Opinion
Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association.
EDITORIAL
Controlling the Metabolic Roller Coaster in Diabetes Anne R. Cappola, MD, ScM; Edward H. Livingston, MD
Diabetes mellitus is caused by the loss of endogenous glucose regulation, leading to fasting hyperglycemia and superimposed glucose elevations with meals. Attempts to restore glucose levels to within the narrow normoglycemic window may result in hypoglycemia, adding to fluctuations in glycemic control. This issue of JAMA is devoted to the topic of diabetes, with the cover depicting the blood glucose variability of poorly controlled diabetes as a roller coaster—the Glucose Excursion—the course of which is based on continuous glucose monitoring data. Loss of pancreatic beta cells below a threshold amount—the β-Cell Drop—triggers the onset of diabetes, causing hypoinsulinemia in type 1 diabetes and inadequate compensation for insulin resistance in type 2 diabetes. The β-Cell Drop provides an early abrupt change and a late plateau. The smoothest ride is the Insulin Coaster, which demonstrates the time course of long-acting insulin preparations. Successful prevention efforts should eliminate the need to ever have to imagine entering a metaphorical diabetes theme park. In this issue of JAMA, Knip et al1 report findings from a randomized clinical trial testing a dietary intervention in infants who were genetically at risk for type 1 diabetes. Prior findings suggested that early exposure to complex dietary proteins increases the risk of β-cell autoimmunity. When children develop 2 diabetes-associated autoantibodies, the risk of type 1 diabetes by age 15 years is 61.6% (95% CI, 53%-70.2%), and 79.1% (95% CI, 73.3%-85%) for children with 3 autoantibodies.2 The investigators randomized 2159 infants at birth into groups receiving extensively hydrolyzed formula, which removes intact proteins, or a comparable formula with only 20% hydrolyzed proteins. At a median of 7 years of age, there were no statistically significant differences between the 2 feeding groups for the development of 2 or more islet autoantibodies (13.4% in the extensively hydrolyzed formula group vs 11.4% in controls; unadjusted hazard ratio, 1.21, 95% CI, 0.94-1.54). This trial provides strong evidence against the potential relationship between dietary proteins in infancy and the development of type 1 diabetes from diabetes-associated autoantibodies and eliminates one potential cause of type 1 diabetes. However, prevention of the disease remains elusive. Even if prevention is not possible, early intervention for patients with genetically driven risk for diabetes may be beneficial. To intervene, the ability to predict that disease might occur based on genetic testing is necessary. In this issue of JAMA, the report from the SIGMA Type 2 Diabetes Consortium examined low-frequency protein-encoding genetic variants associated with type 2 diabetes exclusively in Latino populations.3 This study is important for 2 reasons. First, the Latino population is often not included in diagnostic and thera-
peutic studies and second, the validity of the methods is excellent. Whole-exome sequencing was performed in a casecontrol study of 3756 Mexican and US Latinos, identifying a single missense mutation in HNF1A, the gene responsible for maturity onset diabetes of the young type 3 (MODY3), that was 5 times more common (odds ratio, 5.48; 95% CI, 2.83-10.61) in participants with diabetes than in nondiabetic control patients. In a large, multiethnic replication cohort, this variant was found only in Latino participants, with a 4-fold higher prevalence (odds ratio, 4.16; 95% CI, 1.75-9.92) among patients with diabetes. In vitro assays confirmed a functional effect of this mutation on protein transcription. The estimated magnitude of the effect is large for this variant, higher than any reported from genome-wide association studies to date, but it affects only 2% of Latino patients with type 2 diabetes. Ultimately, there may be a cost-effective way to identify patients with this genetic variant through screening, allowing intervention before diabetes develops, but the technology is not ready yet. Once progression to diabetes has occurred, the therapeutic goal is to make the rides as smooth and uneventful as possible, so that