S P E C I A L
F E A T U R E E d i t o r i a l
Mad About “U” Robert A. Vigersky Diabetes Institute, Walter Reed National Military Medical Center, Bethesda, Maryland 20889
ver the last two decades, “clinical judgment” seems to have taken a back seat to an evidence-based medicine approach to patient care. Clinical practice guidelines, which make recommendations based on systematic reviews or meta-analyses, are transformed into dicta taken literally by the medical community as well as the regulatory and legal communities. In the case of diabetes management, professional organizations have promulgated A1C goals of either 6.5 or 7% (1, 2). A single number is a powerful thing! So despite caveats in the text of these guidelines about how such goals should be individualized, healthcare providers tend to intensify therapy to meet those goals. They do so not only because they believe in the medical benefits that may result but also perhaps because they understand that they are used as metrics to assess their quality of care by healthcare system administrators and/or third-party payers. This is understandable, of course, because it is much easier to determine whether or not a specific number has been achieved (pass or fail) than to account for comorbidities and other factors that may make that goal inappropriate in an individual patient. Fortunately, the pendulum is swinging toward a more nuanced approach to diabetes care. An era of personalized medicine is upon us where a patient’s age, life expectancy, the presence and severity of complications and comorbidities, their personal preferences, psycho-social-educational factors, and costs are among the factors used in selecting the most appropriate antidiabetic medication(s) (3), as well as amending the A1C target from 6.5 or 7% to as high as 8.5–9% (4, 5). There are many reasons for a personalized approach to patient management, but the emerging data that describe U-shaped rather than linear relationships in a variety of clinical situations certainly support this approach (6, 7). Indeed, whereas U-shaped relationships seem to be ap-
O
pearing everywhere, they often defy explanation. Most recently in the diabetes arena, Lipska et al (7) found a U-shaped curve that describes the relationship between hypoglycemia and A1C in elderly patients with type 2 diabetes. What is surprising is that patients with high A1C were just as likely to have hypoglycemia as those with low A1C. In this issue of the JCEM, Schoenaker et al (8) present data from the EURODIAB Prospective Complications Study that demonstrate a U-shaped relationship between A1C and all-cause mortality in patients with type 1 diabetes. This observational study included 2764 European patients ages 15– 60 years at enrollment between 1989 and 1991 and documented 101 deaths in 7 years of follow-up. Although it is not surprising that the risk of death (as well as other complications of diabetes) increased as A1C rose, the data show for the first time in type 1 diabetes that there is an increased all-cause mortality risk at low A1Cs. Using a multivariate restricted cubic spline model with fiveknots placed at the fifth, 25th, 50th, 75th, and 95th percentiles, the “sweet spot” for the lowest mortality appears to be in the low 7% range. The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications study (9) showed a decrease in cardiovascular events (including deaths) in the intensively treated group compared with the conventionally treated group over an average of 18 years of followup, but the number of deaths from cardiovascular disease was small (three in the intensive-treatment group and nine in the conventional treatment group). The all-cause mortality rate for the DCCT has not yet been published but should shed additional light on this issue once it is available. The findings of Schoenaker et al (8) are similar to the Uor J-shaped relationship between mortality and A1C that has been described in patients with type 2 diabetes, al-
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received January 23, 2014. Accepted January 23, 2014. For article see page 800
doi: 10.1210/jc.2014-1200
J Clin Endocrinol Metab, March 2014, 99(3):771–773
jcem.endojournals.org
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 25 May 2014. at 14:13 For personal use only. No other uses without permission. . All rights reserved.
