1.51 (95% CI 1.22-1.89) for one fall to aPR 5.89 (95% CI 3.84-9.05) for four or more falls within the preceding year. Possible DPN was associated with a slightly although non-significantly increased risk of fractures (aPR 1.32, 95% CI 0.75-2.33). CONCLUSIONS: Patients with recently diagnosed type 2 diabetes and symptoms of DPN had a highly increased risk of falling. These results emphasize the need for preventive interventions to reduce fall risk among patients with type 2 diabetes and possible DPN.

Impact of Being Eligible for Type 2 Diabetes Treatment on All-Cause Mortality and Cardiovascular Events: Regression Discontinuity Design Study.

BACKGROUND: Individuals with type 2 diabetes (T2D) have a twofold increased risk for cardiovascular events (CVE), and CVE is responsible for nearly 80% of the mortality. Current treatment guidelines state that individuals should immediately initiate antidiabetic treatment and cardiovascular risk-factor management from T2D diagnosis. However, the evidence base is sparse, and randomized trials are unlikely to be conducted. We examined the impact of being eligible for T2D treatment, as determined by the threshold of HbA1c ≥6.5% (≥48 mmol/mol), on all-cause mortality and CVE. We hypothesised that individuals who were just above this threshold had a lower risk of CVE and all-cause mortality than individuals just below. METHODS AND FINDINGS: We used the regression discontinuity design (RDD), a quasi-experimental design, comparing rates of all-cause mortality and CVE in people just below and just above the eligibility for treatment threshold. We included Danish healthcare records from 43,070 individuals aged 40-80 years with no previous T2D record and the first record of HbA1c in the range of 6.0-7.0% (42-53 mmol/mol) between 2006 and 2014. In total, 36,360 individuals had the first record of HbA1c between 6.0% and 6.4% (42-47 mmol/mol), and 6710 individuals had a first record between 6.5% and 7.0% (48-53 mmol/mol). Individuals with a measurement just above 6.5% (48 mmol/mol) had a 21% lower rate of death or CVE, compared to those just below (hazard ratio: 0.79 (95% CI 0.69-0.90)). Few individuals received early metformin treatment. However, the chance of metformin treatment initiation within 3 months was substantially higher for individuals with an HbA1c measurement above (14%) than below (1%) the threshold. CONCLUSION: Individuals with first record of HbA1c measure just above treatment threshold experienced a 21% lower rate of death or CVE than those just below. Lifestyle modifications and cardiovascular risk-factor management may contribute to this reduced rate.

Higher patient assessed quality of chronic care is associated with lower diabetes distress among adults with early-onset type 2 diabetes: Cross-sectional survey results from the Danish DD2-study.

AIM: Among adults aged 20-45 years with type 2 diabetes mellitus, we examined the perceived quality of chronic care, and its associations with (i) sociodemographic and clinical characteristics, and (ii) diabetes distress. METHODS: In total, 216/460 (47%) completed a self-administered survey assessing sociodemographic characteristics, patient assessed chronic illness care (PACIC-20, scale of 1-5) and diabetes distress (PAID-20, scale of 0-100), and 197 had full quality of care data for assessment. We obtained clinical data from national registers and used linear and logistic regression models to examine associations. RESULTS: The mean (SD) PACIC score was 2.6 (0.9) (score range 1-5). Lower PACIC scores were associated with female sex and current unemployment, and with receiving diabetes care in general practice compared with hospital outpatient clinics [mean difference: -0.4 (95% confidence interval (CI) (-0.7 to -0.2)]. People with upper quartile PACIC scores were less likely to report high diabetes distress compared with people with lower quartile PACIC scores [odds Ratio 0.3 95%CI (0.1-0.8)]. CONCLUSION: Higher quality of care was associated with lower diabetes distress among adults with early onset type 2 diabetes mellitus, but respondents reported less than optimal quality in several core areas of chronic care.

Hospital Records of Pain, Fatigue, or Circulatory Symptoms in Girls Exposed to Human Papillomavirus Vaccination: Cohort, Self-Controlled Case Series, and Population Time Trend Studies.