they resemble a commuter train rather than a roller coaster. Two other research articles in this diabetes theme issue address the association between medical4 and surgical5 treatment and clinical outcomes among patients with type 2 diabetes. In a retrospective cohort study using Veterans Administration administrative data, Roumie and colleagues4 compared the risk of adding a sulfonylurea or insulin to metformin therapy for type 2 diabetes, using propensity score matching to select patients in a 5:1 ratio. Patients who added insulin as second-line therapy had a higher risk of a composite of myocardial infarction, stroke, and death compared with those who added sulfonylureas, with an adjusted hazard ratio of 1.30 (95% CI, 1.07-1.58). This finding was primarily driven by an association with mortality, not cardiovascular outcomes. Although insulin is typically prescribed as third- or fourth-line therapy and not as a second-line therapy, as is discussed in a review of insulin therapy in this issue,6 the relationship between insulin use and mortality warrants further investigation and replication. The ramifications of the findings reported by Roumie et al are further discussed in an accompanying Editorial by Safford7 and trends in insulin use and expenditures are reported in a Research Letter by Lipska and colleagues.8 Bariatric surgery can be an effective means for controlling diabetes.9 However, long-term outcomes are not known. The Swedish Obese Subjects study is the longest-running matched cohort study in progress. Evaluating diabetes remission in patients who had type 2 diabetes when the study was
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JAMA June 11, 2014 Volume 311, Number 22
Copyright 2014 American Medical Association. All rights reserved.
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2277
Opinion Editorial
initiated, Sjöström and colleagues5 assessed 343 patients who underwent bariatric surgery and 260 matched control patients. Control patients did not have surgery and received usual care for obesity and diabetes. At 2 years, the diabetes remission rate in the bariatric surgery group was 72% but declined to 30% at 15 years. Although it is disappointing that diabetes remission waned, a long-term 30% remission rate, along with a sustained weight loss of more than 20 kg, is an important longterm result for any intervention for obese diabetic patients. These data are in contrast to medical therapy, with diabetes remission rates of 16% at 2 years and 7% at 15 years, and a sustained weight loss of 6 kg. Bariatric surgery was also associated with decreased microvascular and macrovascular complications. Reduction in macrovascular complications has not been attained with either lifestyle or medical therapy for type 2 diabetes. Diabetes duration at baseline was associated with diabetes remission, whereas baseline body mass index was not. This suggests that bariatric surgery is most effective before the irreversible β-cell drop has progressed too far, regardless of the degree of baseline insulin resistance. Important limitations include the lack of randomization, significant loss to follow-up by 15 years, and lack of primary outpatient visit inclusion in the registry linkage for diabetes complications. However, the magnitudes of the differences found between the bariatric surgery and control groups suggest that additional refinements in study design are unlikely to negate these results. Three Viewpoints in this diabetes theme issue address several important clinical issues. Seaquist, the current American Diabetes Association President for Medicine and Science, summarizes the state of diabetes management in 201410; Sacks and John discuss interpretation of hemoglobin A1c levels11; and Jampol et al describe key aspects in the treatment of diabetic ARTICLE INFORMATION Author Affiliations: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (Cappola); Associate Editor, JAMA (Cappola); Deputy Editor, JAMA (Livingston). Corresponding Author: Anne R. Cappola, MD, ScM, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Blvd, Bldg 421, 12th Floor, Philadelphia, PA 19104-5160 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Cappola reports serving as a consultant for Novartis and MannKind Corporation. Dr Livingston reports no disclosures.