771
772
Vigersky
Mad About “U”
though the cause of this relationship is just as murky. Much of the confusion emanates from the Action to Control Cardiovascular Disease in Diabetes (ACCORD) study where there is a U-shaped curve relating mortality and A1C in those receiving conventional therapy but not in those in the intensively treated group, where it was linear. This differential relationship was recently confirmed in an age-adjusted analysis of the ACCORD data (10). They found that there is a linear increase in cardiovascular mortality in the intensively treated group in those less than 65 years of age, whereas it was U-shaped in the standard treatment group. Conversely, a J-shaped curve was seen in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study, but only in the intensive group (11). The discrepancies seen in these and other studies like EURODIAB, which is an observational study, reinforce the notion that factors other than the therapeutic intervention may be playing a role. Why might there be an increased mortality at lower A1Cs in patients with either type of diabetes? Is it related to hypoglycemia-induced cardiovascular events? Similar to the DCCT findings, the EURODIAB data show that as the A1C decreased, there was a higher percentage of patients who had severe hypoglycemia (12). However, a previous analysis of the EURODIAB study did not find that the frequency of severe hypoglycemia at the baseline examination increased the risk of cardiovascular events (13). Nevertheless, I do not believe that this puts the hypoglycemia hypothesis to rest. One weakness of the EURODIAB study is that it used questionnaires to obtain the data on the number of hypoglycemic events preceding enrollment. We now know through continuous glucose monitoring that the frequency, severity, and duration of hypoglycemia are much greater than most patients realize and/or report. Furthermore, patients with autonomic neuropathy may have hypoglycemic unawareness. Indeed, 19.3% of EURODIAB patients had abnormal heart rate variability, and 5.9% had postural hypotension at baseline, making hypoglycemic unawareness likely in these patients. The EURODIAB Prospective Study Group previously reported that both peripheral and autonomic neuropathy were associated with an increased risk of death (14). In fact, and perhaps not surprisingly, the hazard ratio for autonomic neuropathy was higher than that of peripheral neuropathy (2.40 vs1.88). Indeed, a meta-analysis by Maser et al (15) has shown that diabetic autonomic neuropathy was associated with a 4-fold increase in mortality. A possible mechanism for this emanates from another analysis of the EURODIAB study in which the frequency of severe hypoglycemia was significantly associated with prolonged QTc intervals, even after adjustment for the presence of macro- and microvascular disease (16). Unfortunately, Schoe-
J Clin Endocrinol Metab, March 2014, 99(3):771–773
naker et al (8) did not adjust for the presence of either form of neuropathy or QTc interval in their multivariate analysis, so we don’t know if or how much that increased the risk of death at either end of the spectrum. With respect to patients with type 2 diabetes, data from both the ACCORD and ADVANCE studies have been thoroughly analyzed with respect to the relationship of hypoglycemia and mortality. Bonds et al (17) found that severe hypoglycemia was associated with an increased risk of death in both study arms, not just those intensively treated. Interestingly, in ACCORD there was a peak in the deaths in the first year in both groups. Because the EURODIAB is an observational and not an interventional study, the timing of the deaths is not an issue. If not hypoglycemia, what else may be contributing to the excess mortality at lower A1Cs? Unfortunately, Schoenaker et al (8) present only all-cause mortality for their patient population, thus precluding any comparison between causes of death of those at the lower vs higher A1C quintiles. Certainly, factors such as major illnesses other than diabetes may be playing an important role. This is supported by studies in nondiabetic populations showing U- or J-shaped curves describing the relationship of A1C to mortality (18). Other confounding factors may contribute to this unexpected relationship such as renal disease, anemia, and hemoglobinopathies. Given the method used for measuring A1C in the EURODIAB study (an enzyme immunoassay using a monoclonal antibody), the presence of a hemoglobinopathy or a chemically modified derivative of hemoglobin (eg, carbamylated hemoglobin present in those with renal failure) might have significantly skewed the results. It should be noted that about half of the participating centers in the EURODIAB study were from southern Europe, increasing the likelihood of including patients with hemoglobinopathies. Indeed, it is curious that 16% of the 3250 subjects had normal A1Cs at the time of enrollment (19). Finally, variations in glycosylation rates are based on ethnicity, age, or other biological factors so that a given A1C may reflect higher or lower mean glucose levels in an individual patient and thereby convey differential risks of complications (20). The observations by Schoenaker et al (8) signal that we should be cautious in trying to meet strict A1C goals in all patients. But do they help us personalize our patients’ care? The findings of Schoenaker et al (8) are certainly hypothesis-generating, but unfortunately their data are unable to provide meaningful clinical information for risk stratification. Part of the reason for this is that those with A1Cs in the lowest quintile (A1C, 6.1%) were generally indistinguishable from those in the second lowest quintile (A1C, 7.3%), except that they tended to have more physical inactivity, were taking fewer antihypertensive medi-
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 25 May 2014. at 14:13 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2014-1200
cations, and had more cardiovascular disease but less neuropathy. In addition, the study’s baseline years were 1989 –1991 with follow-up 7 years later (up to 1999). It is unclear whether the results are still relevant in the postDCCT/post-EURODIAB era where analog insulins, more accurate glucose meters, continuous glucose monitors, and more aggressive approaches to comorbidities are being employed. Finally, as noted above, the study population may not be comparable to current patients because 16% of the subjects had normal A1C at their baseline examination. Should we be mad about “U”? Of course! We should embrace it because the U-shaped curve fundamentally reflects both the complexity of human biology and our inability to sufficiently understand it given the current body of knowledge. At the very least, it provides credible support for the “clinical judgment” embodied in the personalized approach to managing our patients with diabetes.
jcem.endojournals.org
4.
