We show that among patients with advanced T2D, fasting glucose visit-to-visit variability was associated with the development of microvascular complications (both for the composite of nephropathy and retinopathy as well as each outcome category individually) even after adjusting for other risk factors, including overall level of glucose control. A 20% to 30% increase in the risk of developing composite events with 1 SD increase in glucose variability was present in both in ACCORD and the VADT study cohorts. Even greater increases in risk for nephropathy were seen in both studies. Pooled analysis of these 2 separate studies confirmed these findings and showed a nearly 20% increase in risk for the primary microvascular composite outcome, and a 50% increase in risk for nephropathy, for the same 1 SD increase in CV-glucose variability. A unique finding in this pooled analysis was that effects of glucose variability appeared particularly robust in those randomized to the standard treatment group, with an approximate 65% increase in risk for nephropathy in the pooled analysis. Although P values for testing the treatment modification on the risk of glucose variability (0.07 for primary composite outcome and 0.06 for both nephropathy and retinopathy) support stratified analyses, the results should be considered exploratory.
Results from several previous investigations of long-term glycemic variability and microvascular outcomes are generally supportive of our findings.[10,25–29] However, our analysis based on 2 independent glucose-lowering trials, ACCORD (n = 10 026) and VADT (n = 1658), exceeds the sample sizes of all previous reports using trial design[8,25,27–29] and was able to focus on clinically important and carefully adjudicated nephropathy and retinopathy outcomes. Aside from the ADVANCE trial, most other studies were observational (retrospective and prospective cohort studies based on medical records or registries) and were not assessing glucose variation in the context of glucose lowering. Importantly, nephropathy outcomes in these studies were typically not clinically relevant events but were based either on mild changes in urine albumin to creatinine ratio or eGFR.[8,29] However, these studies had also noted a stronger relationship between glucose variability and renal disease than with eye disease, a pattern that is more definitively confirmed with our results. Both ACCORD and VADT also included extensive assessments of demographic, medical history, and laboratory data, permitting comprehensive adjustment for covariates in models. Taking advantage of multiple secondary microvascular outcomes captured in ACCORD also allowed us to investigate the contribution of glucose variability over a spectrum of microvascular events for T2D patients.
As both ACCORD and VADT randomized participants to intensive and standard glucose-lowering arms, this offered a unique opportunity to investigate the differential effects of glucose variability across treatment groups. As was apparent within each cohort and confirmed in the meta-analyses of the 2 trials, glycemic variation appeared most harmful in those with less intensive glucose control. As the unit of comparison, 1 SD of glucose variability, was calculated based on variability in the whole group, the comparison between groups was based on a similar degree of variability and allows us to directly compare the risk between the 2 treatment arms. Of note, despite finding that glucose variability was higher in "insulin users" than in "non-insulin users," the risk of glucose variability remained present after adjusting for insulin use. This indicates that the risk of glucose variability for microvascular outcomes is not simply a function of greater insulin use. For both ACCORD and VADT, when both CV and ARV were included in Model 3, risk of CV for the primary outcome and retinopathy remained the same while the risk of ARV diminished (data not shown). These results suggest that for the primary outcome and retinopathy the spread of glucose as measured by CV better identifies risks. Finally, as the ACCORD study recorded adherence to glycemic medications, we were able to explore whether this behavior explained the relationship between glucose variability and outcomes. As illustrated in Supplementary Table 6, accounting for adherence to diabetes medications in several different ways did not notably alter the risk of glucose variability.