2278
macular edema.12 Also included is a From the JAMA Network synopsis on diabetes overtreatment in elderly patients.13 Diabetes is a global epidemic, and the original articles included in this issue include 2 multinational studies that required substantial collaboration and coordination and sufficient funding to achieve successful completion. In the study by the Knip et al, this allowed for generalizability of findings across ethnicities and environments. The study from the SIGMA Type 2 Diabetes Consortium is the largest exomesequencing study in type 2 diabetes published to date, and it is likely to be the largest conducted in Latino samples for the foreseeable future. This study also has implications beyond diabetes. The effect size and frequency of the p.E508K variant, in between classic MODY mutations and common polymorphisms, demonstrate that there is a spectrum of effects on the function of HNF1A, not just the dichotomy of extremely rare variants of monogenic effects and common polymorphisms in polygenic disease. The articles in this diabetes theme issue of JAMA provide insight into the pathogenesis and treatment of this important disease. However, despite progress in research and understanding of this disease, the prevalence of diabetes is increasing among US children14 and adults around the world.15 Accordingly, prevention of type 1 and type 2 diabetes remains the ultimate goal. For patients with diabetes, optimization of management with diet and medication, and for some patients, perhaps surgical intervention, can help effectively control the metabolic roller coaster that often characterizes the disease. We look forward to publishing more articles in JAMA that report progress in understanding, preventing, and treating diabetes, so that one day, the metaphorical diabetes theme park can be closed forever.
3. The SIGMA Type 2 Diabetes Consortium. Association of a low-frequency variant in HNF1A with type 2 diabetes in a Latino population. JAMA. doi:10.1001/jama.2014.6511.
for the control of type 2 diabetes, hypertension, and hyperlipidemia: the Diabetes Surgery Study randomized clinical trial. JAMA. 2013;309(21): 2240-2249.
4. Roumie CL, Greevy RA, Grijalva CG, et al. Association between intensification of metformin treatment with insulin vs sulfonylureas and cardiovascular events and all-cause mortality among patients with diabetes. JAMA. doi:10.1001 /jama.2014.4312.
10. Seaquist ER. Addressing the burden of diabetes. JAMA. doi:10.1001/jama.2014.6451.
5. Sjöström L, Peltonen M, Jacobson P, et al. Association of bariatric surgery with long-term remission of type 2 diabetes and with microvascular and macrovascular complications. JAMA. doi:10.1001/jama.2014.5988. 6. Wallia A, Molitch ME. Insulin therapy for type 2 diabetes mellitus. JAMA. doi:10.1001 /jama.2014.5951.
REFERENCES
7. Safford MM. Comparative effectiveness research and outcomes of diabetes treatment. JAMA. doi:10.1001/jama.2014.4313.
1. Knip M, Åkerblom HK, Becker D, et al; TRIGR Study Group. Hydrolyzed infant formula and early β-cell autoimmunity: a randomized clinical trial. JAMA. doi:10.1001/jama.2014.5610.
8. Lipska KJ, Ross JS, Van Houten HK, Beran D, Yudkin JS, Shaw ND. Use and out-of-pocket costs of insulin for type 2 diabetes mellitus from 2000 through 2010. JAMA. doi:10.1001/jama.2014.6316.
2. Ziegler AG, Rewers M, Simell O, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA. 2013;309(23):2473-2479.
9. Ikramuddin S, Korner J, Lee WJ, et al. Roux-en-Y gastric bypass vs intensive medical management
11. Sacks DB, John WG. Interpretation of hemoglobin A1C values. JAMA. doi:10.1001 /jama.2014.6342. 12. Jampol LM, Bressler NM, Glassman AR. Revolution to a new standard treatment of diabetic macular edema. JAMA. doi:10.1001 /jama.2014.2536. 13. Andrews MA, O’Malley PG. Diabetes overtreatment in elderly individuals: risky business in need of better management. JAMA. doi:10.1001 /jama.2014.4563. 14. Dabelea D, Mayer-Davis EJ, Saydah S, et al; SEARCH for Diabetes in Youth Study. Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009. JAMA. 2014;311 (17):1778-1786. 15. Xu Y, Wang L, He J, et al; 2010 China Noncommunicable Disease Surveillance Group. Prevalence and control of diabetes in Chinese adults. JAMA. 2013;310(9):948-959.
JAMA June 11, 2014 Volume 311, Number 22
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a New York University User on 05/23/2015
jama.com
Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association.
