NEWS & VIEWS All of the studies demonstrated that presence of the c.617T>G PRKACA mutation is mutually exclusive with other genetic lesions that have been previously identified in adrenocortical neoplasias, such as mutations in CTNN1B1 and GNAS. This obser vation suggests that mutations in these genes probably result in functionally similar or equivalent phenotypic states. In the adrenal cortex, PRKACA encodes PKA Cα, which is the most abundantly expressed isoform of the catalytic subunits of PKA.7 The identification of a hotspot mutation in PRKACA is consistent with a hypothesis that a gain-of-function mutation leads to constitutive PKA activity in adreno cortical tumours. Structural analyses of PKA also support this hypothesis; Leu206 is in an evolutionarily conserved region of the protein, the P+1 loop, which is responsible for catalytic activity. This region binds the regulatory subunit, encoded by PRKAR1A, and Leu206 forms part of the hydrophobic cleft of the catalytic domain.9,10 Substitution of arginine for leucine at position 206 presumably disrupts the interaction between the catalytic and regulatory subunits, which leads to constitutive PKA activation.5–7 Each of the groups reported results from functional studies that support this proposed mechanism. Using fluorescence reso nance energy transfer microscopy and a reporter for PKA activity, Beuschlein and co-workers showed that the Leu206Arg mutation conferred resistance to suppression of PKA activity by the regulatory subunit. Cotransfection experiments with mutant and nonmutant catalytic subunits of PKA indicated that the hotspot mutation functioned in a dominant fashion.5 Goh and colleagues used biochemical approaches to demonstrate that wild-type PKA Cα interacts with the regulatory sub unit, PRKAR1A, whereas the PKA Cα Leu206Arg mutant does not. They further demonstrated that expression of the PKA Cα Leu206Arg protein in HEK298T cells resulted in significantly higher levels of phosphorylated CREB than expression of wildtype PKA Cα. Finally, immunohistochemical staining for phosphorylated CREB in ACAs showed higher levels of immunoreactivity in ACAs with the c.617T>G PRKACA hotspot mutation than in ACAs without the mutation.7 In addition to gain-of-function experiments similar to those described above, Cao and co-workers performed rigorous bioinformatic gene expression analysis to determine the contribution of the c.617T>G 448 | AUGUST 2014 | VOLUME 10
PRKACA mutation to cortisol production. Using RNA-sequence data from 44 tumours in their ACA cohort, they examined gene expression in tumours with wild-type and c.617T>G PRKACA genes. Bioinformatic analysis showed that genes associated with the Gene Ontology terms 10 ‘biosynthesis and metabolism of steroid and cholesterol’ and ‘response to chemical stimulus’ were significantly enriched in ACAs with the c.617T>G PRKACA mutation. In addition, expression of a group of genes that contribute to steroidogenesis and tumour growth and survival, such as STAR, was upregulated in the tumours with the hotspot mutation.6 Collectively, the experiments from all three groups support the hypothesis that the PKA Cα Leu206Arg protein is resistant to suppression by PKA regulatory subunits resulting in enhanced and constitutive catalytic PKA activity, which might lead to excess cortisol production. The identification of c.617T>G PRKACA mutations in a high proportion of cortisolproducing ACAs provides an example of the genotype–phenotype correlations often observed in endocrine neoplasms. Many factors probably contribute to this phe nomenon; however, the correlation might reflect the highly differentiated state of many endocrine tumours with their genomic simplicity and low overall mutation densities. These parallel discoveries illustrate the power of next-generation sequencing as a genetic discovery tool. These findings also represent major advances in understanding and developing potential treatments for the most common primary adrenal cause of Cushing syndrome.
Department of Pathology, 1150 West Medical Centre Drive, MSRB1 4520D, University of Michigan Health System, Ann Arbor, MI 48109, USA. [email protected] Competing interests The author declares no competing interests. 1.
