Several, but not all, sulfonylureas are associated with increased cardiovascular risk compared with metformin therapy in patients with diabetes who do not undergo emergent percutaneous coronary intervention (PCI) after myocardial infarction (MI), research suggests.

Monotherapy with glibenclamide, glimepiride, glipizide, and tolbutamide was associated with an increased risk for nonfatal MI, cardiovascular mortality, and all-cause mortality compared with metformin monotherapy in the retrospective study.

Gliclazide was the only sulfonylurea consistently not associated with increased risk for adverse cardiovascular events.

The Danish researchers say: “The results contribute to data indicating that sulphonylureas may be associated with adverse cardiovascular events in patients with MI and they suggest that metformin should generally not be discontinued in these patients.”

Recently, the team examined long-term outcomes in diabetes patients with MI who underwent emergent PCI and found that glibenclamide, but not other sulphonylurea agents, was associated with increased mortality and morbidity compared with metformin.

Noting that those undergoing emergent PCI only represent a fraction of the MI population, Casper Jørgensen (Copenhagen University Hospital Gentofte, Hellerup) and colleagues studied the effects of oral glucose-lowering drugs on long-term outcomes in other MI patients.

All 9876 Danish patients aged 30 years or older receiving glucose-lowering drugs and admitted to hospital with MI but not treated with emergent PCI were identified from nationwide hospitalization registries and pharmacy drug dispensing records between 1997 and 2006.

A total of 3649 individuals received sulphonylureas and 711 received metformin on admission. Average follow-up was 2.2 years.

Overall, 6171 patients experienced the composite primary endpoint of nonfatal MI and cardiovascular mortality. Glibenclamide, glimepiride, glipizide, and tolbutamide were each associated with increased risk, with hazard ratios of 1.31, 1.19, 1.25, and 1.18, respectively, compared with metformin.

Gliclazide was the only sulphonylurea not significantly associated with increased risk compared with metformin.

Time-dependent Cox proportional-hazards regression analyses only in patients at risk while using medication showed increased risk for cardiovascular mortality, nonfatal MI and cardiovascular mortality, and all-cause mortality with glibenclamide, glimepiride, glipizide, and tolbutamide, compared with metformin.

Reporting in the journal Cardiovascular Diabetology, the researchers suggest: “Different affinities of individual sulphonylureas for pancreatic and cardiac KATP channels may have contributed to these findings.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010

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Metformin use lowers mortality in patients with Type 2 diabetes and atherothrombosis, show results from the REACH registry.

Metformin is known to be effective for treating overweight patients with Type 2 diabetes and reducing their mortality, but it tends not to be used as a therapy in patients who also have cardiovascular disease (CVD) due to concerns about its safety.

Ronan Roussel (INSERM, Paris, France) and colleagues investigated the potential mortality benefits of metformin treatment in 19,691 patients with Type 2 diabetes and atherothrombosis participating in the Reduction of Atherothrombosis for Continued Health (REACH) Registry.

At baseline, 7457 patients were using metformin and 12,234 were not (controls). The participants were followed up for 2 years for all-cause mortality.

As reported in the Archives of Internal Medicine, the team found that 2-year mortality rates in the metformin group were a significant 24% lower than in the control group, at 6.3% versus 9.8%.

The researchers note that this reduction in mortality was consistent and significant across subgroups, including patients with congestive heart failure (31% reduction), those older than 65 years (23% reduction), and those with an estimated creatinine clearance of 30-60 ml/min/1.73 m² (36% reduction).

“Our findings provide data sufficiently pertinent and consistent to initiate a properly defined and powered randomized controlled trial to confirm the effect of metformin use on survival,” write Roussel et al.

They add that such a trial would also “assess definitively the benefits and risks of metformin use as a means of prevention of secondary cardiovascular disorders among patients having diabetes with a history of coronary artery disease, cerebrovascular disease, or peripheral arterial disease.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010

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Cardiovascular disease (CVD) and all-cause mortality are significantly higher in women with diabetes and depression than those with one or neither condition, show results from the Nurses’ Health Study.

Previous research has demonstrated that patients with depression have increased CVD and all-cause mortality compared with the general population, with the risk similarly increased in patients with diabetes.

In this study, Frank Hu (Harvard School of Public Health, Boston, Massachusetts, USA) and colleagues assessed the individual and combined effects of diabetes and depression on mortality in 78,282 women who took part in the Nurse’s Health Study.

