Persistence with IDegLira in Patients in Clinical Practice: A Nationwide Observational Study in Sweden.

AIMS: To explore persistence with insulin degludec/liraglutide (IDegLira) treatment, clinical characteristics and concomitant medications in a large population of patients in clinical practice. METHODS: This was an observational study in patients with type 2 diabetes (n = 2432) who initiated IDegLira between 26 May 2015 and 31 December 2017. Data were obtained from Swedish nationwide registers and linked on an individual level using unique Swedish personal identifiers. Dose calculations were made for patients with ≥ 180 days between the first and last collections of IDegLira prescription. Changes in clinical parameters were evaluated as change from the last observation during 12 months prior to the initiation date until ± 90 days from the last collection of IDegLira. RESULTS: Pre-index regimens (index date being the date of filling the first prescription of IDegLira) included: multiple daily insulin injections (45.1%); insulin and glucagon-like peptide-1 receptor agonist (GLP-1 RA) (19.7%); long-acting insulins (11.8%); non-injectable therapy only (11.4%); GLP-1 RA only (9.8%); and no collection of diabetes medication during the 6-month pre-index period (2.3%). The majority of patients (94 and 84%) were persistent with IDegLira at 6 and 12 months, respectively. The most commonly used concomitant medication was metformin (69.4%). Mean daily dose was 33 dose steps. Overall, there was a mean decrease in HbA1c (approx. 10 mmol/mol [1%]) and body weight (- 1.1 kg). Improvements in HbA1c were observed regardless of pre-index treatment. CONCLUSION: After 12 months, 84% of patients were persistent on IDegLira, with improved glycaemic control and reductions in body weight.

IDegLira Improves Glycemic Control in Japanese Patients with Uncontrolled Type 2 Diabetes on Premixed Insulin Therapy.

INTRODUCTION: DUAL II Japan (NCT02911948) was a 26-week, phase 3a randomized, treat-to-target trial which compared the efficacy and safety of IDegLira with degludec in 210 Japanese patients with type 2 diabetes (T2D) uncontrolled on premixed or basal insulin therapy. The DUAL II Japan trial presented the opportunity for a post hoc analysis to examine the safety and efficacy of switching patients from a premixed regimen (containing both basal and bolus insulin components) to IDegLira. METHODS: Patients from DUAL II Japan were stratified according to prior insulin regimen (premixed or basal insulin). The following endpoints were assessed in this post hoc analysis by pre-trial insulin regimen: change in HbA1c, body weight, daily total insulin dose, nine-point self-measured blood glucose, and severe or blood glucose-confirmed hypoglycemia (defined as severe or plasma glucose less than 56 mg/dL). RESULTS: This post hoc analysis included 39 patients who switched from premixed insulin to IDegLira. The treatment effect in this population was independent of insulin type at baseline (premixed or basal; interaction test, P = 0.2535). In patients switching from premixed insulin to IDegLira, mean [standard deviation (SD)] HbA1c was 8.26% (0.73) at baseline and 6.68% (0.93) at week 26. Mean (SD) body weight was reduced by 1.5 (2.9) kg. At week 26, daily insulin dose was 34.2 dose steps. After 26 weeks, the mean prandial increment was smaller at all meals with IDegLira irrespective of pre-trial insulin regimen. Rate of hypoglycemic events was 2.59 events/patient-year of exposure over the 26 weeks. CONCLUSION: This post hoc study is the first to evaluate the switch from premixed insulin to IDegLira in patients with uncontrolled T2D. IDegLira initiation resulted in improved HbA1c and weight loss. This study offers insight into the effectiveness and safety of switching patients from premixed insulin therapy to IDegLira, and provides support for further investigation. TRIAL REGISTRATION: NCT02911948.

Evaluation of the Short-Term Cost-Effectiveness of IDegLira Versus Basal Insulin and Basal-Bolus Therapy in Patients with Type 2 Diabetes Based on Attainment of Clinically Relevant Treatment Targets.

