Effects of metoprolol and carvedilol on pre-existing and new onset diabetes in patients with chronic heart failure: Data from the Carvedilol Or Metoprolol European Trial (COMET)

University of Hull, Kingston upon Hull, England, United Kingdom
Heart (British Cardiac Society) (Impact Factor: 5.6). 09/2007; 93(8):968-73. DOI: 10.1136/hrt.2006.092379
Source: PubMed


Beta blocker treatment may worsen glucose metabolism.
To study the development of new onset diabetes in a large cohort of patients with heart failure treated with either metoprolol or carvedilol.
Prospective and retrospective analysis of a controlled clinical trial.
Multinational multicentre study.
3029 patients with chronic heart failure.
Randomly assigned treatment with carvedilol (n = 1511, target dose 50 mg daily) or metoprolol tartrate (n = 1518, target dose 100 mg daily).
Diabetic events (diabetic coma, peripheral gangrene, diabetic foot, decreased glucose tolerance or hyperglycaemia) and new onset diabetes (clinical diagnosis, repeated high random glucose level or glucose lowering drugs) were assessed in 2298 patients without diabetes at baseline. Diabetic events occurred in 122/1151 (10.6%) patients in the carvedilol group and 149/1147 (13.0%) patients in the metoprolol group (hazard ratio (HR) = 0.78; 95% confidence interval (CI) 0.61 to 0.99; p = 0.039). New onset diabetes was diagnosed in 119/1151 (10.3%) v 145/1147 (12.6%) cases in the carvedilol and metoprolol treatment groups (HR = 0.78, CI 0.61 to 0.997; p = 0.048), respectively. Patients with diabetes at baseline had an increased mortality compared with non-diabetic subjects (45.3% v 33.9%; HR = 1.45, CI 1.28 to 1.65). Both diabetic and non-diabetic subjects at baseline had a similar reduction in mortality with carvedilol compared with metoprolol (RR = 0.85; CI 0.69 to 1.06 and RR = 0.82; CI 0.71 to 0.94, respectively).
A high prevalence and incidence of diabetes is found in patients with heart failure over a course of 5 years. New onset diabetes is more likely to occur during treatment with metoprolol than during treatment with carvedilol.