Yaneva, M., Vandeva, S., Zacharieva, S., Daly, A. F. & Beckers, A. Genetics of Cushing’s syndrome. Neuroendocrinology 92 (Suppl. 1), 6–10 (2010). 2. Bossis, I. et al. Protein kinase A and its role in human neoplasia: the Carney complex paradigm. Endocr. Relat. Cancer 11, 265–280 (2004). 3. Almeida, M. Q. & Stratakis, C. A. How does cAMP/protein kinase A signaling lead to tumors in the adrenal cortex and other tissues? Mol. Cell Endocrinol. 336, 162–168 (2011). 4. Yu, B., Ragazzon, B., Rizk-Rabin, M. & Bertherat, J. Protein kinase A alterations in endocrine tumors. Horm. Metab. Res. 44, 741–748 (2012). 5. Beuschlein, F. et al. Constitutive activation of PKA catalytic subunit in adrenal Cushing’s syndrome. N. Engl. J. Med. 370, 1019–1028 (2014). 6. Cao, Y. et al. Activating hotspot L205R mutation in PRKACA and adrenal Cushing’s syndrome. Science 344, 913–917 (2014). 7. Goh, G. et al. Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors. Nat. Genet. 46, 613–617 (2014). 8. Moore, M. J., Adams, J. A. & Taylor, S. S. Structural basis for peptide binding in protein kinase A. Role of glutamic acid 203 and tyrosine 204 in the peptide-positioning loop. J. Biol. Chem. 278, 10613–10618 (2003). 9. Yang, J., Ten Eyck, L. F., Xuong, N. H. & Taylor, S. S. Crystal structure of a cAMPdependent protein kinase mutant at 1.26A: new insights into the catalytic mechanism. J. Mol. Biol. 336, 473–487 (2004). 10. Ashburner, M. et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat. Genet. 25, 25–29 (2000).
DIABETES
Glycaemia and insulin after acute myocardial infarction Paresh Dandona and Ajay Chaudhuri
The long-term outcomes of the DIGAMI 1 study indicate that intensive glucose lowering could be beneficial after an acute myocardial infarction in patients with type 2 diabetes mellitus. However, questions have been raised about whether it is acute or long-term glycaemic control or insulin that is beneficial. Dandona, P. & Chaudhuri, A. Nat. Rev. Endocrinol. 10, 448–450 (2014); published online 1 July 2014; doi:10.1038/nrendo.2014.101
The publication of the long-term outcomes of the DIGAMI 1 study, which compared clinical outcomes in patients with acute
myocardial infarction (AMI) after intensive glycaemic control with insulin with those receiving conventional control, is important www.nature.com/nrendo
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS for several reasons. Firstly, it is one of the longest follow-up studies in patients with AMI, covering a period of 20 years. Secondly, 89% of the patients were followed up to the time of their death. Thirdly, over 90% of patients completed follow-up. The patients included in the study were admitted to 19 Swedish centres and had type 2 diabetes mellitus, with a blood glucose concentration of >11.0 mmol/l. The primary end point of the study was mortality; patients who underwent intensive treatment had a life expectancy of 7 years compared with 4.7 years in control individuals.1
‘‘
The results from studies using insulin, glucose and potassium have been variable…
’’
The benefits of intensive glycaemic control were most notable in the low risk and no previous insulin group; they were also important in the high-risk group on insulin, but this group was small. Levels of blood glucose and HbA1c on admission predicted mortality in control individuals, but not in patients who received intensive treatment. As hyperglycaemia on admission and its management thereafter in patients with AMI are important determinants of mortality and morbidity, the findings of this study add to the evidence regarding the potential benefit of intensive glycaemic control with insulin in patients with AMI. In their discussion, the authors link the increased longevity in the intensively treated group primarily to the long-term lowering of blood levels of glucose in spite of the absence of data on glycaemia beyond 1 year. In doing so, the authors fail to acknowledge the substantial evidence that supports the conclusion that acute reduction of glucose levels with an insulin infusion at the time of AMI could have had a considerable role in improving the long-term outcomes in the intensively treated group. The strategy of treating patients with insulin, glucose and potassium started with Demetrio Sodi-Pallares in 1962. The results from studies using insulin, glucose and potassium have been variable and no clear and definitive conclusions can be drawn. However, a careful analysis suggests that studies that ensured a substantial fall in blood glucose or the maintenance of euglycaemia with insulin infusion resulted in reduced morbidity and mortality in patients with AMI. The Hyperglycemia: Intensive Insulin Infusion in Infarction trial found a reduced