5.
6.
7.
8.
9.
10.
11.
Acknowledgments Address all correspondence and requests for reprints to: Robert A. Vigersky, Diabetes Institute, Endocrinology, Diabetes and Metabolism Service, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889. E-mail: [email protected]. The opinions expressed in this paper reflect the personal views of the author and not the official views of the United States Army or the Department of Defense. Disclosure Summary: The author has nothing to disclose that is relevant to this editorial.
12.
13.
14.
15.
16.
17.
References 18. 1. American Diabetes Association. Standards of medical care in diabetes–2014. Diabetes Care. 2014;37:S14 –S80. 2. Handelsman Y, Mechanick JI, Blonde L, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 2011;17(suppl 2): 1–53. 3. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position statement of the Amer-
19.
20.
773
ican Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364 –1379. Raz I, Riddle MC, Rosenstock J, et al. Personalized management of hyperglycemia in type 2 diabetes: reflections from a Diabetes Care Editors’ Expert Forum. Diabetes Care. 2013;36:1779 –1788. US Department of Veterans Affairs. VA/DoD Clinical Practice Guidelines: Management of Diabetes Mellitus in Primary Care (2010). Version 4.0. http:// www.healthquality.va.gov/diabetes_mellitus.asp. Accessed January 20, 2014. Amrein K, Quraishi SA, Litonjua AA, et al. Evidence for a U-shaped relationship between pre-hospital vitamin D status and mortality: a cohort study [published online January 13, 2014]. J Clin Endocrinol Metab. doi:10.1210/jc. 2013–3481. Lipska KJ, Warton EM, Huang ES, et al. HbA1c and risk of severe hypoglycemia in type 2 diabetes: the Diabetes and Aging Study. Diabetes Care. 2013; 36:3535–3542. Schoenaker DA, Simon D, Chaturvedi N, Fuller JH, Soedamah-Muthu SS. Glycemic control and all-cause mortality risk in type 1 diabetes patients: the EURODIAB Prospective Complications Study. J Clin Endocrinol Metab. 2014;99:800 – 807. Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005; 353:2643–2653. Miller ME, Williamson JD, Gerstein HC, et al. Effects of randomization to intensive glucose control on adverse events, cardiovascular disease and mortality in older versus younger adults in the ACCORD Trial [published online October 29, 2013]. Diabetes Care. doi:10.2337/dc13–1545. Zoungas S, Chalmers J, Ninomiya T, et al. Association of HbA1c levels with vascular complications and death in patients with type 2 diabetes: evidence of glycaemic thresholds. Diabetologia. 2012;55:636 – 643. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:977–986. Gruden G, Barutta F, Chaturvedi N, et al. Severe hypoglycemia and cardiovascular disease incidence in type 1 diabetes: the EURODIAB Prospective Complications Study. Diabetes Care. 2012;35:1598 –1604. Soedamah-Muthu SS, Chaturvedi N, Witte DR, Stevens LK, Porta M, Fuller JH. Relationship between risk factors and mortality in type 1 diabetic patients in Europe: the EURODIAB Prospective Complications Study (PCS). Diabetes Care. 2008;31:1360 –1366. Maser RE, Mitchell BD, Vinik AI, Freeman R. The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis. Diabetes Care. 2003;26:1895–1901. Gruden G, Giunti S, Barutta F, et al. QTc interval prolongation is independently associated with severe hypoglycemic attacks in type 1 diabetes from the EURODIAB IDDM complications study. Diabetes Care. 2012;35:125–127. Bonds DE, Miller ME, Bergenstal RM, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ. 2010;340:b4909. Carson AP, Fox CS, McGuire DK, et al. Low hemoglobin A1c and risk of all-cause mortality among US adults without diabetes. Circ Cardiovasc Qual Outcomes. 2010;3:661– 667. EURODIAB IDDM Complication Group. Microvascular and acute complications in IDDM patients: the EURODIAB IDDM Complications Study. Diabetologia. 1994;37:278 –285. McCarter RJ, Hempe JM, Gomez R, Chalew SA. Biological variation in HbA1c predicts risk of retinopathy and nephropathy in type 1 diabetes. Diabetes Care. 2004;27:1259 –1264.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 25 May 2014. at 14:13 For personal use only. No other uses without permission. . All rights reserved.