Human papillomavirus (HPV) vaccination has been associated with subsequent diffuse symptoms in girls, reducing public confidence in the vaccine. We examined whether girls have nonspecific outcomes of HPV vaccination, using triangulation from cohort, self-controlled case series (SCCS), and population time trend analyses carried out in Denmark between 2000 and 2014. The study population consisted of 314,017 HPV-vaccinated girls and 314,017 age-matched HPV-unvaccinated girls (cohort analyses); 11,817 girls with hospital records (SCCS analyses); and 1,465,049 girls and boys (population time trend analyses). The main outcome measures were hospital records of pain, fatigue, or circulatory symptoms. The cohort study revealed no increased risk among HPV vaccine-exposed girls, with incidence rate ratios close to 1.0 for abdominal pain, nonspecific pain, headache, hypotension/syncope, tachycardia (including postural orthostatic tachycardia syndrome), and malaise/fatigue (including chronic fatigue syndrome). In the SCCS analyses, we observed no association between HPV vaccination and subsequent symptoms. In time trend analyses, we observed a steady increase in these hospital records in both girls and (HPV-unvaccinated) boys, with no relationship to the 2009 introduction of HPV vaccine to Denmark's vaccination program. This study, which had nationwide coverage, showed no evidence of a causal link between HPV vaccination and diffuse autonomic symptoms leading to hospital contact.

Beta-blocker, aspirin, and statin usage after first-time myocardial infarction in patients with chronic obstructive pulmonary disease: a nationwide analysis from 1995 to 2015 in Denmark.

AIMS: To determine whether beta-blockers, aspirin, and statins are underutilized after first-time myocardial infarction (MI) in patients with chronic obstructive pulmonary disease (COPD) compared with patients without COPD. Further, to determine temporal trends and risk factors for non-use. METHODS AND RESULTS: Using Danish nationwide registers, we performed a cross-sectional study investigating the utilization of beta-blockers, aspirin, and statins after hospitalization for first-time MI among patients with and without COPD from 1995 to 2015. Risk factors for non-use were examined in multivariable logistic regression models. During 21 years of study, 140 278 patients were included, hereof 13 496 (9.6%) with COPD. Patients with COPD were less likely to use beta-blockers (53.2% vs. 76.2%, P < 0.001), aspirin (73.9% vs. 78.8%, P < 0.001), and statins (53.5% vs. 61.9%, P < 0.001). Medication usage increased during the study period but in multivariable analyses, COPD remained a significant predictor for non-use: odds ratio (95% confidence interval) for non-use of beta-blockers 1.86 (1.76-1.97); aspirin 1.24 (1.16-1.32); statins 1.50 (1.41-1.59). Analyses stratified by ST-segment elevation myocardial infarction (STEMI) and non-STEMI showed similar undertreatment of COPD patients. Risk factors for non-use of beta-blockers in COPD included increasing age, female sex, and increasing severity of COPD (frequent exacerbations, use of multiple inhaled medications, and low lung function). Similar findings were demonstrated for aspirin and statins. CONCLUSION: Beta-blockers, and to a lesser extent aspirin and statins, were systematically underutilized by patients with COPD following hospitalization for MI despite an overall increase in the utilization over time. Increasing severity of COPD was a risk factor for non-use of the medications.

Diabetic polyneuropathy and pain, prevalence, and patient characteristics: a cross-sectional questionnaire study of 5,514 patients with recently diagnosed type 2 diabetes.

Most studies of diabetic polyneuropathy (DPN) and painful DPN are conducted in persons with longstanding diabetes. This cross-sectional study aimed to estimate the prevalence of DPN and painful DPN, important risk factors, and the association with mental health in recently diagnosed type 2 diabetes. A total of 5514 (82%) patients (median diabetes duration 4.6 years) enrolled in the Danish Centre for Strategic Research in Type 2 Diabetes cohort responded to a detailed questionnaire on neuropathy and pain. A score ≥4 on the MNSI questionnaire determined possible DPN, whereas pain presence in both feet together with a score ≥3 on the DN4 questionnaire determined possible painful DPN. The prevalence of possible DPN and possible painful DPN was 18% and 10%, respectively. Female sex, age, diabetes duration, body mass index, and smoking were associated with possible DPN, whereas only smoking showed a clear association with possible painful DPN (odds ratio 1.52 [95% confidence interval: 1.20-1.93]). Possible DPN and painful DPN were independently and additively associated with lower quality of life, poorer sleep, and symptoms of depression and anxiety. Possible DPN itself had greater impact on mental health than neuropathic pain. This large study emphasizes the importance of careful screening for DPN and pain early in the course of type 2 diabetes.

Predictors for repeated hyperkalemia and potassium trajectories in high-risk patients - A population-based cohort study.