BACKGROUND: Effective glycemic control can reduce the risk of complications and their related costs in patients with type 2 diabetes (T2D). Many patients fail to reach hemoglobin A1c (HbA1c) ≤ 6.5% or < 7.0%, often due to adverse effects of treatment, such as hypoglycemia and weight gain. Glycemic targets should be individualized and consider multiple factors, including the risk of adverse events and the patient's characteristics and comorbid conditions. OBJECTIVE: To compare the odds and annual cost of achieving treatment targets, which incorporate HbA1c targets of < 7.5%, < 8.0%, and ≤ 9.0%, with insulin degludec/liraglutide (IDegLira) versus basal insulin and basal-bolus therapy. METHODS: This is a post hoc analysis of the DUAL V and DUAL VII 26-week trials, which randomized patients with T2D uncontrolled (HbA1c 7%-10%) on insulin glargine 100 units/mL (IGlar U100) and metformin to IDegLira or continued IGlar U100 titration (DUAL V) or IGlar U100 + insulin aspart (DUAL VII), all with metformin. Proportions of patients achieving HbA1c targets (< 7.5%, < 8.0%, and ≤ 9.0%) by the end of trial were assessed via 3 outcomes: alone, without either hypoglycemia or weight gain (double composite outcome), or without a combination of hypoglycemia and weight gain (triple composite outcome). The cost per patient achieving the triple composite outcome at each HbA1c target (< 7.5%, < 8.0%, and ≤ 9.0%) was calculated by dividing the annual cost of treatment by the proportion of patients achieving the target. This short-term (1-year) cost-effectiveness analysis was conducted from the perspective of a U.S. health care payer. RESULTS: More patients achieved HbA1c < 7.5% (P < 0.0001) and < 8.0% (P = 0.0003), and a similar percentage achieved HbA1c ≤ 9.0% with IDegLira versus IGlar U100 (DUAL V). Similar proportions of patients achieved all 3 HbA1c targets with IDegLira compared with basal-bolus therapy (DUAL VII). The odds of achieving double or triple composite outcomes were significantly higher for IDegLira versus IGlar U100 or basal-bolus for all 3 HbA1c targets (P < 0.0001 in each case) in both trials. For each $1 spent on IDegLira, the equivalent annual costs per patient to achieve HbA1c targets of < 7.5%, < 8.0%, or ≤ 9.0% without hypoglycemia and without weight gain were $2.43, $2.10, and $2.05, respectively, for IGlar U100 and $6.33, $5.80, and $6.06, respectively, for basal-bolus therapy. CONCLUSIONS: Based on data from DUAL V and DUAL VII, this analysis showed that a greater or similar proportion of patients with T2D reached HbA1c targets with IDegLira compared with IGlar U100/basal-bolus therapy. Odds of achieving double or triple composite outcomes of HbA1c reduction without hypoglycemia and/or without weight gain were greatest for IDegLira. Short-term cost analyses based on the triple composite outcomes suggest that IDegLira is a cost-effective treatment option in the United States compared with either uptitration of IGlar U100 or basal-bolus therapy. DISCLOSURES: This study was supported by Novo Nordisk A/S. The analysis was based on the DUAL V (NCT01952145) and DUAL VII (NCT02420262) trials, which were funded and conducted by Novo Nordisk. This post hoc analysis was conceived and interpreted by the authors and drafted with medical writing support that was funded by Novo Nordisk. Novo Nordisk also reviewed the manuscript for medical accuracy. Hunt and Malkin are employees of Ossian Health Economics and Communications, which received consulting fees from Novo Nordisk during the conduct of this study and has received consulting fees from Novo Nordisk, unrelated to this study. Mocarski, Ranthe, and Schiffman are employees of Novo Nordisk and Novo Nordisk A/S. Cannon has received speaker fees/honoraria from Abbvie, Amgen, and Janssen; speaker fees from Novo Nordisk; and has stock ownership in Novo Nordisk. Bargiota has received speaker fees/honoraria from AstraZeneca, Eli Lilly, MSD, Novo Nordisk, Sanofi, Boehringer Ingelheim, and Novartis. Billings has received personal fees from Novo Nordisk, Sanofi, and Dexcom, unrelated to this study. Leiter reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi, Servier, and GSK, unrelated to this study. Doshi has no relevant conflicts of interest to disclose. Parts of this study were presented as a poster at the AMCP Managed Care & Specialty Pharmacy Annual Meeting; April 23-26, 2018; Boston, MA.