EDITORIAL
Controlling the Metabolic Roller Coaster in Diabetes Anne R. Cappola, MD, ScM; Edward H. Livingston, MD
Diabetes mellitus is caused by the loss of endogenous glucose regulation, leading to fasting hyperglycemia and superimposed glucose elevations with meals. Attempts to restore glucose levels to within the narrow normoglycemic window may result in hypoglycemia, adding to fluctuations in glycemic control. This issue of JAMA is devoted to the topic of diabetes, with the cover depicting the blood glucose variability of poorly controlled diabetes as a roller coaster—the Glucose Excursion—the course of which is based on continuous glucose monitoring data. Loss of pancreatic beta cells below a threshold amount—the β-Cell Drop—triggers the onset of diabetes, causing hypoinsulinemia in type 1 diabetes and inadequate compensation for insulin resistance in type 2 diabetes. The β-Cell Drop provides an early abrupt change and a late plateau. The smoothest ride is the Insulin Coaster, which demonstrates the time course of long-acting insulin preparations. Successful prevention efforts should eliminate the need to ever have to imagine entering a metaphorical diabetes theme park. In this issue of JAMA, Knip et al1 report findings from a randomized clinical trial testing a dietary intervention in infants who were genetically at risk for type 1 diabetes. Prior findings suggested that early exposure to complex dietary proteins increases the risk of β-cell autoimmunity. When children develop 2 diabetes-associated autoantibodies, the risk of type 1 diabetes by age 15 years is 61.6% (95% CI, 53%-70.2%), and 79.1% (95% CI, 73.3%-85%) for children with 3 autoantibodies.2 The investigators randomized 2159 infants at birth into groups receiving extensively hydrolyzed formula, which removes intact proteins, or a comparable formula with only 20% hydrolyzed proteins. At a median of 7 years of age, there were no statistically significant differences between the 2 feeding groups for the development of 2 or more islet autoantibodies (13.4% in the extensively hydrolyzed formula group vs 11.4% in controls; unadjusted hazard ratio, 1.21, 95% CI, 0.94-1.54). This trial provides strong evidence against the potential relationship between dietary proteins in infancy and the development of type 1 diabetes from diabetes-associated autoantibodies and eliminates one potential cause of type 1 diabetes. However, prevention of the disease remains elusive. Even if prevention is not possible, early intervention for patients with genetically driven risk for diabetes may be beneficial. To intervene, the ability to predict that disease might occur based on genetic testing is necessary. In this issue of JAMA, the report from the SIGMA Type 2 Diabetes Consortium examined low-frequency protein-encoding genetic variants associated with type 2 diabetes exclusively in Latino populations.3 This study is important for 2 reasons. First, the Latino population is often not included in diagnostic and thera-
peutic studies and second, the validity of the methods is excellent. Whole-exome sequencing was performed in a casecontrol study of 3756 Mexican and US Latinos, identifying a single missense mutation in HNF1A, the gene responsible for maturity onset diabetes of the young type 3 (MODY3), that was 5 times more common (odds ratio, 5.48; 95% CI, 2.83-10.61) in participants with diabetes than in nondiabetic control patients. In a large, multiethnic replication cohort, this variant was found only in Latino participants, with a 4-fold higher prevalence (odds ratio, 4.16; 95% CI, 1.75-9.92) among patients with diabetes. In vitro assays confirmed a functional effect of this mutation on protein transcription. The estimated magnitude of the effect is large for this variant, higher than any reported from genome-wide association studies to date, but it affects only 2% of Latino patients with type 2 diabetes. Ultimately, there may be a cost-effective way to identify patients with this genetic variant through screening, allowing intervention before diabetes develops, but the technology is not ready yet. Once progression to diabetes has occurred, the therapeutic goal is to make the rides as smooth and uneventful as possible, so that they