Cardiovascular Events, Acute Hospitalizations, and Mortality in Patients With Type 2 Diabetes Mellitus Who Initiate Empagliflozin Versus Liraglutide: A Comparative Effectiveness Study.

Background In cardiovascular outcome trials, the sodium glucose cotransporter 2 inhibitor empagliflozin and glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide caused similar reductions in major adverse cardiac events (MACE). We compared clinical outcomes in routine clinical care. Methods and Results EMPLACE (Cardiovascular and Renal Outcomes, and Mortality in Danish Patients with Type 2 Diabetes Who Initiate Empagliflozin Versus GLP-1RA: A Danish Nationwide Comparative Effectiveness Study) is an ongoing nationwide population-based comparative effectiveness cohort study in Denmark. For the present study, we included 14 498 new users of empagliflozin and 12 706 new users of liraglutide, 2015 to 2018. Co-primary outcomes were expanded major adverse cardiac events (stroke, myocardial infarction, unstable angina, coronary revascularization, hospitalization for heart failure [HHF], or all-cause death); HHF or all-cause death; and first HHF or first initiation of loop-diuretic therapy. Secondary outcomes included all-cause hospitalization or death. We applied propensity score balancing and Cox regression to compute adjusted hazard ratios (aHRs) in on-treatment (OT) and intention-to-treat (ITT) analyses. Cohorts were well balanced at baseline (median age 61 years, 59% men, diabetes mellitus duration 6.6 years, 30% with preexisting cardiovascular disease). During mean follow-up of 1.1 years in OT and 1.5 years in ITT analyses, empagliflozin versus liraglutide was associated with a similar rate of expanded major adverse cardiac events (OT aHR, 1.02; 95% CI, 0.91-1.14; ITT aHR, 1.06; 95% CI, 0.96-1.17), and HHF or all-cause death (OT aHR, 0.97; 95% CI, 0.85-1.11; ITT aHR, 1.02; 95% CI, 0.91-1.14); and a decreased rate of a first incident HHF or loop-diuretic initiation (OT aHR, 0.80; 95% CI, 0.68-0.94; ITT aHR, 0.87; 95% CI, 0.76-1.00), and of all-cause hospitalization or death (OT aHR, 0.93; 95% CI, 0.89-0.98; ITT aHR, 0.93; 95% CI, 0.90-0.97). Conclusions Empagliflozin and liraglutide initiators had comparable rates of expanded major adverse cardiac events, and HHF or all-cause death, whereas empagliflozin initiators had a lower rate of a first HHF or loop-diuretic initiation.

Changes in SGLT2i and GLP-1RA real-world initiator profiles following cardiovascular outcome trials: A Danish nationwide population-based study.

BACKGROUND: We investigated changes in clinical characteristics of SGLT2i and GLP-1RA real-world initiators in Denmark before/after landmark cardiovascular outcome trials. METHODS: We compared first-time SGLT2i (25,070) and GLP-1RA (14,671) initiators to initiators of DPP-4i (n = 34,079), a class without proven cardiovascular benefits. We used linked population-based healthcare data to examine initiation incidence, medication patterns, and pre-existing atherosclerotic cardiovascular disease (ASCVD) during 2014-2017. RESULTS: Nationwide incidence of SGLT2i initiators increased 3.6-fold (53/100,000 to 172/100,000 per year) vs. a 1.5-fold increase for GLP-1RA. DPP-4i initiation remained stable. From the end of 2015, SGLT2i was increasingly used as 2nd-line therapy, while medication patterns were much more stable for GLP-1RA. Among SGLT2i users, ASCVD increased slightly from 28% to 30%; age- and gender-adj. prevalence ratio (aPR) = 1.03 (95% CI:0.97-1.10). In contrast, among GLP-1RA initiators, baseline ASCVD declined from 29% to 27% (aPR: 0.90 (95% CI:0.84-0.97)), and in DPP-4i initiators from 31% to 29% (aPR: 0.91 (95% CI:0.88-0.96)). CONCLUSIONS: Following the EMPA-REG OUTCOME trial in 2015, SGLT2i have become increasingly used as 2nd-line treatment in everyday clinical practice, with only minor increases in patient proportions with ASCVD. For GLP-1RA, we observed more stable therapy lines and slightly decreasing ASCVD in new users despite the LEADER trial.