Association Between Hypertensive Disorders of Pregnancy and Later Risk of Cardiomyopathy.

IMPORTANCE: Women with hypertensive disorders of pregnancy, preeclampsia in particular, have an increased risk of cardiomyopathy during the peripartum period. Whether hypertensive disorders of pregnancy are also associated with cardiomyopathy later in life is unknown. OBJECTIVE: To determine whether hypertensive disorders of pregnancy are associated with cardiomyopathy beyond the peripartum period. DESIGN, SETTING, AND PARTICIPANTS: Nationwide register-based cohort study using Cox regression to compare rates of cardiomyopathy in women with and without a history of hypertensive disorders of pregnancy in a cohort of 1,075,763 women with at least 1 pregnancy ending in live birth or stillbirth in Denmark, 1978-2012, with follow-up through December 31, 2012. EXPOSURES: A hypertensive disorder of pregnancy (severe or moderate preeclampsia or gestational hypertension) registered in the National Patient Register. MAIN OUTCOMES AND MEASURES: Cardiomyopathy more than 5 months after delivery (outside the peripartum period) up to 34 years 7 months. RESULT: The women in the primary cohort had 2,067,633 eligible pregnancies during the study period, 76,108 of which were complicated by a hypertensive disorder of pregnancy. During follow-up, 1577 women (mean age, 48.5 years at cardiomyopathy diagnosis; 2.6% with multiple pregnancies) developed cardiomyopathy. Compared with women with normotensive pregnancies (18,211,603 person-years of follow-up; n = 1408 cardiomyopathy events, 7.7/100,000 person-years [95% CI, 7.3-8.2]), women with a history of hypertensive disorders of pregnancy had significantly increased rates of cardiomyopathy (in 173,062 person-years of follow-up among women with severe preeclampsia, n = 27 cardiomyopathy events; 15.6/100,000 person-years [95% CI, 10.7-22.7]; adjusted hazard ratio [HR], 2.20 [95% CI, 1.50-3.23]; in 697,447 person-years of follow-up among women with moderate preeclampsia, n = 102 cardiomyopathy events; 14.6/100,000 person-years [95% CI, 12.0-17.8]; adjusted HR, 1.89 [95% CI, 1.55-2.23]; in 213,197 person-years of follow-up among women with gestational hypertension, n = 40 cardiomyopathy events; 17.3/100,000 person-years [95% CI, 12.7-23.6]; adjusted HR, 2.06 [95% CI, 1.50-2.82]). These increases persisted more than 5 years after the latest pregnancy. Mediation analyses suggested that only about 50% of the association was an indirect association through postpregnancy chronic hypertension. In this cohort, 11% of all cardiomyopathy events occurred in women with a history of hypertensive disorders of pregnancy. CONCLUSIONS AND RELEVANCE: Women with a history of hypertensive disorders of pregnancy, compared with women without such a history, had a small but statistically significant increased risk of cardiomyopathy more than 5 months after delivery. Further research is necessary to understand whether there is a causal mechanism behind this association.

Association between pregnancy losses in women and risk of atherosclerotic disease in their relatives: a nationwide cohort study†.