resemble a commuter train rather than a roller coaster. Two other research articles in this diabetes theme issue address the association between medical4 and surgical5 treatment and clinical outcomes among patients with type 2 diabetes. In a retrospective cohort study using Veterans Administration administrative data, Roumie and colleagues4 compared the risk of adding a sulfonylurea or insulin to metformin therapy for type 2 diabetes, using propensity score matching to select patients in a 5:1 ratio. Patients who added insulin as second-line therapy had a higher risk of a composite of myocardial infarction, stroke, and death compared with those who added sulfonylureas, with an adjusted hazard ratio of 1.30 (95% CI, 1.07-1.58). This finding was primarily driven by an association with mortality, not cardiovascular outcomes. Although insulin is typically prescribed as third- or fourth-line therapy and not as a second-line therapy, as is discussed in a review of insulin therapy in this issue,6 the relationship between insulin use and mortality warrants further investigation and replication. The ramifications of the findings reported by Roumie et al are further discussed in an accompanying Editorial by Safford7 and trends in insulin use and expenditures are reported in a Research Letter by Lipska and colleagues.8 Bariatric surgery can be an effective means for controlling diabetes.9 However, long-term outcomes are not known. The Swedish Obese Subjects study is the longest-running matched cohort study in progress. Evaluating diabetes remission in patients who had type 2 diabetes when the study was
jama.com
JAMA June 11, 2014 Volume 311, Number 22
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a New York University User on 05/23/2015
2277
Opinion Editorial
initiated, Sjöström and colleagues5 assessed 343 patients who underwent bariatric surgery and 260 matched control patients. Control patients did not have surgery and received usual care for obesity and diabetes. At 2 years, the diabetes remission rate in the bariatric surgery group was 72% but declined to 30% at 15 years. Although it is disappointing that diabetes remission waned, a long-term 30% remission rate, along with a sustained weight loss of more than 20 kg, is an important longterm result for any intervention for obese diabetic patients. These data are in contrast to medical therapy, with diabetes remission rates of 16% at 2 years and 7% at 15 years, and a sustained weight loss of 6 kg. Bariatric surgery was also associated with decreased microvascular and macrovascular complications. Reduction in macrovascular complications has not been attained with either lifestyle or medical therapy for type 2 diabetes. Diabetes duration at baseline was associated with diabetes remission, whereas baseline body mass index was not. This suggests that bariatric surgery is most effective before the irreversible β-cell drop has progressed too far, regardless of the degree of baseline insulin resistance. Important limitations include the lack of randomization, significant loss to follow-up by 15 years, and lack of primary outpatient visit inclusion in the registry linkage for diabetes complications. However, the magnitudes of the differences found between the bariatric surgery and control groups suggest that additional refinements in study design are unlikely to negate these results. Three Viewpoints in this diabetes theme issue address several important clinical issues. Seaquist, the current American Diabetes Association President for Medicine and Science, summarizes the state of diabetes management in 201410; Sacks and John discuss interpretation of hemoglobin A1c levels11; and Jampol et al describe key aspects in the treatment of diabetic ARTICLE INFORMATION Author Affiliations: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (Cappola); Associate Editor, JAMA (Cappola); Deputy Editor, JAMA (Livingston). Corresponding Author: Anne R. Cappola, MD, ScM, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Blvd, Bldg 421, 12th Floor, Philadelphia, PA 19104-5160 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Cappola reports serving as a consultant for Novartis and MannKind Corporation. Dr Livingston reports no disclosures.