incidence of congestive cardiac failure and reinfarction, and another study showed a reduction in the incidence of major adverse cardiac events.2,3 A study published in 2004 found a reduction in infarct size in addition to an antiinflammatory and a profibrinolytic action of insulin.4 The benefits of reducing glucose levels with insulin on infarct size, inflammatory cytokines and mediators of apoptosis have been confirmed in plasma and periinfarct myocardial biopsy samples. 5 Even studies that did not show an improvement with insulin, glucose and potassium (as an infusion of excessive glucose resulted in hyperglycaemia in spite of co-infusion of insulin), demonstrated an improvement in cardiac outcomes in the treated patients compared with patients with similar glucose concentrations who received usual care.6 In the past 2 years, findings from IMMEDIATE on the use of insulin, glucose and potassium in patients with AMI demonstrated that insulin, glucose and potassium infusion soon after the onset of symptoms (in the ambulance) led to a notable reduction in in-hospital mortality and cardiac arrest.7 In addition, a marked reduction in the size of the infarct was observed on single-photon emission CT. This reduction was ~80% in patients with a ST elevation myocardial infarction. While the benefits of this treatment were evident in patients undergoing coronary angioplasty, patients who had not undergone this procedure also benefited considerably. This study is important as it demonstrates an improvement in outcomes in spite of the induction of hyperglycaemia following infusion of large amounts of glucose. This finding emphasizes the cardinal role of insulin in cardioprotection, even in the presence of hyperglycaemia. In the BIOMArCS 2 study, beneficial effects of lowering levels of glucose with insulin on infarct size (estimated by measuring high-sensitivity troponin T values at 72 h) were not observed.8 However, a strong statistical trend indicated benefits of intensive control on infarct size measured by myocardial perfusion scintigraph singlephoton emission CT. The number of deaths and second myocardial infarctions were greater in the intensive arm than in control individuals; however, the study was not sufficiently powered to detect the effects of the treatment on clinical end points, which has led to criticism of this study finding.9 Another major issue that arises out of the results of a treatment that consists of administering insulin and glucose is whether it is
NATURE REVIEWS | ENDOCRINOLOGY
insulin or the reduction in glycaemia that leads to the improvement in outcomes. In patients with AMI, hyperglycaemia on admission and after admission are associated with increased short-term and longterm mortality and infarct size, whereas a reduction in levels of glucose after admission is associated with improved mortality outcomes and a smaller infarct.10 Insulin infusion without a change in glycaemic concentrations can result in a notable reduction in infarct size. 4 The IMMEDIATE study also improved clinical outcomes and induced a reduction in infarct size in spite of the induction of hyperglycaemia.7 Both studies point to an important role of insulin in cardioprotection. The IMMEDIATE study takes the role of insulin in cardioprotection a step further, as it shows that if administered early enough (before reperf usion), insulin can actually prevent the effects of hyperglycaemia induced by the concomitant glucose infusion. As studies have demonstrated a greater benefit in patients who had an improvement in glycaemia,2,3 it seems that both insulin and the reversal of hyper glycaemia have an important role in cardio protection. However, the role of insulin seems to be the dominant one in view of the results of the IMMEDIATE study.
‘‘
…both insulin and the reversal of hyperglycaemia have an important role in cardioprotection
’’
The other important issue raised by the DIGAMI 1 follow-up data is whether the role of long-term reduction in glycaemic control is as important as that of insulin and glycaemic control during the acute admission and treatment period. The authors emphasize the role of long-term glycaemic control, citing the long-term results of the DCCT–EDIC and UKPDS studies. While long-term normoglycaemia might reduce the rate of atherogenesis, it is equally possible and likely that the acute treatment results in sufficient cardioprotection to ensure longevity. These important issues need to be borne in mind when considering future studies of the treatment of AMI. Any regime based on the correction of hyperglycaemia has to use intravenous insulin that must be administered as early as possible to ensure maximal benefit. Such studies should also have an arm assessing the size of the infarct so that the role of acute cardioprotection is confirmed further. VOLUME 10 | AUGUST 2014 | 449
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS State University of New York at Buffalo, Division of Endocrinology, Diabetes and Metabolism, Buffalo, NY 14221, USA (P.D., A.C.). Correspondence to: P.D. [email protected] Competing interests P.D. and A.C. have been speakers for Lilly, Novo‑Nordisk and Sanofi Aventis. 1.