These results have several important implications. They strongly corroborate the additional risk that glucose variation may have in development of microvascular complications, even when accounting for overall glucose control. From a clinical perspective, understanding the risk of glucose variability during glucose lowering is particularly relevant as this may inform healthcare providers when they make decisions to target lower HbA1c goals. Although fasting glucose is inexpensive, routinely measured, and readily extractable for potential use in automated algorithms calculating variability, these results are also valuable as proof-of-principle as more continuous glucose monitoring devices will undoubtedly further refine long-term assessments of glucose variability in the near future. Our data also suggest that additional attention to glucose variability may be needed to prevent microvascular complications in those with relatively poor glycemic control. A potential explanation, consistent with our multivariate analyses, is that glucose variability is an independent contributor to microvascular disease. Indeed, many pathophysiologic mechanisms have been proposed to explain how glucose fluctuations may cause vascular injury.[15,30] Thus, the combination of marked hyperglycemia and increased glucose variability may further increase overall risk for these events, and in particular, for renal outcomes. However, these results do not imply that glucose variation is only important in the setting of very poor glucose control. Moreover, we have previously reported that glucose variation was associated with increased risk for cardiovascular disease and was particularly prominent in those undergoing more aggressive glucose lowering. Thus, the effects of glucose variation on T2D complications may not be relevant solely to those in poor glucose control. These intriguing findings clearly need to be validated.
Our study has several limitations. Despite our efforts to account for key covariates in models predicting microvascular disease, residual confounding remains a possibility. In addition, participants in ACCORD and VADT reflect more advanced diabetes, and caution must be taken when applying our findings to younger and healthier T2D patients. Finally, our study is not able to tease out whether glycemic variability is a key mediator of microvascular disease progression or simply a marker.
In summary, our study indicates higher visit-to-visit fasting glucose variability is related to increased risk for microvascular complications, including nephropathy, and retinopathy. This relationship appears strongest in those individuals who were assigned to the standard treatment arms and who on average had worse overall glucose control. Our results suggest that visit-to-visit glucose variability may be another relevant component of overall glycemic management in T2D. Further efforts are needed to determine how best to clinically track glucose variability and whether therapies reducing variability can improve outcomes.
ACCORD, Action to Control Cardiovascular Risk in Diabetes; ARV, average real variability; CV, coefficient of variation; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; GFR, glomerular filtration rate; HbA1c, glycated hemoglobin A1c; HR, hazard ratio; T2D, type 2 diabetes; VADT, Veteran Affairs Diabetes Trial.