AIMS: A common underlying mechanism with a genetic component could link pregnancy losses with vascular disease. We examined whether pregnancy losses (miscarriages and stillbirths) and atherosclerotic outcomes co-aggregated in families. METHODS AND RESULTS: Using Danish registers, we identified women with pregnancies in 1977-2008, and their parents (>1 million) and brothers (>435 000). We followed parents for incident ischaemic heart disease (IHD), myocardial infarction (MI), and cerebrovascular infarction (CVI), and brothers for a broader combined atherosclerotic endpoint. Using Cox regression, we estimated hazard ratios (HRs) for each outcome by history of pregnancy loss in daughters/sisters. Overall, parents whose daughters had 1, 2, and ≥3 miscarriages had 1.01 [95% confidence interval (CI) 0.99-1.04], 1.07 (95% CI 1.02-1.11), and 1.10 (95% CI 1.02-1.19) times the rate of MI, respectively, as parents whose daughters had no miscarriages. For parents with ≥3 daughters, the HRs were 1.12 (95% CI 1.02-1.24), 1.29 (95% CI 1.13-1.48), and 1.33 (95% CI 1.12-1.57). Effect magnitudes did not differ for fathers and mothers. We observed similar patterns for IHD and CVI (parents) and the atherosclerotic endpoint (brothers). Parents whose daughters had stillbirths had 1.14 (95% CI 1.05-1.24) and 1.07 (95% CI 0.96-1.18) times the rates of MI and CVI, respectively, as parents whose daughters had no stillbirths. CONCLUSION: Certain pregnancy losses and atherosclerotic diseases in both heart and brain may have a common aetiologic mechanism. Women in families with atherosclerotic disease may be predisposed to pregnancy loss; conversely, pregnancy losses in first-degree relatives may have implications for atherosclerotic disease risk.

A detailed family history of myocardial infarction and risk of myocardial infarction--a nationwide cohort study.

BACKGROUND: Family history of myocardial infarction (MI) is an independent risk factor for MI. Several genetic variants are associated with increased risk of MI and family history of MI in a first-degree relative doubles MI risk. However, although family history of MI is not a simple dichotomous risk factor, the impact of specific, detailed family histories has not received much attention, despite its high clinical relevance. We examined risk of MI by MIs in first- and second-degree relatives and by number and age of affected relatives. METHODS AND FINDINGS: Using Danish national registers, we established a nationwide cohort of persons born between 1930 and 1992 with identifiable first- or second-degree relatives. Incident MIs in both cohort members and relatives aged ≥20 years were identified. We calculated incidence rate ratios (IRRs) for MI by family history of MI, by Poisson regression. In 4.4 million persons followed for 104 million person-years, we identified 128,384 incident MIs. IRRs with 95% confidence intervals [CIs] for MI by history of MI in 1, 2 or ≥3 first-degree relatives were 1.46 (1.42-1.49), 2.38 (2.22-2.56) and 3.58 (2.66-4.81), respectively. Corresponding estimates for second-degree relatives were 1.17 (1.05-1.30), 1.87 (1.46-2.38) and 2.18 (1.09-4.36). A history of MI in combinations of first- and second-degree relatives increased risks 1.8- to 7-fold in middle-aged persons (36 to 55 years). Estimates were robust to adjustment for diabetes, hypertension, dyslipidemia and use of cardiovascular medications. CONCLUSION: A detailed family history, particularly number of affected first- and second-degree relatives, contributes meaningfully to risk assessment, especially in middle-aged persons. Future studies should test for potential improvement of risk algorithm prediction using detailed family histories.

Cardiac involvement in myotonic dystrophy: a nationwide cohort study.

AIMS: To quantify the association between myotonic dystrophy (DM) and cardiac disease in a nationwide cohort. METHODS AND RESULTS: We identified a nationwide cohort of 1146 DM patients (period 1977-2011) using the National Patient Registry (NPR) and a subcohort of 485 patients who had undergone genetic testing for DM1. Information on incident cardiac diseases was obtained from the NPR. We estimated standardized incidence ratios (SIRs) of cardiac disease compared with the background population, overall and according to selected diagnostic subgroups (cardiomyopathy, heart failure, conduction disorders, arrhythmias, and device implantation). In the DM cohort, SIR for any cardiac disease was 3.42 [95% confidence interval (CI) 3.01-3.86]; for a cardiac disease belonging to the selected subgroups 6.91 (95% CI: 5.93-8.01) and for other cardiac disease 2.59 (95% CI: 2.03-3.25). For a cardiac disease belonging to the selected subgroups, the risk was particularly high in the first year after DM diagnosis [SIR 15.4 (95% CI: 10.9-21.3)] but remained significantly elevated in subsequent years [SIR 6.07 (95% CI: 5.11-7.16]). The risk was higher in young cohort members [e.g. 20-39 years: SIR 18.1 (95% CI: 12.3-25.8)] compared with older [e.g. 60-79 years: SIR 3.99 (95% CI: 2.98-5.23)] but remained significantly increased in all age categories. Results were similar in separate analyses of the genetically confirmed DM1 patients. CONCLUSION: Myotonic dystrophy is strongly associated with cardiac disease. The risk is pronounced in the young and remains elevated throughout life, stressing the importance of lifelong cardiac follow-up from time of DM diagnosis.