2.
3.
4.
Ritsinger, V. et al. Intensified insulin-based glycaemic control after myocardial infarction: mortality during 20 year follow-up of the randomised Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI 1) trial. Lancet Diabetes Endocrinol. http:// dx.doi.org/10.1016/S2213-8587(14)70088-9. Cheung, N. W., Wong, V. W. & McLean, M. The Hyperglycemia: Intensive Insulin Infusion in Infarction (HI‑5) study: a randomized controlled trial of insulin infusion therapy for myocardial infarction. Diabetes Care 29, 765–770 (2006). Krljanac, G. et al. Effects of glucose–insulin– potassium infusion on ST‑elevation myocardial infarction in patients treated with thrombolytic therapy. Am. J. Cardiol. 96, 1053–1058 (2005). Chaudhuri, A. et al. Anti-inflammatory and profibrinolytic effect of insulin in acute
ST‑segment‑elevation myocardial infarction. Circulation 109, 849–854 (2004). 5. Marfella, R. et al. Tight glycemic control reduces heart inflammation and remodeling during acute myocardial infarction in hyperglycemic patients. J. Am. Coll. Cardiol. 53, 1425–1436 (2009). 6. Mehta, S. R. et al. Effect of glucose–insulin– potassium infusion on mortality in patients with acute ST‑segment elevation myocardial infarction: the CREATE–ECLA randomized controlled trial. JAMA 293, 437–446 (2005). 7. Selker, H. P. et al. Out‑of‑hospital administration of intravenous glucose–insulin–potassium in patients with suspected acute coronary syndromes: the IMMEDIATE randomized controlled trial. JAMA 307, 1925–1933 (2012). 8. de Mulder, M. et al. Intensive glucose regulation in hyperglycemic acute coronary syndrome: results of the randomized BIOMarker study to identify the acute risk of a coronary syndrome‑2 (BIOMArCS‑2) glucose trial. JAMA Intern. Med. 173, 1896–1904 (2013). 9. Dandona, P. & Boden, W. E. Intensive glucose control in hyperglycemic patients with acute coronary syndromes: still smoke, but no fire. JAMA Intern. Med. 173, 1905–1906 (2013). 10. Kosiborod, M. et al. Glucose normalization and outcomes in patients with acute myocardial infarction. Arch. Intern. Med. 169, 438–446 (2009).
THERAPY
Caloric and fat intake in statin users Vasilios G. Athyros and Dimitri P. Mikhailidis
A new report examines trends in caloric and fat intake—known modifiers of cardiovascular risk—among statin users and non-users. As statins are the most effective hypolipidaemic agents currently used to prevent cardiovascular disease, it is important to understand how statin treatment affects dietary attitude. Athyros, V. G. & Mikhailidis, D. P. Nat. Rev. Endocrinol. 10, 450–451 (2014); published online 3 June 2014; doi:10.1038/nrendo.2014.82
In a recent cross-sectional study, Sugiyama and colleagues compared the caloric and fat intake of statin users with that of nonusers in the National Health and Nutrition Examination Survey (NHANES) during the period 1999–2010.1 Caloric and fat intake increased by 9.6% (95% CI 1.8–18.1, P = 0.02) and 14.4% (95% CI 3.8–26.1, P = 0.007), respectively, among statin users and no significant change was observed in non-users.1 The proportion of calories obtained from fat increased during the decade studied from 32.3% to 33.7%, but did not exceed the upper limit (35%) recommended in the guidelines issued by the Adult Treatment Panel III of the National Cholesterol Education Program.2 During the period 2009–2010, the proportion of calories obtained from saturated fat was 11.0% and the cholesterol intake was 450 | AUGUST 2014 | VOLUME 10
278 mg daily;1 levels above the recommended limits of 7% and 200 mg daily, respectively.2 Although these dietary changes were more pronounced in statin users, a comparable trend was recorded in adults in the Framingham Heart Study (1991–2008),3 suggesting a similar trend in increased food and caloric intake in the entire US adult population over both decades. The increasing trend in food and caloric intake suggests that either physicians do not sufficiently emphasize the significance of lifestyle changes to their patients or that patients do not comply with this advice, possibly because they feel protected by statin treatment. The doubling in statin users observed by Sugiyama and colleagues1 over the decade of observation might
