We thank Dr. Bell for his interest in our paper. He states that metformin has never been

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1 ENDOCRINE PRACTICE Rapid Electronic Article in Press Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and accepted for publication, but have yet to be edited, typeset and finalized. This version of the manuscript will be replaced with the final, published version after it has been published in the print edition of the journal. The final, published version may differ from this proof. DOI: /EP LT 2016 AACE. LETTER TO THE EDITOR To the Editor: We thank Dr. Bell for his interest in our paper. He states that metformin has never been shown to decrease sympathetic activity (SA) in humans, citing the work of Gudbjörnsdottir showing no effect of metformin on muscle sympathetic nerve activity or on norepinephrine spillover in nondiabetic, insulin resistant men (1). We have discussed the limitations of that study in detail (2, 3), including the fact that myocardial SA was not measured. This is important because regional and systemic SA are known to diverge in some situations (4). In our review, we conclude that metformin lowers blood pressure when it is given to people with elevated blood pressure. We also cite studies showing a reduction in circulating NE concentrations (5) and an increase in R-R variability (6) in people treated with metformin as at least indirect evidence of decreased SA. Taking these points together, it seems premature to exclude an effect of metformin on SA. It should be pointed out that circulating catecholamines tend to be in the normal range in outpatients with heart failure in spite of the fact that these individuals exhibit sympathetic activation (7). It was perhaps an oversimplification on our part to suggest that weight loss, which is certainly associated with decreases in SA, would necessarily be responsible for a decrease in SA in metformin-treated patients. It is reasonable to say that metformin is a weight neutral drug; although DOI: /EP LT 2016 AACE

2 2 metformin treatment produces a sustained decrease in energy intake (8), changes in weight in response to metformin treatment are variable for reasons we discuss in our review. Metformin therapy does tend to blunt weight gain when given chronically (9). Rather, SA is stimulated acutely by the raised insulin levels that occur in response to absorption of a mixed meal (4, 10) or insulin infusion (10, 11). This insulin-mediated sympathetic activation and the increase in blood pressure that accompanies it (10) appear to be dose-related effects (11). Metformin therapy lowers postprandial insulin levels (12) and would therefore have the potential to blunt prandial sympathetic activation by insulin via the combined effects of reduced energy intake and delayed carbohydrate absorption. In an analogous fashion, a low glycemic index diet lowers blood pressure, possibly due to a decrease in SA resulting from a decrease in postprandial insulin concentrations, in the absence of weight loss (13). Additional research is needed to clarify the effects of metformin on regional and systemic SA. There is little question that 5 -AMP kinase (5-AMPK) is activated in response to treatment with metformin. Whether increased 5-AMPK is responsible for the apparent improvement in heart failure outcomes in metformin-treated patients is less clear, however. Certainly, metformin has been shown to activate 5-AMPK in the heart, although the use of in vitro metformin concentrations that are several orders of magnitude greater than therapeutic levels (14) is problematic. If this effect results in an increase in cellular ATP, it would have the potential to preserve myocardial mass and function. On the other hand, if metformin s effects are independent of 5-AMPK, or if the increase in 5-AMPK observed with metformin treatment is due to ATP depletion (ie, a secondary increase in 5- AMPK in its role as a fuel sensor), then the implications would be quite different. Foretz et al. have shown that in hepatic AMPK-knockout mice, baseline glucose metabolism and the hypoglycemic effect of metformin are intact. Further, they demonstrated that the inhibitory effect of metformin on

3 3 gluconeogenesis was amplified in AMPK-deficient hepatocytes and that this inhibition correlated with a reduction in intracellular ATP (15). Thus, the action of metformin in the liver appear to be independent of AMPK, and the increases in AMPK likely mediated by a decreased energy state. Whether these observations in the liver apply to the myocardium is uncertain, but indirect evidence indicates that this may be the case. van der Meer, et al. demonstrated striking effects of 6 months of metformin therapy on cardiac function in patients with type 2 diabetes. They found borderline decreases in left ventricular mass (p = 0.07) and stroke volume (p = 0.09), together with significant decreases in cardiac index and cardiac work. This was accompanied by a decrease in myocardial fat oxidation (16), suggestive of a global decrease in myocardial oxygen consumption. These effects would be difficult to explain by an increase in myocardial ATP. In contrast, in an ischemia-reperfusion model, 5-AMPK accumulation alters myocardial fuel selection by accelerating fatty acid oxidation rates (17), which would be expected to promote inefficiency in myocardial energetics (18). The changes observed in left ventricular mass, stroke volume, cardiac index and cardiac work in patients treated with metformin are consistent with decreased cardiac demand and would be plausible consequences of decreased SA. Conversely, norepinephrine infusion increases cardiac work and oxygen consumption (19). Further, in patients with and without hypertension, increases in left ventricular mass appear to be closely linked to increased release of norepinephrine from the heart (20). In summary, it is unclear at present whether increased myocardial AMPK is a mediator or a mere marker of apparent beneficial effects of metformin use in heart failure patients. Similarly, although there is circumstantial evidence to suggest that metformin may reduce myocardial SA, additional studies are clearly needed, ideally using a direct measurement of cardiac SA such as such as norepinephrine spillover. Finally, although the association between metformin use and

4 4 improvement in heart failure outcomes is strong, a prospective randomized trial is needed before concluding that there is a causal relationship. Abeer Anabtawi, MD John M. Miles, MD University of Kansas Medical Center REFERENCES 1. Gudbjornsdottir S, Friberg P, Elam M, Attvall S, Lonnroth P, and Wallin BG. The effect of metformin and insulin on sympathetic nerve activity, norepinephrine spillover and blood pressure in obese, insulin resistant, normoglycemic, hypertensive men. Blood Press. 1994;3: Anabtawi A, and Miles JM. Metformin: nonglycemic effects and potential novel indications. Endocr Pract. 2016;22: Miles JM, Rule AD, and Borlaug BA. Use of metformin in diseases of aging. Curr Diab Reports. 2014;14(6): Patel JN, Eisenhofer G, Coppack SW, and Miles JM. Norepinephrine spillover in forearm and subcutaneous adipose tissue before and after eating. J Clin Endocrinol Metab. 1999;84: Giugliano D, De Rosa N, Di Maro G, et al. Metformin improves glucose, lipid metabolism, and reduces blood pressure in hypertensive, obese women. Diabetes Care. 1993;16:

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