F E A T U R E E d i t o r i a l
Mad About “U” Robert A. Vigersky Diabetes Institute, Walter Reed National Military Medical Center, Bethesda, Maryland 20889
ver the last two decades, “clinical judgment” seems to have taken a back seat to an evidence-based medicine approach to patient care. Clinical practice guidelines, which make recommendations based on systematic reviews or meta-analyses, are transformed into dicta taken literally by the medical community as well as the regulatory and legal communities. In the case of diabetes management, professional organizations have promulgated A1C goals of either 6.5 or 7% (1, 2). A single number is a powerful thing! So despite caveats in the text of these guidelines about how such goals should be individualized, healthcare providers tend to intensify therapy to meet those goals. They do so not only because they believe in the medical benefits that may result but also perhaps because they understand that they are used as metrics to assess their quality of care by healthcare system administrators and/or third-party payers. This is understandable, of course, because it is much easier to determine whether or not a specific number has been achieved (pass or fail) than to account for comorbidities and other factors that may make that goal inappropriate in an individual patient. Fortunately, the pendulum is swinging toward a more nuanced approach to diabetes care. An era of personalized medicine is upon us where a patient’s age, life expectancy, the presence and severity of complications and comorbidities, their personal preferences, psycho-social-educational factors, and costs are among the factors used in selecting the most appropriate antidiabetic medication(s) (3), as well as amending the A1C target from 6.5 or 7% to as high as 8.5–9% (4, 5). There are many reasons for a personalized approach to patient management, but the emerging data that describe U-shaped rather than linear relationships in a variety of clinical situations certainly support this approach (6, 7). Indeed, whereas U-shaped relationships seem to be ap-
O
pearing everywhere, they often defy explanation. Most recently in the diabetes arena, Lipska et al (7) found a U-shaped curve that describes the relationship between hypoglycemia and A1C in elderly patients with type 2 diabetes. What is surprising is that patients with high A1C were just as likely to have hypoglycemia as those with low A1C. In this issue of the JCEM, Schoenaker et al (8) present data from the EURODIAB Prospective Complications Study that demonstrate a U-shaped relationship between A1C and all-cause mortality in patients with type 1 diabetes. This observational study included 2764 European patients ages 15– 60 years at enrollment between 1989 and 1991 and documented 101 deaths in 7 years of follow-up. Although it is not surprising that the risk of death (as well as other complications of diabetes) increased as A1C rose, the data show for the first time in type 1 diabetes that there is an increased all-cause mortality risk at low A1Cs. Using a multivariate restricted cubic spline model with fiveknots placed at the fifth, 25th, 50th, 75th, and 95th percentiles, the “sweet spot” for the lowest mortality appears to be in the low 7% range. The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications study (9) showed a decrease in cardiovascular events (including deaths) in the intensively treated group compared with the conventionally treated group over an average of 18 years of followup, but the number of deaths from cardiovascular disease was small (three in the intensive-treatment group and nine in the conventional treatment group). The all-cause mortality rate for the DCCT has not yet been published but should shed additional light on this issue once it is available. The findings of Schoenaker et al (8) are similar to the Uor J-shaped relationship between mortality and A1C that has been described in patients with type 2 diabetes, al-
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received January 23, 2014. Accepted January 23, 2014. For article see page 800
doi: 10.1210/jc.2014-1200
J Clin Endocrinol Metab, March 2014, 99(3):771–773
jcem.endojournals.org
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 25 May 2014. at 14:13 For personal use only. No other uses without permission. . All rights reserved.