have ‘overwhelmed’ prescribing physicians, resulting in them mainly focusing on the statin aspects of treatment. As the Adult Treatment Panel III guidelines recommend a restriction in caloric and fat intake to accompany the lipid targets set for hypolipidaemic drug treatment,2 the lack of dietary compliance suggests suboptimal treatment of the patients who were prescribed statins.2 Optimal long-term lifestyle changes are probably better described by the seven metrics of ideal cardiovascular health adopted by the American Heart Association (AHA).4 The AHA suggests ideal health behaviours, such as not smoking, a BMI
PRKACA mutation to cortisol production. Using RNA-sequence data from 44 tumours in their ACA cohort, they examined gene expression in tumours with wild-type and c.617T>G PRKACA genes. Bioinformatic analysis showed that genes associated with the Gene Ontology terms 10 ‘biosynthesis and metabolism of steroid and cholesterol’ and ‘response to chemical stimulus’ were significantly enriched in ACAs with the c.617T>G PRKACA mutation. In addition, expression of a group of genes that contribute to steroidogenesis and tumour growth and survival, such as STAR, was upregulated in the tumours with the hotspot mutation.6 Collectively, the experiments from all three groups support the hypothesis that the PKA Cα Leu206Arg protein is resistant to suppression by PKA regulatory subunits resulting in enhanced and constitutive catalytic PKA activity, which might lead to excess cortisol production. The identification of c.617T>G PRKACA mutations in a high proportion of cortisolproducing ACAs provides an example of the genotype–phenotype correlations often observed in endocrine neoplasms. Many factors probably contribute to this phe nomenon; however, the correlation might reflect the highly differentiated state of many endocrine tumours with their genomic simplicity and low overall mutation densities. These parallel discoveries illustrate the power of next-generation sequencing as a genetic discovery tool. These findings also represent major advances in understanding and developing potential treatments for the most common primary adrenal cause of Cushing syndrome.
Department of Pathology, 1150 West Medical Centre Drive, MSRB1 4520D, University of Michigan Health System, Ann Arbor, MI 48109, USA. [email protected] Competing interests The author declares no competing interests. 1.
Yaneva, M., Vandeva, S., Zacharieva, S., Daly, A. F. & Beckers, A. Genetics of Cushing’s syndrome. Neuroendocrinology 92 (Suppl. 1), 6–10 (2010). 2. Bossis, I. et al. Protein kinase A and its role in human neoplasia: the Carney complex paradigm. Endocr. Relat. Cancer 11, 265–280 (2004). 3. Almeida, M. Q. & Stratakis, C. A. How does cAMP/protein kinase A signaling lead to tumors in the adrenal cortex and other tissues? Mol. Cell Endocrinol. 336, 162–168 (2011). 4. Yu, B., Ragazzon, B., Rizk-Rabin, M. & Bertherat, J. Protein kinase A alterations in endocrine tumors. Horm. Metab. Res. 44, 741–748 (2012). 5. Beuschlein, F. et al. Constitutive activation of PKA catalytic subunit in adrenal Cushing’s syndrome. N. Engl. J. Med. 370, 1019–1028 (2014). 6. Cao, Y. et al. Activating hotspot L205R mutation in PRKACA and adrenal Cushing’s syndrome. Science 344, 913–917 (2014). 7. Goh, G. et al. Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors. Nat. Genet. 46, 613–617 (2014). 8. Moore, M. J., Adams, J. A. & Taylor, S. S. Structural basis for peptide binding in protein kinase A. Role of glutamic acid 203 and tyrosine 204 in the peptide-positioning loop. J. Biol. Chem. 278, 10613–10618 (2003). 9. Yang, J., Ten Eyck, L. F., Xuong, N. H. & Taylor, S. S. Crystal structure of a cAMPdependent protein kinase mutant at 1.26A: new insights into the catalytic mechanism. J. Mol. Biol. 336, 473–487 (2004). 10. Ashburner, M. et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat. Genet. 25, 25–29 (2000).
