Cardiovascular safety of combination therapies with incretin-based drugs and metformin compared with a combination of metformin and sulphonylurea in type 2 diabetes mellitus--a retrospective nationwide study.

AIM: Dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists are widely used in combinations with metformin in the treatment of type 2 diabetes; however, data on long-term safety compared with conventional combination therapies are limited. METHODS: Danish individuals without prior myocardial infarction or stroke that initiated combinations of metformin with sulphonylurea (SU), DPP-4 inhibitors, GLP-1 agonists or insulin between 9 May 2007 and 31 December 2011 were followed up for the risk of all-cause mortality, cardiovascular (CV) mortality or a combined end point of myocardial infarction, stroke and CV mortality. Rate ratios (RR) were calculated using time-dependent multivariable Poisson regression analysis. RESULTS: A total of 40 028 patients (59% men, mean age 60 ± 13 years) used metformin with SU (n = 25 092), DPP-4 inhibitor (n = 11 138), GLP-1 agonist (n = 4345) or insulin (n = 6858). Crude incidence rates per 1000 patient years for the combined end point were 18 (SU), 10 (DPP-4 inhibitor), 8 (GLP-1 agonist) and 21 (insulin). In adjusted analyses with metformin + SU as reference, metformin + DPP-4 inhibitor was associated with an RR of 0.65 (0.54-0.80) for mortality, an RR of 0.57 (0.40-0.80) for CV mortality and an RR of 0.70 (0.57-0.85) for the combined end point. For metformin + GLP-1 agonist, the RR for mortality was 0.77 (0.51-1.17), for CV mortality 0.89 (0.47-1.68), and for the combined end point 0.82 (0.55-1.21). CONCLUSION: Incretin-based drugs combined with metformin were safe compared with conventional combinations of glucose-lowering therapy. Use of incretin-based therapy may be target for strategies to lower CV risk in type 2 diabetes, although it should be recognized that the multivariable analysis may not have fully accounted for important baseline differences.

Changes in short- and long-term cardiovascular risk of incident diabetes and incident myocardial infarction--a nationwide study.

AIMS/HYPOTHESIS: We assessed secular trends of cardiovascular outcomes following first diagnosis of myocardial infarction (MI) or diabetes in an unselected population. METHODS: All Danish residents aged > or = 30 years without prior diabetes or MI were identified by individual-level linkage of nationwide registers. Individuals hospitalised with MI or claiming a first-time prescription for a glucose-lowering medication (GLM) during the period from 1997 to 2006 were included. Analyses were by Poisson regression models. Primary endpoints were death by all causes, cardiovascular death and MI. RESULTS: The study included 3,092,580 individuals, of whom 77,147 had incident MI and 118,247 new-onset diabetes. MI patients had an increased short-term risk of all endpoints compared with the general population. The rate ratio (RR) for cardiovascular death within the first year after MI was 11.1 (95% CI 10.8-11.5) in men and 14.8 (14.3-15.3) in women, respectively. The risk rapidly declined and 1 year after the index MI, RR was 2.11 (2.00-2.23) and 2.8 (2.64-2.97) in men and women, respectively. Patients with diabetes carried a constantly elevated risk of all endpoints compared with the general population. The cardiovascular death RR was 1.90 (1.77-2.04) and 1.92 (1.78-2.07) in men and women, respectively during the first year after GLM initiation. CONCLUSIONS/INTERPRETATION: Incident MI is associated with high short-term risk, which decreases rapidly over time. Incident diabetes is associated with a persistent excessive cardiovascular risk after initiation of GLM therapy. This further strengthens the necessity of early multi-factorial intervention in diabetes patients for long-term benefit.

Metformin treatment is associated with a low risk of mortality in diabetic patients with heart failure: a retrospective nationwide cohort study.

AIMS/HYPOTHESIS: The safety of metformin in heart failure has been questioned because of a perceived risk of life-threatening lactic acidosis, though recent studies have not supported this concern. We investigated the risk of all-cause mortality associated with individual glucose-lowering treatment regimens used in current clinical practice in Denmark. METHODS: All patients aged ≥ 30 years hospitalised for the first time for heart failure in 1997-2006 were identified and followed until the end of 2006. Patients who received treatment with metformin, a sulfonylurea and/or insulin were included and assigned to mono-, bi- or triple therapy groups. Multivariable Cox proportional hazard regression models were used to assess the risk of all-cause mortality. RESULTS: A total of 10,920 patients were included. The median observational time was 844 days (interquartile range 365-1,395 days). In total, 6,187 (57%) patients died. With sulfonylurea monotherapy used as the reference, adjusted hazard ratios for all-cause mortality associated with the different treatment groups were as follows: metformin 0.85 (95% CI 0.75-0.98, p = 0.02), metformin + sulfonylurea 0.89 (95% CI 0.82-0.96, p = 0.003), metformin + insulin 0.96 (95% CI 0.82-1.13, p = 0.6), metformin + insulin + sulfonylurea 0.94 (95% CI 0.77-1.15, p = 0.5), sulfonylurea + insulin 0.97 (95% CI 0.86-1.08, p = 0.5) and insulin 1.14 (95% CI 1.06-1.20, p = 0.0001). CONCLUSIONS/INTERPRETATION: Treatment with metformin is associated with a low risk of mortality in diabetic patients with heart failure compared with treatment with a sulfonylurea or insulin.

Clinical consequences of hospital variation in use of oral anticoagulant therapy after first-time admission for atrial fibrillation.

