Heart failure has been suggested to increase the risk of developing diabetes. We investigated the relation between heart failure severity, defined by loop-diuretic dosage, and the risk of developing diabetes in a nationwide cohort of patients with heart failure.
We followed all Danish patients discharged from hospitalisation for first-time heart failure in 1997-2010, without prior use of hypoglycaemic agents, until a claimed prescription for hypoglycaemic agents, death or 31 December 2010. The association of loop-diuretic dosage (furosemide equivalents) 90 days after discharge (study baseline) with risk of diabetes was estimated by multivariate Cox regression models.
In total, 99,362 patients were included and divided into five loop-diuretic dose groups: 30,838 (31%) used no loop diuretics; 24,389 (25%) used >0-40 mg/day; 17,355 (17%) used >40-80 mg/day; 11,973 (12%) used >80-159 mg/day; and 14,807 (15%) used =160 mg/day. A total of 7,958 patients (8%) developed diabetes. Loop-diuretic dosages were associated with an increased risk of developing diabetes in a dose-dependent manner. Concomitant use of renin-angiotensin system inhibitors (RASis) attenuated the risk (p value for interaction
Heart failure (HF) is associated with increased insulin resistance, but the consequences of HF for development of diabetes are not well studied. The aim of the present study was to investigate the relationship between HF severity and risk of developing diabetes in a nationwide cohort of patients with myocardial infarction (MI).
Patients discharged from first-time MI during 1997-2006 and not previously treated with glucose-lowering medications (GLM) or loop diuretics were identified from Danish nationwide registers. Heart failure severity was determined by loop diuretic dosage after discharge. Patients were followed until first claimed prescription of GLM, death, or until the end of 2006. The cohort comprised 50 874 patients. A total of 3006 (6%) had mild (loop-diuretic dosage=40 mg/day), 5383 (11%) moderate (>40-120 mg/day), and 1127 (2%) severe (>120 mg/day) HF. During follow-up, 2531 (5%) patients developed diabetes. Increasing HF severity was associated with increased risk of diabetes, but the use of renin-angiotensin system inhibitors (RASi) attenuated the risk (P-value for interaction between the HF group and RASi
Metformin is the first-line treatment for most patients with type 2 diabetes but many patients need additional treatment with insulin secretagogues (IS) to achieve glycemic control. We aimed to compare mortality and cardiovascular risk among users of metformin in combination with pharmacologically different ISs.
Using nationwide administrative Danish registries, we followed all individuals without prior stroke or myocardial infarction who initiated metformin and an IS from 1997 through 2009. Rate ratios (RR) of all-cause mortality, cardiovascular death, and a composite of myocardial infarction, stroke, or cardiovascular death were compared between user groups using time-dependent multivariable Poisson regression models. The most common combination, glimepiride+metformin, was used as reference.
A total of 56,827 patients were included, 56% male, the mean age was 61 ± 12.5 years, and median duration of prior monotherapy was 2.2 (inter quartile range 0.5-4.5) years. Crude incidence rates of mortality for combinations of ISs with metformin were; 15.4 (repaglinide), 28.1 (glipizide), 23.7 (glibenclamide), 21.1 (gliclazide), 20.7 (glimepiride), 27.7 (tolbutamide) deaths per 1000 person years. In adjusted analysis, the associated mortality risk was similar for users of gliclazide+metformin (RR=1.01 [0.88-1.15]), repaglinide+metformin (RR=0.81 [0.62-1.05]), glibenclamide+metformin (RR=0.98 [0.87-1.10]), and tolbutamide+metformin (RR=1.04 [0.85-1.28]). Users of glipizide+metformin was associated with increased all-cause mortality (RR=1.16 [1.02-1.32], p=0.02), cardiovascular death (RR=1.21 [1.01-1.46], p=0.04), and the combined endpoint (RR=1.20 [1.06-1.36, p=0.005).
Most ISs in combination with metformin were associated with similar mortality and cardiovascular risk. Whether glipizide is associated with increased risk compared with other ISs when used in combinations with metformin warrants further study.
The impact of insulin secretagogues (ISs) on long-term major clinical outcomes in type 2 diabetes remains unclear. We examined mortality and cardiovascular risk associated with all available ISs compared with metformin in a nationwide study.