DIABETES
Glycaemia and insulin after acute myocardial infarction Paresh Dandona and Ajay Chaudhuri
The long-term outcomes of the DIGAMI 1 study indicate that intensive glucose lowering could be beneficial after an acute myocardial infarction in patients with type 2 diabetes mellitus. However, questions have been raised about whether it is acute or long-term glycaemic control or insulin that is beneficial. Dandona, P. & Chaudhuri, A. Nat. Rev. Endocrinol. 10, 448–450 (2014); published online 1 July 2014; doi:10.1038/nrendo.2014.101
The publication of the long-term outcomes of the DIGAMI 1 study, which compared clinical outcomes in patients with acute
myocardial infarction (AMI) after intensive glycaemic control with insulin with those receiving conventional control, is important www.nature.com/nrendo
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS for several reasons. Firstly, it is one of the longest follow-up studies in patients with AMI, covering a period of 20 years. Secondly, 89% of the patients were followed up to the time of their death. Thirdly, over 90% of patients completed follow-up. The patients included in the study were admitted to 19 Swedish centres and had type 2 diabetes mellitus, with a blood glucose concentration of >11.0 mmol/l. The primary end point of the study was mortality; patients who underwent intensive treatment had a life expectancy of 7 years compared with 4.7 years in control individuals.1
‘‘
The results from studies using insulin, glucose and potassium have been variable…
’’
The benefits of intensive glycaemic control were most notable in the low risk and no previous insulin group; they were also important in the high-risk group on insulin, but this group was small. Levels of blood glucose and HbA1c on admission predicted mortality in control individuals, but not in patients who received intensive treatment. As hyperglycaemia on admission and its management thereafter in patients with AMI are important determinants of mortality and morbidity, the findings of this study add to the evidence regarding the potential benefit of intensive glycaemic control with insulin in patients with AMI. In their discussion, the authors link the increased longevity in the intensively treated group primarily to the long-term lowering of blood levels of glucose in spite of the absence of data on glycaemia beyond 1 year. In doing so, the authors fail to acknowledge the substantial evidence that supports the conclusion that acute reduction of glucose levels with an insulin infusion at the time of AMI could have had a considerable role in improving the long-term outcomes in the intensively treated group. The strategy of treating patients with insulin, glucose and potassium started with Demetrio Sodi-Pallares in 1962. The results from studies using insulin, glucose and potassium have been variable and no clear and definitive conclusions can be drawn. However, a careful analysis suggests that studies that ensured a substantial fall in blood glucose or the maintenance of euglycaemia with insulin infusion resulted in reduced morbidity and mortality in patients with AMI. The Hyperglycemia: Intensive Insulin Infusion in Infarction trial found a reduced
incidence of congestive cardiac failure and reinfarction, and another study showed a reduction in the incidence of major adverse cardiac events.2,3 A study published in 2004 found a reduction in infarct size in addition to an antiinflammatory and a profibrinolytic action of insulin.4 The benefits of reducing glucose levels with insulin on infarct size, inflammatory cytokines and mediators of apoptosis have been confirmed in plasma and periinfarct myocardial biopsy samples. 