European Heart Journal Advance Access originally published online on November 2, 2005
European Heart Journal 2006 27(1):5-6; doi:10.1093/eurheartj/ehi624
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Ranolazine is associated with cardiovascular and metabolic improvement: a win–win for patients with diabetes
University of Florida, College of Medicine, Division of Cardiovascular Medicine, 1600 SW Archer Road, Gainesville, FL, USA
* Corresponding author. E-mail address: pepincj{at}medicine.ufl.edu
This editorial refers to ‘Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes’
by A. Timmis et al., on page 42
Ranolazine is a novel therapeutic agent which increases exercise duration and time to angina episodes in patients with persistent chronic angina pectoris. These benefits have been observed following monotherapy and in combination with ß-blockers and calcium antagonists.1 Although the mechanism of action of ranolazine is not completely understood, emerging data suggest that ranolazine may be a potent and selective inhibitor of the late sodium current across the membrane of cardiomyocytes, which may result in improved diastolic function, microvascular flow, and cardiac efficiency without altering blood pressure, heart rate, or contractility.2
Timmis et al.,3 focus on a particularly high-risk group of patients with chronic angina, those with diabetes mellitus, enrolled in CARISA.1 In patients with coronary artery disease, we have found that diabetes is associated with approximately double the risk for adverse cardiovascular outcomes and aggressive control of blood pressure is associated with significant reduction in diabetes risk.4,5 Antianginal and antihypertensive regimens often contain drugs (e.g. ß-blockers and thiazide diuretics) that alter glucose metabolism and/or insulin sensitivity and thus, negatively impact glucose and HbA1c in those with diabetes. In patients at high risk of developing diabetes, these regimens may promote diabetes6 and lead to adverse cardiovascular outcomes.7 When prescribing cardiovascular regimens for the increasing numbers of diabetic or insulin resistant patients that we are seeing, consideration should be given not only on the intended short-term therapeutic benefit (e.g. reduced symptoms), but also to the potential for detrimental metabolic impact over the longer term.
In the last decade, several large, contemporary hypertension trials have compared regimens containing either ß-blockers and/or diuretics with regimens containing calcium antagonists and/or angiotensin-converting enzyme (ACE)-inhibitors. Rates of newly diagnosed diabetes are consistently and significantly higher in patients receiving regimens containing primarily ß-blockers and/or diuretics.6 Therefore, identification of drugs without adverse, or preferably, with beneficial metabolic effects is critical to the future care of the growing number of patients with diabetes or insulin resistance.
Timmis et al.3 provide data to suggest that the ability of ranolazine to improve exercise time and reduce angina symptoms in patients with diabetes does not differ compared with those without diabetes. Additionally, an exploratory analysis provides data to support the notion that ranolazine may improve metabolic function compared with baseline, illustrated by a significant reduction in HbA1C. This reduction in HbA1C was observed despite chronic use of insulin and/or oral hypoglycaemic agents in all of the diabetic patients at baseline. An increase in the percentage of diabetic patients with HbA1C <7% compared with baseline, a value associated with good diabetes control, is also noted.
As the reduction in HbA1c was greatest in diabetics taking insulin, the authors speculate that in exogenous insulin users, ranolazine may be enhancing insulin sensitivity. Though Timmis discounts this, an alternate theory could be that ranolazine's ability to increase exercise tolerance further translated to increased leisure time physical activity as well as total daily activity. Walking just 30 min/day, most days of the week, has been associated with a reduction in HbA1c.8 Improving exercise tolerance improves vascular and microvascular function, and has been suggested to improve metabolic function in diabetic patients.
As described in CARISA,1 in addition to the randomly assigned ranolazine or placebo, for angina control patients also received either atenolol 50 mg, amlodipine 5 mg, or diltiazem 180 mg. Although the distribution of those with and without diabetes receiving these concomitant therapies is not provided in the current analyses, we speculate that the magnitude of change observed in HbA1c in both diabetics and non-diabetics taking the combination of atenolol and ranolazine may have been substantially reduced compared with those taking a calcium antagonist and ranolazine, as calcium antagonists are thought to be metabolically neutral,9 whereas ß-blockers are known to increase insulin resistance.10
Ranolazine significantly improves angina in diabetic and non-diabetic patients receiving maximally tolerated doses of available anti-angina agents. We are encouraged that in diabetics, regardless of insulin use, ranolazine was also associated with a reduction in HbA1c concentration. This finding makes ranolazine an attractive alternative to ß-blockers for treatment of persistent angina, particularly in diabetic patients, where outcomes have been closely linked with glucose control.