Effect of Roux-en-Y gastric bypass surgery on diabetes remission and complications in individuals with type 2 diabetes: a Danish population-based matched cohort study.

AIMS/HYPOTHESIS: The aim of this study was to examine the effect of Roux-en-Y gastric bypass (RYGB) surgery on diabetes remission, subsequent diabetes relapse and micro- and macrovascular complications in individuals with type 2 diabetes and obesity (BMI >35 kg/m2) in a real-world setting. METHODS: This was a population-based cohort study of 1111 individuals with type 2 diabetes treated by RYGB at hospitals in Northern Denmark (2006-2015), and 1074 matched non-operated individuals with type 2 diabetes. Diabetes remission was defined as no glucose-lowering drug use with HbA1c <48 mmol/mol (<6.5%), or metformin monotherapy with HbA1c <42 mmol/mol (<6.0%). Data on complications were ascertained from medical registries with complete follow-up. RESULTS: At 1 year of follow-up, 74% of the cohort treated by RYGB experienced diabetes remission, while 27% had relapsed after 5 years. Predictors of non-remission were age >50 years, diabetes duration >5 years, use of glucose-lowering drugs other than metformin, and baseline HbA1c >53 mmol/mol (>7.0%). Compared with the non-operated cohort using adjusted Cox regression (5.3 years follow-up), the cohort treated by RYGB had 47% lower risk of microvascular complications (HR 0.53 [95% CI 0.38, 0.73]) and a statistically non-significant 24% lower risk of macrovascular complications (HR 0.76 [95% CI 0.49, 1.18]). Diabetes remission vs non-remission at 1 year was associated with reduced HR of 0.43 (95% CI 0.25, 0.72) for microvascular complications and with HR of 0.76 (95% CI 0.40, 1.45) for macrovascular complications. CONCLUSIONS/INTERPRETATION: In routine clinical care, three out of four individuals with type 2 diabetes and obesity treated by RYGB experienced diabetes remission after 1 year, whereas 27% of these individuals had relapsed at 5 years follow-up. RYGB was associated with substantially decreased risk of microvascular complications and non-significantly fewer macrovascular complications, with early diabetes remission as a clear predictor of reduced microvascular complications.

Prevaccination epidemiology of herpes zoster in Denmark: Quantification of occurrence and risk factors.

BACKGROUND: Herpes zoster (HZ) is a vaccine-preventable disease caused by reactivation of the varicella-zoster virus. Unfortunately, formulation of recommendations on routine immunization is hampered by a lack of data on disease burden, since most countries do not record cases of HZ in the general population. We developed and validated an algorithm to identify HZ based on routinely collected registry data and used it to quantify HZ occurrence and risk factors in Denmark prior to marketing of the HZ vaccine. METHODS: We included patients aged ≥40years with a first-time systemic Acyclovir, Valacyclovir, or Famciclovir prescription or a hospital-based HZ diagnosis in the Danish nationwide health registries during 1997-2013. In a validation substudy (n=176), we computed the proportion of persons with HZ among patients who redeemed antiviral prescriptions. In a cohort study, we computed age-specific rates of HZ (45,297,258 person-years). In a case-control study, we then computed odds ratios (ORs) for common chronic diseases and immunosuppressive factors among HZ cases (n=189,025) vs. matched population controls (n=945,111). RESULTS: Medical record review confirmed HZ in 87% (95% confidence interval: 79-93%) of persons ≥40years who dispensed antivirals at doses recommended for HZ. HZ rates increased from 2.15/1000 person-years in 40-year-olds to 9.45/1000 person-years in 95-year-olds. Rates were highest in women. HZ was diagnosed during hospitalization among 3.5%. As expected, persons with severe immunosuppressive conditions had the highest ORs of HZ (between 1.82 and 4.12), but various autoimmune diseases, asthma, chronic kidney disease, and inhaled glucocorticoids were also associated with increased ORs (between 1.06 and 1.64). CONCLUSION: This algorithm is a valid tool for identifying HZ in routine healthcare data. It shows that HZ is common in Denmark, especially in patients with certain chronic conditions. Prioritized vaccination of such high-risk patients might be an option in countries considering alternatives to universal vaccination.

Early Glycemic Control and Magnitude of HbA1c Reduction Predict Cardiovascular Events and Mortality: Population-Based Cohort Study of 24,752 Metformin Initiators.