5 Even studies that did not show an improvement with insulin, glucose and potassium (as an infusion of excessive glucose resulted in hyperglycaemia in spite of co-infusion of insulin), demonstrated an improvement in cardiac outcomes in the treated patients compared with patients with similar glucose concentrations who received usual care.6 In the past 2 years, findings from IMMEDIATE on the use of insulin, glucose and potassium in patients with AMI demonstrated that insulin, glucose and potassium infusion soon after the onset of symptoms (in the ambulance) led to a notable reduction in in-hospital mortality and cardiac arrest.7 In addition, a marked reduction in the size of the infarct was observed on single-photon emission CT. This reduction was ~80% in patients with a ST elevation myocardial infarction. While the benefits of this treatment were evident in patients undergoing coronary angioplasty, patients who had not undergone this procedure also benefited considerably. This study is important as it demonstrates an improvement in outcomes in spite of the induction of hyperglycaemia following infusion of large amounts of glucose. This finding emphasizes the cardinal role of insulin in cardioprotection, even in the presence of hyperglycaemia. In the BIOMArCS 2 study, beneficial effects of lowering levels of glucose with insulin on infarct size (estimated by measuring high-sensitivity troponin T values at 72 h) were not observed.8 However, a strong statistical trend indicated benefits of intensive control on infarct size measured by myocardial perfusion scintigraph singlephoton emission CT. The number of deaths and second myocardial infarctions were greater in the intensive arm than in control individuals; however, the study was not sufficiently powered to detect the effects of the treatment on clinical end points, which has led to criticism of this study finding.9 Another major issue that arises out of the results of a treatment that consists of administering insulin and glucose is whether it is
NATURE REVIEWS | ENDOCRINOLOGY
insulin or the reduction in glycaemia that leads to the improvement in outcomes. In patients with AMI, hyperglycaemia on admission and after admission are associated with increased short-term and longterm mortality and infarct size, whereas a reduction in levels of glucose after admission is associated with improved mortality outcomes and a smaller infarct.10 Insulin infusion without a change in glycaemic concentrations can result in a notable reduction in infarct size. 4 The IMMEDIATE study also improved clinical outcomes and induced a reduction in infarct size in spite of the induction of hyperglycaemia.7 Both studies point to an important role of insulin in cardioprotection. The IMMEDIATE study takes the role of insulin in cardioprotection a step further, as it shows that if administered early enough (before reperf usion), insulin can actually prevent the effects of hyperglycaemia induced by the concomitant glucose infusion. As studies have demonstrated a greater benefit in patients who had an improvement in glycaemia,2,3 it seems that both insulin and the reversal of hyper glycaemia have an important role in cardio protection. However, the role of insulin seems to be the dominant one in view of the results of the IMMEDIATE study.
‘‘
…both insulin and the reversal of hyperglycaemia have an important role in cardioprotection
’’
The other important issue raised by the DIGAMI 1 follow-up data is whether the role of long-term reduction in glycaemic control is as important as that of insulin and glycaemic control during the acute admission and treatment period. The authors emphasize the role of long-term glycaemic control, citing the long-term results of the DCCT–EDIC and UKPDS studies. While long-term normoglycaemia might reduce the rate of atherogenesis, it is equally possible and likely that the acute treatment results in sufficient cardioprotection to ensure longevity. These important issues need to be borne in mind when considering future studies of the treatment of AMI. Any regime based on the correction of hyperglycaemia has to use intravenous insulin that must be administered as early as possible to ensure maximal benefit. Such studies should also have an arm assessing the size of the infarct so that the role of acute cardioprotection is confirmed further. VOLUME 10 | AUGUST 2014 | 449
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS State University of New York at Buffalo, Division of Endocrinology, Diabetes and Metabolism, Buffalo, NY 14221, USA (P.D., A.C.). Correspondence to: P.D. [email protected] Competing interests P.D. and A.C. have been speakers for Lilly, Novo‑Nordisk and Sanofi Aventis. 1.
2.
3.
4.