The contents of this article do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. The authors also acknowledge the contributions of the Hines VA Cooperative Studies Program Coordinating Center.
VADT Study Co-Chairs: Carlos Abraira, M.D., Miami VA Medical Center; William C. Duckworth, M.D., Carl T. Hayden VA Medical; Center Co-Chairs Miami Office: Christina Paul, Danielle Arca, L.M.H.C.* Lottie Cason*, Rebecca Martinez Zolotor, M.S.*, Louisa Williams*; Carl T. Hayden VA Medical Center Office: Susan L. Collier, H.T., M.M.T., C.R.C., Nafis Ahmed, B.S.*, Angela Boyd, R.T., C.R.C., C.C.R.C.* CSP Coordinating Center Edward Hines Jr. VA Hospital: Domenic Reda, Ph.D, Director, Hines CSPCC Thomas Moritz, M.S., Study Biostatistician: Robert Anderson, Ph.D., Sub-Protocol Biostatistician; Mary Ellen Vitek, Quality Assurance Specialist, Tamara Paine, National Study Coordinator, Lizy Thottapurathu, M.S., Statistical Programmer, Ping Luo, Ph.D., M.S., Sub-Protocol Statistical Programmer, Ken Bukowski, B.S., Database Programmer, Danuta Motyka, Database Programmer, Victoria Barillas, Statistical Assistant, Rodney Brown, A.A., Statistical Assistant, Barbara Christine, Statistical Assistant, Laurel Anfinsen, M.S.*, Statistical Programmer; Mary Biondic, B.A.* Database Programmer; Rita Havlicek*, Statistical Assistant; Joe Kubal, M.A.* National Study Coordinator, Statistical Assistant; Maureen McAuliffe*, Statistical Assistant; Madeline McCarren, Ph.D., M.P.H.*, Study Biostatistician; Maria Rachelle*, Statistical Assistant; Linda Rose, M.P.A.*, National Study Coordinator; Jerome Sacks, Ph.D.*, Subprotocol Biostatistician; Tom Sindowski, B.A.*, Statistical Assistant; Jonathan Thomas, M.A.*, National Study Coordinator; Candice Zahora, B.S.*, National Study Coordinator; CSPCRPCC Albuquerque, NM: Mike R. Sather, Ph.D., F.A.S.H.P., Center Director; Stuart Warren, J.D., Pharm.D., Study Pharmacist, Jolene Day, Pharmaceutical Project Manager; Jeff Haroldson, Pharm.D., B.C.P.S.*, Study Pharmacist; Executive Committee: Carlos Abraira, M.D., William Duckworth, M.D., Stephen N. Davis, M.D., Nicholas Emanuele, M.D., Steven Goldman, M.D., Rodney Hayward, M.D., Jennifer Marks, M.D., Thomas Moritz, M.S., Peter Reaven, M.D., Domenic Reda, Ph.D., Stuart Warren, J.D., Pharm.D., Franklin Zieve, M.D., Ph.D., Wendy Wendell, R.N., B.S.N., Jeff Haroldson, Pharm.D., B.C.P.S.*, Paula Harper, R.N., C.D.E.*, William G. Henderson, Ph.D.*, Robert R. Henry, M.D.*, M. Sue Kirkman, M.D.* Madeline McCarren, Ph.D., M.P.H.*, Jerome Sacks, Ph.D.*; Data and Safety Monitoring Board James Gavin, III, M.D., Ph.D., Emily Chew, M.D., Barbara Howard, Ph.D. Ted Karrison, Ph.D., Ivan V. Pacold, M.D., Daniel Seigel, Sc.D., Frank Vinicor, M.D., Barry Massie, M.D. (consultant)* Steven Goldman, M.D. Steven Rapcsak, M.D., Gulshan Sethi, M.D., Mark Sharon, M.D., Hoang Thai, M.D., Karen Zadina, R.N., M.A., Janice Christensen, M.D.*, Douglass Morrison, M.D., Ph.D.*, Peter Spooner, M.D.*, Alex Westerband, M.D.