771
772
Vigersky
Mad About “U”
though the cause of this relationship is just as murky. Much of the confusion emanates from the Action to Control Cardiovascular Disease in Diabetes (ACCORD) study where there is a U-shaped curve relating mortality and A1C in those receiving conventional therapy but not in those in the intensively treated group, where it was linear. This differential relationship was recently confirmed in an age-adjusted analysis of the ACCORD data (10). They found that there is a linear increase in cardiovascular mortality in the intensively treated group in those less than 65 years of age, whereas it was U-shaped in the standard treatment group. Conversely, a J-shaped curve was seen in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study, but only in the intensive group (11). The discrepancies seen in these and other studies like EURODIAB, which is an observational study, reinforce the notion that factors other than the therapeutic intervention may be playing a role. Why might there be an increased mortality at lower A1Cs in patients with either type of diabetes? Is it related to hypoglycemia-induced cardiovascular events? Similar to the DCCT findings, the EURODIAB data show that as the A1C decreased, there was a higher percentage of patients who had severe hypoglycemia (12). However, a previous analysis of the EURODIAB study did not find that the frequency of severe hypoglycemia at the baseline examination increased the risk of cardiovascular events (13). Nevertheless, I do not believe that this puts the hypoglycemia hypothesis to rest. One weakness of the EURODIAB study is that it used questionnaires to obtain the data on the number of hypoglycemic events preceding enrollment. We now know through continuous glucose monitoring that the frequency, severity, and duration of hypoglycemia are much greater than most patients realize and/or report. Furthermore, patients with autonomic neuropathy may have hypoglycemic unawareness. Indeed, 19.3% of EURODIAB patients had abnormal heart rate variability, and 5.9% had postural hypotension at baseline, making hypoglycemic unawareness likely in these patients. The EURODIAB Prospective Study Group previously reported that both peripheral and autonomic neuropathy were associated with an increased risk of death (14). In fact, and perhaps not surprisingly, the hazard ratio for autonomic neuropathy was higher than that of peripheral neuropathy (2.40 vs1.88). Indeed, a meta-analysis by Maser et al (15) has shown that diabetic autonomic neuropathy was associated with a 4-fold increase in mortality. A possible mechanism for this emanates from another analysis of the EURODIAB study in which the frequency of severe hypoglycemia was significantly associated with prolonged QTc intervals, even after adjustment for the presence of macro- and microvascular disease (16). Unfortunately, Schoe-
J Clin Endocrinol Metab, March 2014, 99(3):771–773
naker et al (8) did not adjust for the presence of either form of neuropathy or QTc interval in their multivariate analysis, so we don’t know if or how much that increased the risk of death at either end of the spectrum. With respect to patients with type 2 diabetes, data from both the ACCORD and ADVANCE studies have been thoroughly analyzed with respect to the relationship of hypoglycemia and mortality. Bonds et al (17) found that severe hypoglycemia was associated with an increased risk of death in both study arms, not just those intensively treated. Interestingly, in ACCORD there was a peak in the deaths in the first year in both groups. Because the EURODIAB is an observational and not an interventional study, the timing of the deaths is not an issue. If not hypoglycemia, what else may be contributing to the excess mortality at lower A1Cs? Unfortunately, Schoenaker et al (8) present only all-cause mortality for their patient population, thus precluding any comparison between causes of death of those at the lower vs higher A1C quintiles. Certainly, factors such as major illnesses other than diabetes may be playing an important role. This is supported by studies in nondiabetic populations showing U- or J-shaped curves describing the relationship of A1C to mortality (18). Other confounding factors may contribute to this unexpected relationship such as renal disease, anemia, and hemoglobinopathies. Given the method used for measuring A1C in the EURODIAB study (an enzyme immunoassay using a monoclonal antibody), the presence of a hemoglobinopathy or a chemically modified derivative of hemoglobin (eg, carbamylated hemoglobin present in those with renal failure) might have significantly skewed the results. It should be noted that about half of the participating centers in the EURODIAB study were from southern Europe, increasing the likelihood of including patients with hemoglobinopathies. Indeed, it is curious that 16% of the 3250 subjects had normal A1Cs at the time of enrollment (19). Finally, variations in glycosylation rates are based on ethnicity, age, or other biological factors so that a given A1C may reflect higher or lower mean glucose levels in an individual patient and thereby convey differential risks of complications (20). The observations by Schoenaker et al (8) signal that we should be cautious in trying to meet strict A1C goals in all patients. But do they help us personalize our patients’ care? The findings of Schoenaker et al (8) are certainly hypothesis-generating, but unfortunately their data are unable to provide meaningful clinical information for risk stratification. Part of the reason for this is that those with A1Cs in the lowest quintile (A1C, 6.1%) were generally indistinguishable from those in the second lowest quintile (A1C, 7.3%), except that they tended to have more physical inactivity, were taking fewer antihypertensive medi-
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 25 May 2014. at 14:13 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2014-1200
cations, and had more cardiovascular disease but less neuropathy. In addition, the study’s baseline years were 1989 –1991 with follow-up 7 years later (up to 1999). It is unclear whether the results are still relevant in the postDCCT/post-EURODIAB era where analog insulins, more accurate glucose meters, continuous glucose monitors, and more aggressive approaches to comorbidities are being employed. Finally, as noted above, the study population may not be comparable to current patients because 16% of the subjects had normal A1C at their baseline examination. Should we be mad about “U”? Of course! We should embrace it because the U-shaped curve fundamentally reflects both the complexity of human biology and our inability to sufficiently understand it given the current body of knowledge. At the very least, it provides credible support for the “clinical judgment” embodied in the personalized approach to managing our patients with diabetes.
jcem.endojournals.org
4.