Understanding predictors and trajectories of increased potassium may inform testing and treatment of hyperkalemia. We examined predictors for repeated hyperkalemia among patients after first-time renin angiotensin system inhibitor (RASi) prescription, chronic kidney disease (CKD), or chronic heart failure (CHF); and we also examined potassium trajectories in these patients after their first hyperkalemia event. We used Danish population-based registries to identify all patients with first-time RASi prescription, incident CKD, or incident CHF (2000-2012). For patients with a first hyperkalemia event, potassium trajectories over the following 6 months were examined. The predictors associated with repeated hyperkalemia were assessed, with repeated hyperkalemia defined as a potassium test >5.0 mmol/L after the first event within 6 months. Overall 262,375 first-time RASi users, 157,283 incident CKD patients, and 14,600 incident CHF patients were included. Of patients with a first hyperkalemia event, repeated hyperkalemia within 6 months occurred in 37% of RASi users, 40% with CKD, and 49% of patients with CHF. Predictors included severe hyperkalemia, low eGFR, diabetes, and spironolactone use. In all cohorts, the median potassium levels declined over 2-4 weeks after a hyperkalemia event for the first time, but reverted to levels higher than before the initial hyperkalemia event in those who had repeated hyperkalemia. Following hyperkalemia, discontinuation of RASi and spironolactone was common in the RASi and CHF cohorts. Repeated hyperkalemia was common among the explored cohorts. The first hyperkalemia event was an indicator of increased median potassium levels. Predictors may identify patients likely to benefit from intensified monitoring and intervention.

Can diabetic polyneuropathy and foot ulcers in patients with type 2 diabetes be accurately identified based on ICD-10 hospital diagnoses and drug prescriptions?

Purpose: We examined whether diabetic polyneuropathy (DPN) and diabetic foot ulcers in type 2 diabetes can be accurately identified using International Classification of Diseases, 10th revision discharge diagnosis codes, surgery codes, and drug prescription codes. Methods: We identified all type 2 diabetes patients in the Central Denmark region, 2009-2016, who had ≥1 primary/secondary diagnosis code of "diabetes with neurological complication" (E10.4-E14.4), "diabetic polyneuropathy" (G63.2), or "polyneuropathy, unspecified" (G62.9). Patients with potential painful DPN and non-painful DPN were identified based on prescription history for serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, or gabapentinoids. Likewise, type 2 diabetes patients with potential foot ulcers were identified based on diagnosis or surgery codes. We used medical record review as the reference standard and calculated positive predictive values (PPVs). Results: Of 53 randomly selected patients with potential painful DPN, 38 were classified as having DPN when validated against medical records; of these, 18 also had neuropathic pain, yielding a PPV of 72% (95% CI: 58-83%) for DPN and 34% (95% CI: 22-48%) for painful DPN. Likewise, among 54 randomly selected patients with potential non-painful DPN, 30 had DPN based on medical record data; of these, 27 had non-painful DPN, yielding PPVs of 56% (95% CI: 41-69%) and 50% (95% CI: 36-64%), respectively. Secondary E-chapter codes often denoted stroke or mononeuropathies, rather than DPN. Excluding secondary E-chapter codes from the algorithm increased the PPV for DPN to 78% (95% CI: 63-89%) for the painful DPN cohort and to 74% (95% CI: 56-87%) for the non-painful DPN cohort. Of 53 randomly selected patients with potential diabetic foot ulcer, only 18 diagnoses were confirmed; PPV=34% (95% CI: 22-48%). Conclusion: G-chapter and primary E-chapter diagnosis codes can detect type 2 diabetes patients with hospital-diagnosed DPN, and may be useful in epidemiological research. In contrast, our diabetic foot ulcer algorithm did not perform well.

Healthcare resource utilisation and cost associated with elevated potassium levels: a Danish population-based cohort study.

OBJECTIVES: To investigate healthcare costs associated with hyperkalaemia (HK) among patients with chronic kidney disease (CKD), heart failure (HF) or diabetes. DESIGN: Before-after cohort study of patients with HK and matched patients without HK. SETTING: Population-based databases covering primary and secondary care for the entire of Northern Denmark. PARTICIPANTS: Patients with a first incident record of CKD (n=78 372), HF (n=14 233) or diabetes (n=37 479) during 2005-2011. Among all patients experiencing a first HK event (potassium level >5.0 mmol/L), healthcare costs were compared during 6 months before and 6 months after the HK event. The same cost assessment was conducted 6 months before and after a matched index date in a comparison cohort of patients without HK. PRIMARY AND SECONDARY OUTCOME MEASURES: Mean costs of hospital care, general practice and dispensed drugs converted to 2018 Euros. RESULTS: Overall, 17 747 (23%) CKD patients, 5141 (36%) HF patients and 4183 (11%) diabetes patients with a first HK event were identified. More than 40% of all HK patients across the patient groups had subsequent HK events with successively shorter times between the events. In CKD patients, overall mean costs were €5518 higher 6 months after versus before first HK, while €441 higher in matched CKD patients without HK, yielding HK-associated costs of €5077. Corresponding costs associated with a HK event were €6018 in HF patients, and €4862 in diabetes patients. CONCLUSIONS: Among CKD, HF and diabetes patients, an incident HK event was common, and a large proportion of the patients experienced recurrent HK events. Substantial increase in healthcare costs associated with a HK event was observed in the HK patients compared with non-HK patients. These results are important to better understand the potential economic impact of HK among high-risk comorbid patients in a real-wold setting and help inform decision-making for clinicians and healthcare providers.

