original article

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 U. M. Mogensen1 , C. Andersson2 , E. L. Fosbøl1 , T. K. Schramm3 , A. Vaag4 , N. M. Scheller 7 , C. Torp-Pedersen7 , G. Gislason2,5,6 & L. Køber1 1 Department of Cardiology, University Hospital Rigshospitalet, Copenhagen, Denmark 2 Department of Cardiology, University Hospital Gentofte, Copenhagen, Denmark 3 Department of Cardiology, University Hospital Frederiksberg, Copenhagen, Denmark 4 Department of Endocrinology, University Hospital Rigshospitalet, Copenhagen, Denmark 5 Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 6 National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark 7 Department of Health Science and Technology, Aalborg University, Aalborg, Denmark

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. Keywords: cardiovascular disease, DPP-IV inhibitor, GLP-1 analogue, incretin therapy, type 2 diabetes Date submitted 6 December 2013; date of first decision 5 January 2014; date of final acceptance 2 May 2014

Introduction Dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists have recently been introduced in the treatment of type 2 diabetes mellitus (T2DM). These incretinbased drugs are widely used in combination with metformin, but data on their cardiovascular disease (CVD) risk compared with conventional combination therapy regimens [metformin with sulphonylurea (SU) or insulin] remain limited.

Correspondence to: Ulrik Madvig Mogensen, MD, Department of Cardiology, The Heart Centre, University Hospital Rigshospitalet, 9441, Blegdamsvej 9, 2100 Copenhagen, Denmark. E-mail: [email protected]

Metformin is generally recommended as first-line therapy [1], but the majority of T2DM patients eventually need more than one glucose-lowering therapy (GLT) to maintain glycaemic control [2]. SUs have been the most widely used add-on therapy for several years, but controversies exist with respect to their individual or general CVD risk when administered alone or in combination with metformin [3–7]. Thus, the optimal strategy for glucose-lowering treatment as add-on to metformin as second-line therapy is not clear [1,8]. Compared with SU and insulin, incretin-based therapies have a low risk of hypoglycaemia and favourable or neutral effects on body weight [9]. Furthermore, incretin-based therapies have been associated with positive cardiovascular effects beyond glucose lowering [9–12]. Two recent randomized

original article

Diabetes, Obesity and Metabolism 2014. © 2014 John Wiley & Sons Ltd

original article

DIABETES, OBESITY AND METABOLISM

trials reported neutral composite CVD outcome results of adding a DPP-4 inhibitor to standard therapy in T2D patients at high risk for CV events [13,14]. However, data for direct comparisons of the most commonly used combinations with metformin treatment are lacking. In this study, we aimed to compare mortality and CVD risk associated with combinations of incretin-based therapy and metformin versus the two other most widely used secondline combination therapies in low-risk T2DM patients without previous CV events.

Methods Registry Data Sources All residents in Denmark are assigned a unique civil registration number at birth enabling linkage of nationwide administrative registries at an individual level. For this study, we used four different registries. We obtained information on hospitalizations from The Danish National Patient Registry, which holds information on all admissions in Denmark since 1978 with discharge diagnoses coded according to the International Classification of Diseases (ICD) system, ICD-8 before and ICD-10 after 1994. All prescriptions dispensed from Danish Pharmacies have been consistently registered according to the Anatomical Therapeutic Chemical (ATC) system in the Danish Registry of Medicinal Product Statistics since 1995. We used information on amount and strength of dispensed tablets as well as date of dispensing, which has been shown to be accurate, to define treatment exposures [15]. We obtained information on vital status from The Danish National Population Registry, where all deaths of Danish residents are registered within 2 weeks of occurrence. Causes of death were obtained from the National Causes of Death Register, which holds information on primary and contributing causes of death according to ICD-10.

Patient Population All individuals ≥18 years who initiated a combination of GLT after 9 May 2007 were identified. Users of GLT before 1 January 1997 with unknown treatment duration, and patients with prior myocardial infarction (ICD-10: I21-I22, ICD-8: 410) or stroke (ICD-10: I61-I64, ICD-8: 431–434) were excluded. Patients using metformin in combination with SU, DPP-4 inhibitors, GLP-1 agonists or insulin were included at date of first claimed prescription of combined therapy (Figure 1). Danish physicians generally comply with guidelines issued from EASD/ADA [1,16].

Outcomes All-cause mortality, CV mortality (ICD-10: I00-I99) and a combined end point of myocardial infarction (I21-I22), stroke (I61-I64) or CV mortality were assessed.

Figure 1. Flow chart of patient population. MI, myocardial infarction.

tolbutamide (A10BB03) and glipizide (A10BB07)], DPP-4 inhibitors [sitagliptin (A10BH01 and A10BD07), vildagliptin (A10BH02 and A10BD08) and saxagliptin (A10BH03)] and GLP1-analogues [exenatide (A10BX04) and liraglutide (A10BX07)]. Intervals of treatment with each type of GLT were calculated by dividing the amount of claimed medication by time elapsed between prescription claims. A continuous treatment period was assumed if this was compatible with at least the minimal dose when considering up to four consecutively claimed prescriptions (in a retrospective manner to avoid conditioning on the future) [17–19]. All intervals were extended with 30 days to avoid artificial breaks in the calculated treatment durations. A sensitivity analysis without this extension was performed.

Co-morbidity, Concomitant CV Therapy and Income Co-morbidities were included as Charlson co-morbidity score based on discharge diagnoses 10 year prior to baseline [20,21]. An additional analysis was conducted using the following CV risk factors: peripheral vascular disease, ischaemic heart disease, cerebrovascular disease, renal disease atrial fibrillation and congestive heart failure. Concomitant CV therapy was included in the models as time-dependent dichotomized variables indicating use of the respective drugs within the last year. These drugs included statins (C10AA), angiotensin-converting enzyme inhibitors/angiotensin receptor inhibitors (renin angiotensin system inhibitor, RASi) (C09), β-blockers (C07), calcium channel blockers (C08), other antihypertensive drugs (C02), nitrates (C01D), aspirin (B01AC06), vitamin K antagonists (B01AA), digoxin (C01AA) and spironolactone (C03D). Household income among all included patients 5 years prior to baseline was graded in quintiles and included in the analysis to account for socio-economic status.

Statistics Exposure Classification All types of GLTs were classified according to drug type including metformin (A10B), insulin (A10A), SUs [glibenclamide (A10BB01), gliclazide (A10BB09), glimepiride (A10BB12),

2 Mogensen et al.

sas version 9.2 (SAS Institute, Cary, NC, USA) was used for statistical analysis. A p-value of

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.

Dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists are widely used in combinations with metformin in the treatment...
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