OBJECTIVE: To analyse how hospital factors influence the use of oral anticoagulants (OAC) in atrial fibrillation (AF) patients and address the clinical consequences of hospital variation in OAC use. DESIGN AND SUBJECTS: By linkage of nationwide Danish administrative registers we conducted an observational study including all patients with a first-time hospitalization for AF between 1995 and 2004 as well as prescription claims for OAC. Multivariable logistic regression analysis was used to evaluate hospital factors associated with prescription of OAC therapy. Cox proportional-hazard models were used to estimate the risk of re-hospitalization for thromboembolism and haemorrhagic stroke with respect to discharge from a low, intermediate, or high OAC use hospital. RESULTS: Overall 40,133 (37%) out of 108,504 patients received OAC; ranging from 17% to 50% between the hospitals with the lowest and highest OAC use, respectively. Cardiology departments had the highest use of OAC, but neither tertiary university hospitals nor high volume hospitals had higher OAC use than local community hospitals and low volume hospitals. Risk of a thromboembolic event was significantly increased amongst patients from hospitals with a low OAC use (hazard ratio 1.16, confidence interval 1.10-1.22). Notably, higher OAC use was not associated with a higher risk of haemorrhagic stroke. CONCLUSION: In Denmark between 1995 and 2004, there was a major hospital variation in AF patients receiving OAC, and consequently, more thromboembolic events were observed amongst patients from low OAC use hospitals. Our study emphasizes the need for a continued vigilance on implementation of international AF management guidelines.

Glyburide increases risk in patients with diabetes mellitus after emergent percutaneous intervention for myocardial infarction--a nationwide study.

BACKGROUND: Sulfonylureas have been linked to an increased cardiovascular risk by inhibition of myocardial preconditioning. Whether individual sulfonylureas affect outcomes in diabetic patients after emergent percutaneous coronary intervention for myocardial infarction is unknown. METHODS: All Danish patients receiving glucose-lowering drugs admitted with myocardial infarction between 1997 and 2006 who underwent emergent percutaneous coronary intervention were identified from national registers. Multivariable Cox proportional hazards models were used to analyze the risk of cardiovascular mortality and morbidity associated with sulfonylureas. RESULTS: A total of 926 patients were included and 163 (17.6%) patients died during the first year of which 155 (16.7%) were cardiovascular deaths. The most common treatment was sulfonylureas which were received by 271 (29.3%) patients, and 129 (13.9%) received metformin. Cox proportional hazard regression analyses adjusted for age, sex, calendar year, comorbidity and concomitant pharmacotherapy showed an increased risk of cardiovascular mortality (hazard ratio [HR] 2.91, 95% confidence interval [CI] 1.26-6.72 ; p=0.012), cardiovascular mortality and nonfatal myocardial infarction (HR 2.69 , 95% CI 1.21-6.00; p=0.016), and all-cause mortality (HR 2.46, 95% CI 1.11-5.47; p=0.027), respectively, with glyburide compared to metformin. CONCLUSIONS: Glyburide is associated with increased cardiovascular mortality and morbidity in patients with diabetes mellitus undergoing emergent percutaneous coronary intervention after myocardial infarction. Early reperfusion therapy is the mainstay in modern treatment of myocardial infarction and the time may have come to discard glyburide in favour of sulfonylureas that do not appear to confer increased cardiovascular risk.

Initiation and persistence to statin treatment in patients with diabetes receiving glucose-lowering medications 1997- 2006.

AIMS: Since 2001 guidelines recommend statin treatment in most patients with diabetes. We investigated secular changes in initiation and persistence to statin treatment during a 10-year period in a nationwide cohort of patients initiating glucose-lowering medication (GLM). METHODS: All Danish citizens 30 years and older who claimed prescriptions of GLM between 1997 and 2006 were identified from nationwide registers of drug dispensing from pharmacies and hospitalizations, and followed until 2006. Statin treatment was registered if a prescription was claimed during the period. By logistic regression we analyzed factors related to initiation and persistence to statin treatment. RESULTS: In total 128,106 patients were included. In 1997 only 7% of the patients receiving GLM claimed statins within the first year after GLM initiation. Despite increasing statin prescriptions the following years, only 62% were using statins at the end of follow up. The chance of ever receiving statins was lowest if not initiated within 180-days following the first purchase of GLM (OR 0.75, 95% CI 0.74-0.76). A previous myocardial infarction was associated with increased statin treatment (OR 4.51; 95% CI 4.31 - 4.71), while low income was associated with lower use of statins (OR 0.68; 95%CI 0.66-0.72). Between 75-85 % of the patients who initiated statins treatment were persistent to treatment by 2007. CONCLUSIONS: In spite of increasing use of statins in diabetes patients over time, many patients remain untreated. Early initiation of statin treatment in diabetic patients and focus on patients with low socioeconomic status is needed to give long-term benefits.

Risk of myocardial infarction and death associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) among healthy individuals: a nationwide cohort study.

Use of some nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with increased cardiovascular risk in several patient groups, but whether this excess risk exists in apparently healthy individuals has not been clarified. Using a historical cohort design, we estimated the risk of death and myocardial infarction associated with the use of NSAIDs. Participants in the study were selected from the Danish population and were defined as healthy according to a history of no hospital admissions and no concomitant selected pharmacotherapy. The source population consisted of 4,614,807 individuals, of whom 1,028,437 were included in the study after applying selection criteria. Compared to no NSAID use, hazard ratios (95% confidence limits) for death/myocardial infarction were 1.01 (0.96-1.07) for ibuprofen, 1.63 (1.52-1.76) for diclofenac, 0.97 (0.83-1.12) for naproxen, 2.13 (1.89-2.41) for rofecoxib, and 2.01 (1.78-2.27) for celecoxib. A dose-dependent increase in cardiovascular risk was seen for selective COX-2 inhibitors and diclofenac. Caution should be exercised in NSAID use in all individuals, and particularly high doses should be avoided if possible.