Elevated Potassium Levels in Patients With Congestive Heart Failure: Occurrence, Risk Factors, and Clinical Outcomes: A Danish Population-Based Cohort Study.

BACKGROUND: Data on the true burden of hyperkalemia in patients with heart failure (HF) in a real-world setting are limited. METHODS AND RESULTS: Incidence rates of hyperkalemia (first blood test with a potassium level >5.0 mmol/L) in primary or hospital care were assessed in a population-based cohort of patients with incident HF diagnoses in northern Denmark from 2000 to 2012. Risk factors and clinical outcomes were compared in patients with HF with versus without hyperkalemia. Of 31 649 patients with HF, 39% experienced hyperkalemia (mean follow-up, 2.2 years). Risks of experiencing a second, third, or fourth event were 43%, 54%, and 60%, respectively. Among patients with HF with stage 3A, 3B, 4, or 5 kidney dysfunction, 26%, 35%, 44%, and 48% experienced hyperkalemia within the first year. Important hyperkalemia risk factors included chronic kidney disease (prevalence ratio, 1.46; 95% confidence interval [CI], 1.43-1.49), diabetes mellitus (prevalence ratio, 1.38; 95% CI, 1.32-1.45), and spironolactone use (prevalence ratio, 1.48; 95% CI, 1.42-1.54). In patients with HF who developed hyperkalemia, 53% had any acute-care hospitalization 6 months before the hyperkalemia event, increasing to 74% 6 months after hyperkalemia (before-after risk ratio, 1.41; 95% CI, 1.38-1.44). Compared with matched patients with HF without hyperkalemia, adjusted 6-month hazard ratios in patients with hyperkalemia were 2.75-fold (95% CI, 2.65-2.85) higher for acute-care hospitalization and 3.39-fold (95% CI, 3.19-3.61) higher for death. CONCLUSIONS: Almost 4 in 10 patients with HF develop hyperkalemia, and many patients have recurrent hyperkalemia episodes. Hyperkalemia risk is strongly associated with degree of reduced kidney function and use of spironolactone. Hyperkalemia is associated with severe clinical outcomes and death in HF.

Danish Centre for Strategic Research in Type 2 Diabetes (DD2) project cohort of newly diagnosed patients with type 2 diabetes: a cohort profile.

PURPOSE: The aim of this article is to provide a detailed description of the ongoing nationwide Danish Centre for Strategic Research in Type 2 Diabetes (DD2) project cohort and biobank. The DD2 cohort continuously enrols newly diagnosed patients with type 2 diabetes (T2D) throughout Denmark. The overall goal of the DD2 project is to establish a large and data-rich T2D cohort that can serve as a platform for exhaustive T2D research including (1) improved genotypic and phenotypic characterisation of T2D, (2) intervention studies of more individualised T2D treatment, (3) pharmacoepidemiological studies and (4) long-term follow-up studies on predictors of T2D complications and prognosis. PARTICIPANTS: Between 2010 and 2016, 7011 individuals with T2D have been enrolled and assessed at baseline. Information collected include interview data (eg, body weight at age 20 years, physical activity and alcohol consumption), clinical examination data (eg, hip-waist ratio and resting heart rate) and biological samples (whole blood, DNA, plasma and urine) stored at -80°C and currently analysed for a range of biomarkers and genotypes. FINDINGS TO DATE: Registry linkage has provided extensive supplemental continuous data on glycosylated haemoglobin A, lipids, albuminuria, blood pressure, smoking habits, body mass index, primary care contacts, hospital diagnoses and procedures, medication use, cancer and mortality. Cross-sectional associations between biomarkers, family history, anthropometric and lifestyle measures and presence of complications at baseline have been reported. FUTURE PLANS: During 2016, a detailed follow-up questionnaire has been answered by 85% of initial participants, providing follow-up information on baseline variables and on presence of diabetic neuropathy. The DD2 cohort has now been followed for a total of 18 862 person-years, and nested intervention trials and follow-up studies are ongoing. In the future, the cohort will serve as a strong national and international resource for recruiting patients to nested case studies, clinical trials, postmarketing surveillance, large-scale genome studies and follow-up studies of T2D complications.