OBJECTIVE: We investigated the association of early achieved HbA1c level and magnitude of HbA1c reduction with subsequent risk of cardiovascular events or death in patients with type 2 diabetes who initiate metformin. RESEARCH DESIGN AND METHODS: This was a population-based cohort study including all metformin initiators with HbA1c tests in Northern Denmark, 2000-2012. Six months after metformin initiation, we classified patients by HbA1c achieved (<6.5% or higher) and by magnitude of HbA1c change from the pretreatment baseline. We used Cox regression to examine subsequent rates of acute myocardial infarction, stroke, or death, controlling for baseline HbA1c and other confounding factors. RESULTS: We included 24,752 metformin initiators (median age 62.5 years, 55% males) with a median follow-up of 2.6 years. The risk of a combined outcome event gradually increased with rising levels of HbA1c achieved compared with a target HbA1c of <6.5%: adjusted hazard ratio (HR) 1.18 (95% CI 1.07-1.30) for 6.5-6.99%, HR 1.23 (1.09-1.40) for 7.0-7.49%, HR 1.34 (1.14-1.57) for 7.5-7.99%, and HR 1.59 (1.37-1.84) for ≥8%. Results were consistent for individual outcome events and robust by age-group and other patient characteristics. A large absolute HbA1c reduction from baseline also predicted outcome: adjusted HR 0.80 (0.65-0.97) for Δ = -4, HR 0.98 (0.80-1.20) for Δ = -3, HR 0.92 (0.78-1.08) for Δ = -2, and HR 0.99 (0.89-1.10) for Δ = -1 compared with no HbA1c change (Δ = 0). CONCLUSIONS: A large initial HbA1c reduction and achievement of low HbA1c levels within 6 months after metformin initiation are associated with a lower risk of cardiovascular events and death in patients with type 2 diabetes.

Early glycaemic control in metformin users receiving their first add-on therapy: a population-based study of 4,734 people with type 2 diabetes.

AIMS/HYPOTHESIS: The aims of this work were to assess glycaemic control in metformin users receiving their first add-on glucose-lowering therapy and to examine the real-life effectiveness of different add-on drugs. METHODS: We carried out a population-based cohort study using healthcare databases in northern Denmark during 2000-2012. We included 4,734 persons who initiated metformin monotherapy and added another glucose-lowering drug within 3 years. Attainment of recommended HbA1c goals within 6 months of add-on was investigated, using Poisson regression analysis adjusted for age, sex, baseline HbA(1c), diabetes duration, complications and Charlson Comorbidity Index. RESULTS: Median metformin treatment duration at intensification was 12 months (interquartile range [IQR] 4-23 months) and pre-intensification HbA(1c) was 8.0% (IQR 7.2-9.2%) (64 [IQR 55-77] mmol/mol). Median HbA(1c) dropped 1.2% (13 mmol/mol) with a sulfonylurea (SU) add-on, 0.8% (9 mmol/mol) with a dipeptidyl peptidase-4 (DPP-4) inhibitor, 1.3% (14 mmol/mol) with a glucagon-like peptide-1 (GLP-1) receptor agonist, 0.9% (10 mmol/mol) with other non-insulin drugs and 2.4% (26 mmol/mol) with insulin. Compared with SU add-on, attainment of HbA(1c) <7% (<53 mmol/mol) was higher with GLP-1 receptor agonists (adjusted RR [aRR] 1.10; 95% CI 1.01, 1.19) and lower with DPP-4 inhibitors (aRR 0.94; 95% CI 0.89, 0.99), other drugs (aRR 0.86; 95% CI 0.77, 0.96) and insulin (aRR 0.88; 95% CI 0.77, 0.99). The proportion of metformin add-on users who attained HbA(1c) <7% (<53 mmol/mol) increased from 46% in 2000-2003 to 59% in 2010-2012, whereas attainment of HbA(1c) <6.5% (<48 mmol/mol) remained 30% among patients aged <65 years without comorbidities. CONCLUSIONS/INTERPRETATION: Among early type 2 diabetes patients receiving their first metformin add-on treatment, HbA(1c) reduction with different non-insulin drugs is similar to, and comparable with, that observed in randomised trials, yet 41% do not achieve HbA(1c) <7% (<53 mmol/mol) within 6 months.