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Available from: Christian Torp-Pedersen, May 21, 2014
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    • "Carvedilol, on the other hand, has been reported to improve serum lipid profile and insulin sensitivity (Jacob et al. 1996). Analysis of the Carvedilol Or Metoprolol European Trial (COMET) results indicated that the risk for developing diabetes was reduced by 22% with carvedilol (Torp-Pedersen et al. 2007). Taken together, nonselective b-blockers are accepted as " pro-insulin resistant, " whereas carvedilol, the drug that also blocks a1 adrenoceptors, is known to have the opposite effect (reviewed in Kostis and Sanders 2005; Ashrafian et al. 2007). "
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    ABSTRACT: Beta adrenergic receptor blocking drugs (β-blockers) are used chronically in many cardiovascular diseases such as hypertension, ischemic heart disease, arrhythmia, and heart failure. Beneficial effects are associated with the inhibition of symphathetic nervous system hyperactivity, reduction of heart rate, and remodeling by blocking the mitogenic activity of catecholamines. A possible effect of β-blockers on substrate metabolism has also been suggested. The direct effects of β-blockers on mouse C2C12 cells were investigated in this study. C2C12 cells were grown in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and differentiated into myotubes in the same medium that contained 1% FBS. Palmitic acid oxidation and glycolysis were measured by using [9,10-(3)H]palmitate and [5-(3)H]glucose, respectively. The amount of (3)H(2)O was measured as an indicator of substrate usage. Carvedilol (100 µmol/L) inhibited palmitate oxidation and increased glycolysis by nearly 50%. Prazosin altered substrate metabolism in a similar fashion as carvedilol, whereas propranolol or bisoprolol were devoid of metabolic effects. When added to mimic sympathetic activation, epinephrine stimulated glycolysis but did not alter fatty acid oxidation. Based on these results, carvedilol appears to have direct effects on substrate metabolism that are related to the blockade of α1 adrenergic receptors.
    Full-text · Article · Apr 2012 · Canadian Journal of Physiology and Pharmacology
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    • "Patients with HF are at increased risk of developing diabetes and frequently demonstrate insulin resistance [5,6]. In the Carvedilol Or Metoprolol European Trial (Comet) study it was observed that metoprolol deteriorates metabolic glucose control whereas carvedilol does not [7] and, accordingly, there was a larger number of new-onset diabetes in patients treated with metoprolol [8]. We have observed that vascular insulin sensitivity was deteriorated after treatment with metoprolol in patients with type 2 diabetes, whereas no change was found after treatment with carvedilol [9]. "
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    ABSTRACT: Carvedilol has been shown to be superior to metoprolol tartrate to improve clinical outcomes in patients with heart failure (HF), yet the mechanisms responsible for these differences remain unclear. We examined if there were differences in endothelial function, insulin stimulated endothelial function, 24 hour ambulatory blood pressure and heart rate during treatment with carvedilol, metoprolol tartrate and metoprolol succinate in patients with HF. Twenty-seven patients with mild HF, all initially treated with carvedilol, were randomized to a two-month treatment with carvedilol, metoprolol tartrate or metoprolol succinate. Venous occlusion plethysmography, 24-hour blood pressure and heart rate measurements were done before and after a two-month treatment period. Endothelium-dependent vasodilatation was not affected by changing from carvedilol to either metoprolol tartrate or metoprolol succinate. The relative forearm blood flow at the highest dose of serotonin was 2.42 ± 0.33 in the carvedilol group at baseline and 2.14 ± 0.24 after two months continuation of carvedilol (P = 0.34); 2.57 ± 0.33 before metoprolol tartrate treatment and 2.42 ± 0.55 after treatment (p = 0.74) and in the metoprolol succinate group 1.82 ± 0.29 and 2.10 ± 0.37 before and after treatment, respectively (p = 0.27). Diurnal blood pressures as well as heart rate were also unchanged by changing from carvedilol to metoprolol tartrate or metoprolol succinate. Endothelial function remained unchanged when switching the beta blocker treatment from carvedilol to either metoprolol tartrate or metoprolol succinate in this study, where blood pressure and heart rate also remained unchanged in patients with mild HF. Current Controlled Trials NCT00497003.
    Full-text · Article · Oct 2011 · Cardiovascular Diabetology
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    • "A study to compare the effects on insulin sensitivity between carvedilol and metoprolol showed that carvedilol increased the insulin sensitivity index by 9% while metoprolol decreased it by 14%.[1] In addition, in a large-scale clinical trial in the US (GEMINI [The Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives]), carvedilol was also compared with metoprolol and reported to have no effect on glycosylated hemoglobin, but did improve insulin resistance while managing BP well.[2] Another report showed that carvedilol had no negative impact on glucose metabolism but decreased the new onset of diabetes compared with other β-blockers.[29] Further to these data, in this survey we investigated the long-term effects of carvedilol on fasting blood glucose levels and its long-term safety in hypertensive patients with diabetes, as well as its safety and efficacy for long-term use in hypertensive patients in general. "
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    ABSTRACT: In Japan, when pharmaceutical companies launch a new drug, they are obligated to conduct a post-marketing survey to evaluate the safety and efficacy of the drug in accordance with Good Post-Marketing Surveillance Practice under Article 14-4 (re-examination) of the Pharmaceutical Affairs Law at contracted medical institutions. We report the results of a long-term special survey that we conducted as a post-marketing survey. The results of a prospective post-marketing survey that was conducted to assess the safety and efficacy of the β-adrenergic receptor antagonist (β-blocker) Artist® tablets 10 mg, 20 mg (carvedilol) in patients with hypertension in Japan, were investigated in order to examine the safety and efficacy of the drug during long-term treatment (18 months). Patients were carvedilol-naive and had essential hypertension or renal parenchymal hypertension. Methods: We performed this survey as a prospective cohort study (special survey) utilizing a centralized registration method over 3 years (starting from April 1994), for an observation period of 18 months of carvedilol treatment. Sixty-one medical institutions across Japan collected 380 case report forms of patients who received long-term administration of carvedilol, with 363 and 341 cases evaluated for safety and efficacy, respectively. The discontinuation rate was 7.2% and the incidence of adverse drug reactions was 5.23% (19 of 363) in the safety population. There was no significant change in fasting plasma glucose levels from baseline (118.1 ± 46.5 mg/dL) to after carvedilol treatment (114.6 ± 43.3 mg/dL).[n = 141; p = 0.310]. In 341 evaluable patients in the efficacy population, decreases in both blood pressure and pulse rate were statistically significant at all assessment points in comparison with baseline data (p < 0.001). Similarly, in hypertensive patients with diabetes mellitus, decreases in blood pressure were statistically significant at all assessment points in comparison with baseline data (p < 0.001). The results of this study show that carvedilol exerted stable antihypertensive effects leading to favorable blood pressure control throughout long-term treatment, without showing any safety concerns. It was concluded that there were no clinically significant issues in terms of safety or efficacy with the long-term treatment of carvedilol in patients with hypertension.
    Preview · Article · Jun 2011
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