*; Consultants: Barry Materson, M.D., M.B.A., Eliot Brinton, M.D.; Ronald Klein, M.D., M.P.H., John A. Colwell, M.D., Ph.D, Ernst J. Schaefer, M.D., Carlton S. Gass, Ph.D.; Central Laboratories: David A. Ehrmann, M.D., Paul Rue; Central Biochemistry Lab: Ernst J. Schaefer, M.D., Judith R. McNamara, M.T. (retired); MAVERIC Core Laboratory: Mary Brophy, M.D., Donald Humphries, Deborah Govan, Laurie McDonnell, Laura Carlton, Yugia Weng; Cost-Effectiveness Lab: Rodney A. Hayward, M.D., Sarah Krein, Ph.D., R.N.; ECG Laboratory: Steven Goldman, M.D, Karen Zadina, R.N., M.A. Study Sites: Charleston: Jeremy Soule, M.D., Susan Caulder, R.N., M.S.N, C.D.E., Clare Pittman, R.N., M.S., C.D.E., Omayra Alston, Ronald K. Mayfield, M.D.*, Greg Moffitt, M.D.*, Julius Sagel, M.D.*, Frank Sanacor, Pharm.D.* Elizabeth Ganaway, R.N.*; Miami: Jennifer Marks, M.D., Lorraine Okur, R.N., Lucille Jones, R.N., Hermes Florez, M.D., Donna Pfeifer, Ph.D, ARNP, APRN, BC, Luis Samos, M.D., Andrew L. Taylor, M.D.* Lyons/East Orange Mark B. Zimering, M.D., Adilia Sama, R.N., Frances Rosenberg, R.N., Heidi Garcia, R.N., Norman Ertel, M.D., Leonard Pogach, M.D., John J. Shin, M.D., Felice Caldarella, M.D.*, Constantino Carseli, M.D.* Mamta Shah, M.D.* Fresno: Paulette Ginier, M.D., F.A.C.P., George Arakel, M.D., Yangheng Fu, M.D. Don Tayloe, M.D., Jack E. Allen, R.N.*, Elizabeth Fox, M.S.N, C.N.S, NP-C, C.D.E*, Paula G. Hensley, R.N.*; Hines: Nicholas Emanuele, M.D., Kathleen Kahsen, R.N., C.D.E., Patricia Linnerud, R.N., M.S., Lily Agrawal, M.D., Nasrin Azad, M.D.; Houston: Marco Marcelli, M.D., Glenn R. Cunningham, M.D., Natalie M. Nichols, L.V.N., Emilia Cordero, R.N., Rabih Hijazi, M.D.* Farid Roman, M.D.* Paromita Datta*, Mariana Garcia Touza*; Indianapolis: Amale Lteif, M.D., Karen L. Moore, R.N., B.S.N, Christina Lazar-Robinson, M.D., Sanjay Gupta, M.D.*, M. Sue Kirkman, M.D.*, Martha Mendez, R.N.*, Zehra Haider, M.D.*, Lora Risley, R.N.*; Lexington: Dennis Karounos, M.D., Linda Barber, R.N., C.D.E., Janet Hibbard, B.S., James W. Anderson, M.D., L. Raymond Reynolds, M.D., Jeff Carlsen, M.D.*, Robert W. Collins, M.D.*, As'ad Ehtisham, M.D.*; Long Beach: Moti L. Kashyap, M.D., Barbara Matheus, RNP,MSN,CDE,BC-ADM, Tina Rahbarnia, B.S., Anthony N. Vo, M.D., Nancy Downey, M.S.N., N.P.*, Lynette Fox, M.S.N., N.P.-C*, Richard M. Gonzales, M.D.*, C. Daniel Meyers, M.D.*, Subramaniam Tavintharan, M.D.*; Minneapolis: Frank Q. Nuttall, M.D., Ph.D., Lisa Cupersmith, R.N., Kathy Dardick, R.N., Linda Kollman, R.N., Angeliki Georgopoulos, M.D., Catherine Niewoehner, M.D.; Nashville Stephen N. Davis, M.D., Paula Harper, R.N., C.D.E., Diana Davis, R.N., B.S.N., C.D.E., Jessica Devin, M.D., Annis Marney, M.D., Julia Passyn-Dunn, M.D., Jennifer Perkins, M.D., John Stafford, M.D. Al Powers, M.D.*, Linda Balch, R.N., C.D.E.*, Patricia Harris, R.N.*, Omaha: Robert J. Anderson, M.D., Diana Dunning, B.S.N., M.A., C.D.E. Steve Ludwig, R.N., Marlene Vogel, R.N., Cyrus DeSouza, M.D., Robert Ecklund, M.D.*, Sarah Doran, B.S.N.*, Claire Korolchuk, R.N.*, Mary McElmeel, B.S.N., M.S.*, Sarah Wagstaff, B.S.N.*; Phoenix: Peter Reaven, M.D., Bradley Solie, R.N., C.D.E., John Matchette, P.A.-C, Christian Meyer, M.D., Sylvia Vela, M.D., Nadeem Aslam, M.D.*, Eliot Brinton, M.D.*, Joy Clark, M.S.N, F.N.P-C, C.C.R.C., C.D.E.*, Alisa Domb, R.N.