All Danish residents >20 years, initiating single-agent ISs or metformin between 1997 and 2006 were followed for up to 9 years (median 3.3 years) by individual-level linkage of nationwide registers. All-cause mortality, cardiovascular mortality, and the composite of myocardial infarction (MI), stroke, and cardiovascular mortality associated with individual ISs were investigated in patients with or without previous MI by multivariable Cox proportional-hazard analyses including propensity analyses. A total of 107 806 subjects were included, of whom 9607 had previous MI. Compared with metformin, glimepiride (hazard ratios and 95% confidence intervals): 1.32 (1.24-1.40), glibenclamide: 1.19 (1.11-1.28), glipizide: 1.27 (1.17-1.38), and tolbutamide: 1.28 (1.17-1.39) were associated with increased all-cause mortality in patients without previous MI. The corresponding results for patients with previous MI were as follows: glimepiride: 1.30 (1.11-1.44), glibenclamide: 1.47 (1.22-1.76), glipizide: 1.53 (1.23-1.89), and tolbutamide: 1.47 (1.17-1.84). Results for gliclazide [1.05 (0.94-1.16) and 0.90 (0.68-1.20)] and repaglinide and [0.97 (0.81-1.15) and 1.29 (0.86-1.94)] were not statistically different from metformin in both patients without and with previous MI, respectively. Results were similar for cardiovascular mortality and for the composite endpoint.
Monotherapy with the most used ISs, including glimepiride, glibenclamide, glipizide, and tolbutamide, seems to be associated with increased mortality and cardiovascular risk compared with metformin. Gliclazide and repaglinide appear to be associated with a lower risk than other ISs.
Comment In: Ann Intern Med. 2012 Jan 17;156(2):JC1-722250169
Comment In: Eur Heart J. 2011 Aug;32(15):1832-421471136
Individual sulfonylureas (SUs) and metformin have, in some studies, been associated with unequal hypoglycaemic, cardiovascular and mortality risks when used as monotherapy in type 2 diabetes. We investigated the outcomes in patients treated with different combinations of SUs and insulin vs a combination of metformin and insulin in a retrospective nationwide study.
All Danish individuals using dual therapy with SU?+?insulin or metformin?+?insulin without prior myocardial infarction (MI) or stroke were followed from 1 January 1997 to 31 December 2009 in nationwide registries. Risks of all-cause mortality, cardiovascular death, hypoglycaemia and a composite endpoint of MI, stroke and cardiovascular death were compared. Rate ratios (RR) [95% CIs] were calculated using time-dependent multivariable Poisson regression analysis.
A total of 11,081 patients used SU?+?insulin and 16,910 used metformin?+?insulin. Patients receiving metformin?+?insulin were younger and had less comorbidity and a longer history of glucose-lowering treatment. SU?+?insulin was associated with higher mortality rates compared with metformin?+?insulin (76-126 vs 23 per 1,000 person-years). In adjusted analyses, SU?+?insulin was associated with increased all-cause mortality (RR 1.81 [1.63, 2.01]), cardiovascular death (RR 1.35 [1.14, 1.60]) and the composite endpoint (RR 1.25 [1.09, 1.42]) compared with metformin?+?insulin. Hypoglycaemia was more frequent with SU?+?insulin than with metformin?+?insulin (17-23 vs six events per 1,000 person-years) and was associated with increased mortality (RR 2.13 [1.97, 2.37]). There were no significant differences in risk between individual SUs in combination with insulin.
In combination with insulin, the use of SUs was associated with increased mortality compared with metformin. There were no significant risk differences between SUs.
Type 2 diabetes is a well-established risk factor for cardiovascular disease and is common among patients with acute myocardial infarction (MI). The extent to which patients with first-time MI develop diabetes requiring glucose-lowering medications (GLM) is largely unknown. The aim of the study was to investigate temporal trends in the initiation of GLM among patients discharged after first-time MI.
All Danish residents aged = 30 years without prior diabetes hospitalized with first-time MI between 1997 and 2006 were identified by individual-level-linkage of nationwide registers. Initiation of GLM during follow-up was assessed by claimed prescriptions from pharmacies. Temporal trends in initiation of GLM were assessed by incidence rate calculations in the MI population as in the general population. Multivariable Cox proportional-hazard models were used to investigate the likelihood of initiating GLM within a year post-MI.
The population comprised 66,788 patients. Among these patients 3962 patients initiated GLM, of whom 1567 started within one year post-MI. An increase in incidence rates of GLM initiation in the MI population from 19.6 per 1000 person years in 1997 to approximately 27.6 in 2001 was demonstrated. After 2001 the incidence rates stabilized. A similar trend was observed in the general population where the incidence rates increased from 2.8 in 1997 to 4.0 in 2004 and then stabilized.
Our study demonstrated an increase in incidence rates of GLM initiation within the first year post- MI. A similar trend was observed in the general population suggesting that the increase in GLM among MI patients was primarily the effect of a general increased awareness of diabetes. From a public heath perspective, this study underscores a continuous need for diagnostic and therapeutic improvement in the care of MI patients that develop diabetes.
Cites: N Engl J Med. 2008 Jun 12;358(24):2560-7218539916
Cites: N Engl J Med. 2008 Jun 12;358(24):2545-5918539917