5.
6.
7.
8.
9.
10.
11.
Acknowledgments Address all correspondence and requests for reprints to: Robert A. Vigersky, Diabetes Institute, Endocrinology, Diabetes and Metabolism Service, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889. E-mail: [email protected]. The opinions expressed in this paper reflect the personal views of the author and not the official views of the United States Army or the Department of Defense. Disclosure Summary: The author has nothing to disclose that is relevant to this editorial.
12.
13.
14.
15.
16.
17.
References 18. 1. American Diabetes Association. Standards of medical care in diabetes–2014. Diabetes Care. 2014;37:S14 –S80. 2. Handelsman Y, Mechanick JI, Blonde L, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 2011;17(suppl 2): 1–53. 3. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position statement of the Amer-
19.
20.
773
ican Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364 –1379. Raz I, Riddle MC, Rosenstock J, et al. Personalized management of hyperglycemia in type 2 diabetes: reflections from a Diabetes Care Editors’ Expert Forum. Diabetes Care. 2013;36:1779 –1788. US Department of Veterans Affairs. VA/DoD Clinical Practice Guidelines: Management of Diabetes Mellitus in Primary Care (2010). Version 4.0. http:// www.healthquality.va.gov/diabetes_mellitus.asp. Accessed January 20, 2014. Amrein K, Quraishi SA, Litonjua AA, et al. Evidence for a U-shaped relationship between pre-hospital vitamin D status and mortality: a cohort study [published online January 13, 2014]. J Clin Endocrinol Metab. doi:10.1210/jc. 2013–3481. Lipska KJ, Warton EM, Huang ES, et al. HbA1c and risk of severe hypoglycemia in type 2 diabetes: the Diabetes and Aging Study. Diabetes Care. 2013; 36:3535–3542. Schoenaker DA, Simon D, Chaturvedi N, Fuller JH, Soedamah-Muthu SS. Glycemic control and all-cause mortality risk in type 1 diabetes patients: the EURODIAB Prospective Complications Study. J Clin Endocrinol Metab. 2014;99:800 – 807. Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005; 353:2643–2653. Miller ME, Williamson JD, Gerstein HC, et al. Effects of randomization to intensive glucose control on adverse events, cardiovascular disease and mortality in older versus younger adults in the ACCORD Trial [published online October 29, 2013]. Diabetes Care. doi:10.2337/dc13–1545. Zoungas S, Chalmers J, Ninomiya T, et al. Association of HbA1c levels with vascular complications and death in patients with type 2 diabetes: evidence of glycaemic thresholds. Diabetologia. 2012;55:636 – 643. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:977–986. Gruden G, Barutta F, Chaturvedi N, et al. Severe hypoglycemia and cardiovascular disease incidence in type 1 diabetes: the EURODIAB Prospective Complications Study. Diabetes Care. 2012;35:1598 –1604. Soedamah-Muthu SS, Chaturvedi N, Witte DR, Stevens LK, Porta M, Fuller JH. Relationship between risk factors and mortality in type 1 diabetic patients in Europe: the EURODIAB Prospective Complications Study (PCS). Diabetes Care. 2008;31:1360 –1366. Maser RE, Mitchell BD, Vinik AI, Freeman R. The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis. Diabetes Care. 2003;26:1895–1901. Gruden G, Giunti S, Barutta F, et al. QTc interval prolongation is independently associated with severe hypoglycemic attacks in type 1 diabetes from the EURODIAB IDDM complications study. Diabetes Care. 2012;35:125–127. Bonds DE, Miller ME, Bergenstal RM, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ. 2010;340:b4909. Carson AP, Fox CS, McGuire DK, et al. Low hemoglobin A1c and risk of all-cause mortality among US adults without diabetes. Circ Cardiovasc Qual Outcomes. 2010;3:661– 667. EURODIAB IDDM Complication Group. Microvascular and acute complications in IDDM patients: the EURODIAB IDDM Complications Study. Diabetologia. 1994;37:278 –285. McCarter RJ, Hempe JM, Gomez R, Chalew SA. Biological variation in HbA1c predicts risk of retinopathy and nephropathy in type 1 diabetes. Diabetes Care. 2004;27:1259 –1264.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 25 May 2014. at 14:13 For personal use only. No other uses without permission. . All rights reserved.