*, Linda McDonald, R.N.*, Lynae Shurtz, R.N., B.S.N.*; Pittsburgh: R. Harsha Rao, M.D., Janice N. Beattie, B.S.N., C.D.E., Carol Franko, C.R.N.P., Frederick R. DeRubertis, M.D., David Kelly, M.D.*, Melisse Maser, C.R.N.P.*, Juleen Paul, CRNP, C.D.E.*, Richmond: Franklin Zieve, M.D., Ph.D., Susan J. Clark, R.N., M.S., C.C.R.C., Ann Grimsdale, R.N., Sonja Fredrickson, M.D., James Levy, M.D., Dianne Schroeder, M.D.; Salem: Ali Iranmanesh, M.D., Barbara Dunn, P.A.-C, Donna Arsura, R.N., Csaba Kovesdy, M.D., Suzanne Hanna, M.D.* Ashraf Iranmanesh, Pharm.D.*, Christy Florow*, Fe Remandaban, R.N.*, Erica Smith, L.P.N.*; San Diego: Robert R. Henry, M.D., Miriam Keller, R.N., B.S., Vanita Aroda, M.D., Charles Choe, M.D., Steven Edelman, M.D., Andrea Gasper, PA-C, Dereck MaFong, M.D., Sunder Mudaliar, M.D., Deborah Oh, M.D., Rahil Bandukwala, M.D.*, Anna Chang, M.D.*, Sandeep Chaudhary, M.D.*, Sithophol Chinnapongse, M.D.*, Louie Christiansen, M.D.*, Neelima Chu, M.D.*, Dennis Kim, M.D.*, Mark Lupo, M.D.*, Chandran, Manju, M.D.*, Ray Plodkowski, M.D.*, Roopa Sathyaprakash, M.D.*, Janet Wilson, M.D.*, Joseph Yu, M.D.*, Gina Macaraeg, R.N.*, Shelley Townes, R.N.*; San Antonio: Ralph DeFronzo, M.D., Lisa Johnson, M.S., RD/LD, Ken Cusi, M.D., Devjit Tripathy, M.D. Mandeep Bajaj, M.D.*, Janet Blodgett, M.D.*, Sangeeta Kayshup, M.D.*, Mary Helen Vasquez, R.N., C.D.E.*, Barbara Walz, R.N., B.S.N., C.D.E.*, Tess Weaver, M.S.N., APRN., B.C., F.N.P.*; San Juan. Julio Benabe, M.D., Zuleika Mercado, M.P.H., Brunilda Padilla, B.S.N., Jocelyn Serrano-Rodriguez, R.N., Carlos Rosado, M.D., Edwin Mejias, M.D.*, Tania Tejera, M.D.*, Clorinda Geldrez*, Elda Gonzalez-Melendez, B.S.N.*, Maria Natal, R.N.* Maribel Rios Jimenez, R.N.*; Tucson: Jayendra H. Shah, M.D., Wendy S. Wendel, R.N., B.S.N., Lynnette Scott, R.N., Lynne A. Gurnsey, R.N, Fabia A. Kwiecinski, M.D., Thomas Boyden, M.D.*, Merilyn G. Goldschmid, M.D., Virginia Easton*.
*Participants who left the VADT before its conclusion.
This work was supported by the Veterans Affairs Cooperative Studies Program, Department of Veterans Affairs Office of Research and Development. Additional support was received from the National Institute of Health R01-067690 and 5R01-094775 to P.D.R., and the American Diabetes Association to P.D.R. J.J.Z is supported by National Institute of Health grant K01DK106116, R21HL150374, R01HG006139, and Arizona Biomedical Research Centre (ABRC) new investigator award.
Clinical Trial Information
Glycemic Control and Complications in Diabetes Mellitus Type 2 (VADT) is registered at ClinicalTrials.gov with identifier: NCT00032487. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is registered at ClinicalTrials.gov number, NCT00000620. The study protocols are available on ClinicalTrials.gov.
The datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.
Individual deidentified participant data of ACCORD was requested through biolincc (https://biolincc.nhlbi.nih.gov/home/). The independent scientific review board reviewed and approved the request. VADT deidentified participant data will not be available online but upon request, as permitted by VA policy.
J Clin Endocrinol Metab. 2021;106(4):1150-1162. © 2021 Endocrine Society