The women were aged 54-79 years at study initiation in 2000 and were followed up until 2006. Diabetes and depression were self-reported by questionnaire. Overall, 333,805 women had neither condition, 68,799 had depression alone, 23,561 had diabetes alone, and 6901 had both. Deaths were reported by next of kin or in the National Death Index.

Writing in the Archives of General Psychiatry, the authors report that women with depression or diabetes alone had a significant 1.76- and 1.71-fold increased relative risk for all-cause mortality, respectively, compared with women with neither condition.

Similarly, the corresponding risks for CVD mortality in these women were 1.81- and 2.67-fold higher compared with in those without depression or diabetes.

The combination of both conditions led to significantly higher risks for both all-cause and CVD mortality, with a respective 3.11- and 5.38-fold increased risk in these women compared with those without depression or diabetes.

The researchers note that multivariate adjustment for various confounders such as body mass index, smoking status, and major comorbidities did weaken the associations, reducing the increased risk for all-cause and CVD mortality to 2.07- and 2.72-fold in those with both conditions, respectively, but these increased risks were still statistically significant.

Patients who had a long duration of diabetes (over 10 years) or who were being treated with insulin and also suffered from depression were found to be at particularly high risk for all-cause or CVD mortality after multivariate adjustment (3.22- and 4.90-fold risk increase in those with both conditions compared with those without either condition).

“Considering the size of the population that could be affected by these two prevalent disorders, further consideration is required to design strategies aimed to provide adequate psychological management and support among those with longstanding chronic conditions, such as diabetes,” conclude Hu et al.

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2011

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Tight control of systolic blood pressure (SBP) to a target of less than 130 mmHg in diabetics with coronary artery disease (CAD) does not significantly reduce the incidence of cardiovascular (CV) events compared with usual control, and is associated with increased all-cause mortality, shows an analysis of INVEST.

In INVEST (International Verapamil SR ??” trandolapril Study), patients with diabetes and CAD were randomly assigned to receive antihypertensive therapy with either a calcium-channel blocker or a beta blocker, plus an ACE inhibitor and/or a thiazide diuretic. In extended follow-up of 6400 patients enrolled in the trial, those who achieved SBPs lower than 130 mmHg had cardiovascular outcomes equivalent to those who achieved SBPs between 130 and 140 mmHg.

But a subanalysis of 5077 patients from the USA showed that the tight BP control strategy was associated with an adjusted hazard ratio (HR) of 1.15 (p=0.036) for all-cause mortality compared with usual control, defined as a SBP lower than 140 mm Hg.

“We wonder whether it’s time to rethink lower BP goals in patients with diabetes and CAD,” said Rhonda Cooper-DeHoff from the University of Florida in Gainesville, Florida, USA, who presented the data during a late-breaking clinical trials session at the 2010 annual scientific sessions of the American College of Cardiology in Atlanta, Georgia, USA.

The findings appear to contravene the position of the American Diabetes Association, which has previously issued a position statement saying that “there is no threshold value for BP [in diabetics], and risk continues to decrease well into the normal range.”

INVEST was designed to determine whether lowering SBP below 130 mmHg could provide additional CV benefits, particularly among diabetic patients with CAD. The international trial enrolled 22,576 patients with CAD and hypertension, and randomly assigned them to receive either verapamil SR plus trandolapril and the thiazide diuretic hydrochlorothiazide [HCTZ], or atenolol plus HCTZ and trandolapril. Trandolapril was recommended for all diabetic patients in the study.

The analysis focused on mortality rates among a US cohort of diabetic patients followed for an extended period, from September 1997 through November 2008. To evaluate the effects of very low SBP, the authors further categorized on-treatment SBP in increments of 5 mmHg.

During the extended follow-up period of 22,700 patient-years, the investigators found that, as predicted, patients whose BP was not controlled on therapy had an approximately 50% higher risk for a composite endpoint of death, nonfatal myocardial infarction (MI) or nonfatal stroke compared with those in the usual-control group. There were no significant differences between the tight- or usual-control groups with regard to either nonfatal MI of nonfatal stroke.

But in a Cox regression analysis of all-cause mortality, both the 110 to less than 115 mmHg and the less than 110 mmHg SBP categories were associated with increased risk for death. Other factors associated with increased mortality risk were age, race, peripheral arterial disease, coronary heart failure, US residency, renal impairment, left-ventricular hypertrophy, and transient ischemia.

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010

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