Pregnancy loss and later risk of atherosclerotic disease.

BACKGROUND: Pregnancy losses and atherosclerotic disease may be etiologically linked through underlying pathology. We examined whether miscarriage and stillbirth increase later risk of myocardial infarction, cerebral infarction, and renovascular hypertension. METHODS AND RESULTS: Among women pregnant at least once between 1977 and 2008, we identified a cohort of women with miscarriages, stillbirths, or live singleton births. These women were followed from the end of pregnancy for incident myocardial infarction, cerebral infarction, and renovascular hypertension. Using Poisson regression, we estimated incidence rate ratios for each of the outcomes by history of miscarriage and stillbirth. Among 1,031,279 women followed for >15,928,900 person-years, we identified 27 98 myocardial infarctions, 40 53 cerebral infarctions, and 1269 instances of renovascular hypertension. Women with stillbirths had 2.69 (95% confidence interval, 2.06-3.50), 1.74 (1.32-2.28), and 2.42 (1.59-3.69) times the rates of myocardial infarction, cerebral infarction, and renovascular hypertension, respectively, as women with no stillbirths. Compared with women with no miscarriages, women with miscarriages had 1.13 (1.03-1.24), 1.16 (1.07-1.25), and 1.20 (1.05-1.38) times the rates of these same outcomes, respectively; these associations were dose dependent, with each additional miscarriage increasing the rates of myocardial and cerebral infarction and renovascular hypertension by 9% (3% to 16%), 13% (7% to 19%), and 19% (9% to 30%), respectively. Associations were strongest in younger women (<35 years). CONCLUSIONS: Pregnancy losses were associated with subsequent risks of myocardial infarction, cerebral infarction, and renovascular hypertension, consistent with either shared etiology or the initiation of pathological processes by a pregnancy loss leading to atherosclerosis.

Risk of ischaemic heart disease in patients with inflammatory bowel disease: a nationwide Danish cohort study.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder. Systemic inflammation increases the risk of atherosclerosis and ischaemic heart disease (IHD). OBJECTIVE: To examine the impact of IBD, including its duration and treatment, on the risk of IHD. METHODS: In a nationwide population-based cohort of 4.6 million Danes aged ≥ 15 years, we compared people diagnosed with IBD during 1997-2009 (n=28 833) with IBD-free individuals. Subjects with IHD were identified in the National Patient Register. Using Poisson regression, we estimated the incidence rate ratios (IRRs) for IHD with 95% CI with adjustment for age, gender, socioeconomic status, calendar year and use of drugs for comorbidities. RESULTS: A markedly increased risk of IHD was seen within the first year after IBD diagnosis (IRR=2.13 95% CI 1.91 to 2.38). During 1-13 years of follow-up after IBD diagnosis, the risk of IHD was 1.22 (95% CI 1.14 to 1.30). The risk of IHD was lower among patients with IBD using 5-aminosalicylic acids (IRR=1.16; 95% CI 1.06 to 1.26) than among non-users (IRR=1.36; 95% CI 1.22 to 1.51) (p=0.02), in particular among oral corticosteroid users, used as a proxy for disease severity. Likewise patients treated surgically or with thiopurines and tumour necrosis factor α antagonists tended to have reduced IRRs for IHD. CONCLUSIONS: The risk of IHD was highest in the first year after IBD diagnosis, possibly owing to ascertainment bias. The increased long-term risk of IHD in IBD may be related to chronic inflammation, and interventions reducing the inflammatory burden may attenuate this risk.