Although the data reported here represent short-term use of ranolazine, long-term studies of ranolazine should provide additional information related to the clinical importance of its ability to positively impact metabolic function. We encourage continued investigation of ranolazine with focus on efforts to better understand the impact of ranolazine on insulin resistance in those with metabolic syndrome, a growing population often associated with chronic angina. Ranolazine has the potential to become an anti-anginal agent of choice in patients at high risk of developing diabetes, due to its apparent beneficial metabolic effects.
As these data are based on an unplanned, retrospective analysis, they require confirmation in prospective studies. Assuming these findings are reproduced, particularly in diabetic patients with other adverse cardiovascular comorbidities, the mechanistic pathways whereby ranolazine reduces HbA1c require thorough investigation.
Aggressive use of anti-anginal and anti-hypertensive agents that facilitate glycaemic control in diabetic and pre-diabetic patients is likely to improve cardiovascular risk factors, and has the potential to translate to reduced cardiovascular outcomes over the long-term.
Conflict of interest: R.C.D. has no conflict of interest. C.J.P. has received grant funding (research and educational) from, and served as a consultant to, CV Therapeutics.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehi495 
References
- Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J, Wang W, Skettino SL, Wolff AA. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA 2004;291:309–316.
[Abstract/Free Full Text] - Tavazzi L. Ranolazine, a new antianginal drug. Future Cardiol 2005;1:447–455.[CrossRef]
- Timmis A, Chaitman BR, Crager M. Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes. Eur Heart J 2006;27:42–48. First published on September 21, 2005, doi:10.1093/eurheartj/ehi495.
[Abstract/Free Full Text] - Bakris GL, Gaxiola E, Messerli FH, Mancia G, Erdine S, Cooper-DeHoff R, Pepine CJ. Clinical outcomes in the diabetes cohort of the INternational VErapamil SR-Trandolapril study. Hypertension 2004;44:637–642.
[Abstract/Free Full Text] - Pepine CJ, Handberg EM, Cooper-DeHoff RM, Marks RG, Kowey P, Messerli FH, Mancia G, Cangiano JL, Garcia-Barreto D, Keltai M, Erdine S, Bristol HA, Kolb HR, Bakris GL, Cohen JD, Parmley WW. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil–Trandolapril Study (INVEST): a randomized controlled trial. JAMA 2003;290:2805–2816.
[Abstract/Free Full Text] - Pepine CJ, Cooper-Dehoff RM. Cardiovascular therapies and risk for development of diabetes. J Am Coll Cardiol 2004;44:509–512.
[Abstract/Free Full Text] - Verdecchia P, Reboldi G, Angeli F, Borgioni C, Gattobigio R, Filippucci L, Norgiolini S, Bracco C, Porcellati C. Adverse prognostic significance of new diabetes in treated hypertensive subjects. Hypertension 2004;43:963–969.
[Abstract/Free Full Text] - Di Loreto C, Fanelli C, Lucidi P, Murdolo G, De Cicco A, Parlanti N, Ranchelli A, Fatone C, Taglioni C, Santeusanio F, De Feo P. Make your diabetic patients walk: long-term impact of different amounts of physical activity on type 2 diabetes. Diabetes Care 2005;28:1295–1302.
[Abstract/Free Full Text] - Tatti P, Pahor M, Byington RP, Di Mauro P, Guarisco R, Strollo G, Strollo F. Outcome results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care 1998;21:597–603.[Abstract]
- Samuelsson O, Hedner T, Berglund G, Persson B, Andersson OK, Wilhelmsen L. Diabetes mellitus in treated hypertension: incidence, predictive factors and the impact of non-selective beta-blockers and thiazide diuretics during 15 years treatment of middle-aged hypertensive men in the Primary Prevention Trial Goteborg, Sweden. J Hum Hypertens 1994;8:257–263.[ISI][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
Related articles in EHJ:
- Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes
- Adam D. Timmis, Bernard R. Chaitman, and Michael Crager
EHJ 2006 27: 42-48.[Abstract] [Full Text]
This article has been cited by other articles:
|
|
 |
|
  J. J. Bax, B. De Bruyne, A. K. Gitt, S. Kristensen, C. Linde, D. Poldermans, F. J. Pinto, P. Ponikowski, B. D. Prendergast, E. Abagiti-Rosei, et al. Highlights of the 2006 Scientific Sessions of the European Society of Cardiology: Barcelona, Spain, September 2-5, 2006 J. Am. Coll. Cardiol., December 19, 2006; 48(12): 2564 - 2574. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||