Beta Blockers in Subjects With T2DM and Heart Failure
The major finding of this study is that BB use did not worsen glycaemic control, lipid profile nor albuminuria status in patients with T2DM and SHF, suggesting that these medications should not be withheld in this high-risk group. This is in contradiction to the GEMINI study, where hypertensive T2DM patients randomized to carvedilol (nonselective BB) did not have a significant change in HbA1c whereas patients on metoprolol tartrate (selective β1 BB) had a significant increase in HbA1c. Futhermore, in a sub-analysis of the GEMINI study an increase in insulin resistance as measured by homeostasis model assessment-insulin resistance (HOMA-IR) was found in patients treated with metoprolol compared to carvedilol. In another study, metoprolol use in patients with type 2 diabetes mellitus was shown to be associated with a significant reduction in insulin-stimulated endothelial function where as this function was preserved with carvedilol use One proposed mechanism for this was that selective β1 BB's such as atenolol and metoprolol may cause vasoconstriction, decreased peripheral blood flow and may exacerbate insulin resistance, whereas the α-adrenergic blocking effect of carvedilol may allow greater peripheral blood flow and hence increased utilization of glucose. This differential effect on glycaemic control seen in hypertensive diabetics may not be applicable to patients with systolic heart failure due to their overactive sympathetic tone. In addition we found that there was a significant improvement in glycaemic control between baseline to peak BB dose within the carvedilol group but not within the bisoprolol group. Whilst there was also a strong trend for better glycaemic control in the carvedilol group compared to the bisoprolol group, this did not quite reach statistical significance. This result could possibly have been biased by different baseline HbA1c levels between the two groups and therefore does not provide absolute evidence for the differential effects on glycaemic control between carvedilol and bisoprolol.
The GEMINI study also showed that patients on carvedilol had a greater reduction in microalbuminuria when compared to patients taking metoprolol. Such differences were not seen in our study. This could be explained by the fact that there is a known higher incidence of microalbuminuria in patients with SHF. Half of the patients in our study had microalbuminuria for the duration of the study, which is a higher proportion than found in the general population of patients with T2DM. The National Health and Nutrition Examination Survey found microalbuminuria in 29% of patients with diabetes mellitus whereas the PREVEND study noted only 16% of patients with diabetes mellitus had microalbuminuria. The higher incidence of microalbuminuria in our study is likely to be mediated via impairment of endothelial function. A recent study by Jawa et al. in African American subjects with T2DM and hypertension suggested that there was an improvement in endothelial function and albuminuria with commencement of carvedilol but without significant change in albuminuria with metoprolol. In contrast, a recent study in in patients with mild heart failure (16% diabetic) failed to show a change in endothelium-dependent vasodilatation when the beta-blocker was changed from carvedilol to metoprolol succinate or tartrate. We did not find any significant changes in albuminuria over the follow-up period in either group.
A concern of treating physicians has often been that BB use would lead to elevation of triglycerides and lowering of HDL. A study by Pollare et al. demonstrated significant elevation in LDL to HDL ratio and triglyceride levels with the use of metoprolol or atenolol. In a more contemporary cohort, beta-blocker use was not associated with a deterioration in lipid profile but suggest greater statin use with metoprolol when compared to carvedilol. In our study, no worsening in lipid profiles was seen in either group of patients whilst on BB. This might be related to a greater use of statins amongst our cohort of patients.
Traditional teaching for T2DM has been that BB may worsen hypoglycaemic awareness, glycaemic control and lipid metabolism and should be used with caution. However, the prognosis of patients that develop SHF is poor and is markedly improved by appropriate BB therapy. Although the use of beta-blockers in T2DM and SHF has not been specifically studied, meta-analyses of large-scale clinical trials have demonstrated the prognostic benefit of beta-blockers in SHF patients who also have diabetes mellitus. Indeed to the authors knowledge there is only one other study that has compared carvedilol to bisoprolol in patients with SHF where, retrospectively after 18 months of follow up, no significant differences were found in survival or cardiac morbidity In addition, strict glycaemic control is essential to the management of patients with diabetes mellitus. In the United Kingdom Prospective Diabetic Study, lowering of HbA1c toward 6% resulted in significant reductions of micro vascular and macro vascular complications and death related to T2DM, including SHF. Furthermore, poor glycaemic control is associated with increased incidence of heart failure, hospitalization and death. It is clear that in the management of patients with T2DM and SHF, the use of beta-blockers whilst maintaining good glycaemic control is important.