Risk of cardiovascular disease in family members of young sudden cardiac death victims.

AIMS: Descriptive and genetic studies suggest that relatives of sudden cardiac death (SCD) victims have an increased risk of several cardiovascular diseases (CVDs). Given the severe consequences of undiagnosed CVD and the availability of effective treatment, the potential for prevention in this group is enormous if they do have an increased CVD risk. This nationwide prospective population-based cohort study described the risk of CVDs in relatives of young SCD victims, compared with the general population. METHODS AND RESULTS: All SCD victims aged 1-35 years in Denmark, 2000-2006, were identified (n = 470), along with their first- and second-degree relatives (n = 3073). We compared the incidence of CVD in those relatives with that in the background population using standardized incidence ratios (SIRs). The observed number of CVDs over 11 years of follow-up was 292, compared with 219 expected based on national rates [SIR 1.33, 95% confidence interval (CI) 1.19-1.50]. Risks varied significantly with age; the SIR for those <35 years was 3.53 (95% CI 2.65-4.69), compared with SIRs of 1.59 (95% CI 1.35-1.89) and 0.91 (95% CI 0.75-1.10) for those aged 35-60 years or >60 years, respectively (P(homogeneity) < 0.0001). For first-degree relatives <35 years, SIRs for ischaemic heart disease, cardiomyopathy, and ventricular arrhythmia were 5.99 (95% CI 1.95-0.13.98), 17.91 (95% CI 4.88-45.87), and 19.15 (95% CI 7.70-39.45), respectively. CONCLUSION: CVDs co-aggregated significantly with SCD in families, with young first-degree relatives at greatest risk. Results clearly indicate that family members of young SCD victims should be offered comprehensive and systematic screening, with focus on the youngest relatives.

Family history of premature death and risk of early onset cardiovascular disease.

OBJECTIVES: The purpose of this study was to examine the effect of a family history of premature death, cardiovascular death in particular, on the risk of early cardiovascular disease. BACKGROUND: Studies suggest that fatal cardiovascular events and less severe cardiovascular diseases may co-occur in families. Consequently, a family history of premature death may indicate a familial cardiac frailty that predisposes to early cardiovascular disease. METHODS: We ascertained family history of premature death (age <60 years) in all individuals born in Denmark from 1950 to 2008 and followed this cohort for early cardiovascular disease (age <50 years). Using Poisson regression, we estimated incidence rate ratios (IRRs) reflecting the effect of premature death in the family on early cardiovascular disease risk. RESULTS: Among 3,985,301 persons followed up for 89,294,258 person-years, 129,825, 31,172, and 5,214 were diagnosed with any early cardiovascular disease, ischemic heart disease, and ventricular arrhythmia, respectively. IRRs for these conditions given a history of premature cardiovascular death in first-degree relatives were 1.72 (95% confidence interval [CI]: 1.68 to 1.77), 2.21 (95% CI: 2.11 to 2.31), and 1.94 (95% CI: 1.70 to 2.20), respectively. With ≥2 cardiovascular deaths in a family, corresponding IRRs were 3.30 (95% CI: 2.77 to 3.94), 5.00 (95% CI: 3.87 to 6.45), and 6.18 (95% CI: 3.32 to 11.50). The IRR for any early cardiovascular disease given a family history of premature noncardiovascular death was significantly lower, 1.12 (95% CI: 1.10 to 1.14) (p(cardiac vs. noncardiac) < 0.0001). CONCLUSIONS: Family history of premature cardiovascular death was consistently and significantly associated with a risk of early cardiovascular disease, suggesting an inherited cardiac vulnerability. These results should be kept in mind when assessing cardiovascular disease risk in persons with a family history of premature cardiovascular death.