Ritsinger, V. et al. Intensified insulin-based glycaemic control after myocardial infarction: mortality during 20 year follow-up of the randomised Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI 1) trial. Lancet Diabetes Endocrinol. http:// dx.doi.org/10.1016/S2213-8587(14)70088-9. Cheung, N. W., Wong, V. W. & McLean, M. The Hyperglycemia: Intensive Insulin Infusion in Infarction (HI‑5) study: a randomized controlled trial of insulin infusion therapy for myocardial infarction. Diabetes Care 29, 765–770 (2006). Krljanac, G. et al. Effects of glucose–insulin– potassium infusion on ST‑elevation myocardial infarction in patients treated with thrombolytic therapy. Am. J. Cardiol. 96, 1053–1058 (2005). Chaudhuri, A. et al. Anti-inflammatory and profibrinolytic effect of insulin in acute
ST‑segment‑elevation myocardial infarction. Circulation 109, 849–854 (2004). 5. Marfella, R. et al. Tight glycemic control reduces heart inflammation and remodeling during acute myocardial infarction in hyperglycemic patients. J. Am. Coll. Cardiol. 53, 1425–1436 (2009). 6. Mehta, S. R. et al. Effect of glucose–insulin– potassium infusion on mortality in patients with acute ST‑segment elevation myocardial infarction: the CREATE–ECLA randomized controlled trial. JAMA 293, 437–446 (2005). 7. Selker, H. P. et al. Out‑of‑hospital administration of intravenous glucose–insulin–potassium in patients with suspected acute coronary syndromes: the IMMEDIATE randomized controlled trial. JAMA 307, 1925–1933 (2012). 8. de Mulder, M. et al. Intensive glucose regulation in hyperglycemic acute coronary syndrome: results of the randomized BIOMarker study to identify the acute risk of a coronary syndrome‑2 (BIOMArCS‑2) glucose trial. JAMA Intern. Med. 173, 1896–1904 (2013). 9. Dandona, P. & Boden, W. E. Intensive glucose control in hyperglycemic patients with acute coronary syndromes: still smoke, but no fire. JAMA Intern. Med. 173, 1905–1906 (2013). 10. Kosiborod, M. et al. Glucose normalization and outcomes in patients with acute myocardial infarction. Arch. Intern. Med. 169, 438–446 (2009).
THERAPY
Caloric and fat intake in statin users Vasilios G. Athyros and Dimitri P. Mikhailidis
A new report examines trends in caloric and fat intake—known modifiers of cardiovascular risk—among statin users and non-users. As statins are the most effective hypolipidaemic agents currently used to prevent cardiovascular disease, it is important to understand how statin treatment affects dietary attitude. Athyros, V. G. & Mikhailidis, D. P. Nat. Rev. Endocrinol. 10, 450–451 (2014); published online 3 June 2014; doi:10.1038/nrendo.2014.82
In a recent cross-sectional study, Sugiyama and colleagues compared the caloric and fat intake of statin users with that of nonusers in the National Health and Nutrition Examination Survey (NHANES) during the period 1999–2010.1 Caloric and fat intake increased by 9.6% (95% CI 1.8–18.1, P = 0.02) and 14.4% (95% CI 3.8–26.1, P = 0.007), respectively, among statin users and no significant change was observed in non-users.1 The proportion of calories obtained from fat increased during the decade studied from 32.3% to 33.7%, but did not exceed the upper limit (35%) recommended in the guidelines issued by the Adult Treatment Panel III of the National Cholesterol Education Program.2 During the period 2009–2010, the proportion of calories obtained from saturated fat was 11.0% and the cholesterol intake was 450 | AUGUST 2014 | VOLUME 10
278 mg daily;1 levels above the recommended limits of 7% and 200 mg daily, respectively.2 Although these dietary changes were more pronounced in statin users, a comparable trend was recorded in adults in the Framingham Heart Study (1991–2008),3 suggesting a similar trend in increased food and caloric intake in the entire US adult population over both decades. The increasing trend in food and caloric intake suggests that either physicians do not sufficiently emphasize the significance of lifestyle changes to their patients or that patients do not comply with this advice, possibly because they feel protected by statin treatment. The doubling in statin users observed by Sugiyama and colleagues1 over the decade of observation might
have ‘overwhelmed’ prescribing physicians, resulting in them mainly focusing on the statin aspects of treatment. As the Adult Treatment Panel III guidelines recommend a restriction in caloric and fat intake to accompany the lipid targets set for hypolipidaemic drug treatment,2 the lack of dietary compliance suggests suboptimal treatment of the patients who were prescribed statins.2 Optimal long-term lifestyle changes are probably better described by the seven metrics of ideal cardiovascular health adopted by the American Heart Association (AHA).4 The AHA suggests ideal health behaviours, such as not smoking, a BMI