Discussion
The major finding of this study is that BB use did not worsen glycaemic control, lipid profile nor albuminuria status in patients with T2DM and SHF, suggesting that these medications should not be withheld in this high-risk group. This is in contradiction to the GEMINI study, where hypertensive T2DM patients randomized to carvedilol (nonselective BB) did not have a significant change in HbA1c whereas patients on metoprolol tartrate (selective β1 BB) had a significant increase in HbA1c. Futhermore, in a sub-analysis of the GEMINI study an increase in insulin resistance as measured by homeostasis model assessment-insulin resistance (HOMA-IR) was found in patients treated with metoprolol compared to carvedilol. In another study, metoprolol use in patients with type 2 diabetes mellitus was shown to be associated with a significant reduction in insulin-stimulated endothelial function where as this function was preserved with carvedilol use One proposed mechanism for this was that selective β1 BB's such as atenolol and metoprolol may cause vasoconstriction, decreased peripheral blood flow and may exacerbate insulin resistance, whereas the α-adrenergic blocking effect of carvedilol may allow greater peripheral blood flow and hence increased utilization of glucose. This differential effect on glycaemic control seen in hypertensive diabetics may not be applicable to patients with systolic heart failure due to their overactive sympathetic tone. In addition we found that there was a significant improvement in glycaemic control between baseline to peak BB dose within the carvedilol group but not within the bisoprolol group. Whilst there was also a strong trend for better glycaemic control in the carvedilol group compared to the bisoprolol group, this did not quite reach statistical significance. This result could possibly have been biased by different baseline HbA1c levels between the two groups and therefore does not provide absolute evidence for the differential effects on glycaemic control between carvedilol and bisoprolol.
The GEMINI study also showed that patients on carvedilol had a greater reduction in microalbuminuria when compared to patients taking metoprolol. Such differences were not seen in our study. This could be explained by the fact that there is a known higher incidence of microalbuminuria in patients with SHF. Half of the patients in our study had microalbuminuria for the duration of the study, which is a higher proportion than found in the general population of patients with T2DM. The National Health and Nutrition Examination Survey found microalbuminuria in 29% of patients with diabetes mellitus whereas the PREVEND study noted only 16% of patients with diabetes mellitus had microalbuminuria. The higher incidence of microalbuminuria in our study is likely to be mediated via impairment of endothelial function. A recent study by Jawa et al. in African American subjects with T2DM and hypertension suggested that there was an improvement in endothelial function and albuminuria with commencement of carvedilol but without significant change in albuminuria with metoprolol. In contrast, a recent study in in patients with mild heart failure (16% diabetic) failed to show a change in endothelium-dependent vasodilatation when the beta-blocker was changed from carvedilol to metoprolol succinate or tartrate. We did not find any significant changes in albuminuria over the follow-up period in either group.
A concern of treating physicians has often been that BB use would lead to elevation of triglycerides and lowering of HDL. A study by Pollare et al. demonstrated significant elevation in LDL to HDL ratio and triglyceride levels with the use of metoprolol or atenolol. In a more contemporary cohort, beta-blocker use was not associated with a deterioration in lipid profile but suggest greater statin use with metoprolol when compared to carvedilol. In our study, no worsening in lipid profiles was seen in either group of patients whilst on BB. This might be related to a greater use of statins amongst our cohort of patients.
Traditional teaching for T2DM has been that BB may worsen hypoglycaemic awareness, glycaemic control and lipid metabolism and should be used with caution. However, the prognosis of patients that develop SHF is poor and is markedly improved by appropriate BB therapy. Although the use of beta-blockers in T2DM and SHF has not been specifically studied, meta-analyses of large-scale clinical trials have demonstrated the prognostic benefit of beta-blockers in SHF patients who also have diabetes mellitus. Indeed to the authors knowledge there is only one other study that has compared carvedilol to bisoprolol in patients with SHF where, retrospectively after 18 months of follow up, no significant differences were found in survival or cardiac morbidity In addition, strict glycaemic control is essential to the management of patients with diabetes mellitus. In the United Kingdom Prospective Diabetic Study, lowering of HbA1c toward 6% resulted in significant reductions of micro vascular and macro vascular complications and death related to T2DM, including SHF. Furthermore, poor glycaemic control is associated with increased incidence of heart failure, hospitalization and death. It is clear that in the management of patients with T2DM and SHF, the use of beta-blockers whilst maintaining good glycaemic control is important.
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