2278
macular edema.12 Also included is a From the JAMA Network synopsis on diabetes overtreatment in elderly patients.13 Diabetes is a global epidemic, and the original articles included in this issue include 2 multinational studies that required substantial collaboration and coordination and sufficient funding to achieve successful completion. In the study by the Knip et al, this allowed for generalizability of findings across ethnicities and environments. The study from the SIGMA Type 2 Diabetes Consortium is the largest exomesequencing study in type 2 diabetes published to date, and it is likely to be the largest conducted in Latino samples for the foreseeable future. This study also has implications beyond diabetes. The effect size and frequency of the p.E508K variant, in between classic MODY mutations and common polymorphisms, demonstrate that there is a spectrum of effects on the function of HNF1A, not just the dichotomy of extremely rare variants of monogenic effects and common polymorphisms in polygenic disease. The articles in this diabetes theme issue of JAMA provide insight into the pathogenesis and treatment of this important disease. However, despite progress in research and understanding of this disease, the prevalence of diabetes is increasing among US children14 and adults around the world.15 Accordingly, prevention of type 1 and type 2 diabetes remains the ultimate goal. For patients with diabetes, optimization of management with diet and medication, and for some patients, perhaps surgical intervention, can help effectively control the metabolic roller coaster that often characterizes the disease. We look forward to publishing more articles in JAMA that report progress in understanding, preventing, and treating diabetes, so that one day, the metaphorical diabetes theme park can be closed forever.
3. The SIGMA Type 2 Diabetes Consortium. Association of a low-frequency variant in HNF1A with type 2 diabetes in a Latino population. JAMA. doi:10.1001/jama.2014.6511.
for the control of type 2 diabetes, hypertension, and hyperlipidemia: the Diabetes Surgery Study randomized clinical trial. JAMA. 2013;309(21): 2240-2249.
4. Roumie CL, Greevy RA, Grijalva CG, et al. Association between intensification of metformin treatment with insulin vs sulfonylureas and cardiovascular events and all-cause mortality among patients with diabetes. JAMA. doi:10.1001 /jama.2014.4312.
10. Seaquist ER. Addressing the burden of diabetes. JAMA. doi:10.1001/jama.2014.6451.
5. Sjöström L, Peltonen M, Jacobson P, et al. Association of bariatric surgery with long-term remission of type 2 diabetes and with microvascular and macrovascular complications. JAMA. doi:10.1001/jama.2014.5988. 6. Wallia A, Molitch ME. Insulin therapy for type 2 diabetes mellitus. JAMA. doi:10.1001 /jama.2014.5951.
REFERENCES
7. Safford MM. Comparative effectiveness research and outcomes of diabetes treatment. JAMA. doi:10.1001/jama.2014.4313.
1. Knip M, Åkerblom HK, Becker D, et al; TRIGR Study Group. Hydrolyzed infant formula and early β-cell autoimmunity: a randomized clinical trial. JAMA. doi:10.1001/jama.2014.5610.
8. Lipska KJ, Ross JS, Van Houten HK, Beran D, Yudkin JS, Shaw ND. Use and out-of-pocket costs of insulin for type 2 diabetes mellitus from 2000 through 2010. JAMA. doi:10.1001/jama.2014.6316.
2. Ziegler AG, Rewers M, Simell O, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA. 2013;309(23):2473-2479.
9. Ikramuddin S, Korner J, Lee WJ, et al. Roux-en-Y gastric bypass vs intensive medical management
11. Sacks DB, John WG. Interpretation of hemoglobin A1C values. JAMA. doi:10.1001 /jama.2014.6342. 12. Jampol LM, Bressler NM, Glassman AR. Revolution to a new standard treatment of diabetic macular edema. JAMA. doi:10.1001 /jama.2014.2536. 13. Andrews MA, O’Malley PG. Diabetes overtreatment in elderly individuals: risky business in need of better management. JAMA. doi:10.1001 /jama.2014.4563. 14. Dabelea D, Mayer-Davis EJ, Saydah S, et al; SEARCH for Diabetes in Youth Study. Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009. JAMA. 2014;311 (17):1778-1786. 15. Xu Y, Wang L, He J, et al; 2010 China Noncommunicable Disease Surveillance Group. Prevalence and control of diabetes in Chinese adults. JAMA. 2013;310(9):948-959.
JAMA June 11, 2014 Volume 311, Number 22
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a New York University User on 05/23/2015
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