[140] What to do about borderline hyperglycemia?

07 Feb 2023 [140] What to do about borderline hyperglycemia?

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Posted at 22:38h in Therapeutics Letter by

Case vignette: A 55-year-old male with a BMI of 32 kg/m2 has been your patient for 2 years. At an annual health review, you order laboratory tests including fasting plasma glucose (FPG) and A1c to screen for diabetes. The FPG of 6.3 mM and A1c of 6.2% are flagged as abnormal; he has already seen the results. What should you do?

People characterized as borderline hyperglycemic by laboratory tests are at higher risk of progressing to confirmed type 2 diabetes (T2DM) than those who are normoglycemic.1 But for those who will not develop T2DM, is recognition and treatment of a “prediabetes” phase beneficial? A 2020 summary of available evidence suggests that about two-thirds of people characterized as “prediabetic” do not develop diabetes when followed for up to 12 years,2 and a 2010 systematic review reached similar findings.1 One cohort study followed 6,241 people for 5 years after discovery of “prediabetes”: 20-30% reverted to normoglycemia.3

The term “prediabetes” has been used to describe screening test results that are higher than normal but do not meet diagnostic criteria for T2DM.4 There is debate as to whether there is long-term benefit from identifying “prediabetes.” As with other laboratory tests, concerns raised by an abnormal glycemic result can be hard to shed. Unwelcome consequences (testing and monitoring, stigma, potentially costly or harmful treatments, eligibility for life insurance or cost) should be balanced against potential benefits before applying this diagnostic label.5,6,7

Definitions of borderline hyperglycemia 

Thresholds for borderline hyperglycemia are based on expert interpretation of studies that rely on surrogate outcomes (e.g. future hyperglycemia or diabetes diagnosis) or on predicted risk (e.g. Framingham Risk Score).1,8,9,10 

Diabetes Canada defines “prediabetic” glycemia as either impaired fasting glucose (FPG 6.1-6.9 mM), impaired glucose tolerance (glucose of 7.8-11.0 mM at 2 hours after 75g oral glucose), or an A1c between 6.0 and 6.4%.4 The American Diabetes Association defines as “prediabetic” any one of: fasting plasma glucose (FPG) of 5.6 to 6.9 mM, 2-hour postprandial glucose 7.8 to 11.0 mM, or A1c 5.7 to 6.4%.8 The World Health Organization (WHO) considers evidence insufficient to use A1c levels to define “prediabetes.” WHO accepts either impaired FPG or 2-hour postprandial glucose, using the same ranges as Diabetes Canada.8 

Using its own criteria, Diabetes Canada estimates that approximately 20% of Canadians are at elevated risk of developing diabetes.4 Prevalence and incidence of borderline hyperglycemia are not well documented in Canada. But trends likely mirror T2DM, which is more prevalent in people with lower educational attainment or socioeconomic status;  women with prior gestational diabetes; and among people who are physically inactive, overweight, or obese.11,12 Rates also vary by ethnicity.11,13 Moving from a neighbourhood with a high level of poverty to one with less poverty reduced diabetes and extreme obesity in a housing subsidy experiment in Chicago in the 1990s.14

Choosing lower thresholds and accepting any of 3 criteria (rather than a combination) identifies more people who may progress to T2DM; but it also increases the number of false positives.15 And individual plasma glucose and A1c vary over time. 

Further, whether intensive glycemic control itself reduces important clinical outcomes of T2DM remains at issue.16 In recent clinical trials of SGLT-2 inhibitors and GLP-1 receptor agonists for T2DM, clinical benefits accrued at A1c levels somewhat greater than 7%. These drugs may work by mechanisms other than glucose lowering.17,18,19

Implications for health 

The most important clinical issue is to reduce or delay long-term outcomes, primarily cardiovascular (CV) disease, in people who progress to T2DM. A 2020 meta-analysis applied the WHO and Diabetes Canada criteria for “prediabetes” to 129 cohort studies including over 10 million people followed for a median of 9.8 years.20 The Table shows the authors’ relative risk estimates for all-cause mortality and CV events. They estimate absolute risk differences from “prediabetes” vs normoglycemia for all-cause mortality as 7.36 per 10,000 person years, and for composite CV disease as 8.75/10,000 person years.

Glycemic criterion Outcome Relative Risk (RR) 95% CI
Impaired FPG All-cause mortality
CV events		 1.13
1.20		 1.05-1.20
1.09-1.34
Impaired 2h glucose tolerance All-cause mortality
CV events		 1.25
1.23		 1.17-1.32
1.13-1.32
A1c 6.0-6.4% All-cause mortality
CV events		 1.21
1.15		 1.06-1.38
0.98-1.35

Whether “prediabetes” causes microvascular complications is less studied.21

Is this a key predictor of future health problems?

Hyperglycemia in “prediabetes” is not independently associated with CV disease, but is associated with co-existing non-glycemic risk factors such as smoking, hypertension, inactivity, or obesity.2 So, as with T2DM, the association between “prediabetes” and future CV disease is multifactorial.8 Hyperglycemia may be one indicator of increased CV risk, but not the major driver.

How should we manage borderline hyperglycemia?

The US Diabetes Prevention Program trial (DPP) compared metformin 850 mg twice/day (plus standard lifestyle recommendations) with intensive lifestyle intervention alone, or standard lifestyle recommendations (control). Between 1996 and 2001, DPP followed 3,234 “prediabetic” Americans (mean age 51 years, mean BMI 34 kg/m2) for a mean of 2.8 years to evaluate their risk of progression to T2DM.22 Enrolment criteria were elevated FPG (5.3-6.9 mmol/L) and impaired glucose tolerance (2h-PPG 7.8-11.0 mmol/L). The intensive lifestyle intervention involved 150 minutes of physical activity/week and a meal plan (reduced calories and fat) aiming to achieve >7% weight loss. Compared with standard lifestyle recommendations, the intensive lifestyle intervention (NNT: 7 for 3 years) and metformin (NNT: 14 for 3 years) each reduced progression to T2DM. Therapeutics Letter 137 recommended exercise prescriptions to facilitate such change. 

A 2019 Cochrane systematic review of 20 RCTs (N = 6,774 people) found that both metformin and lifestyle interventions reduced progression to T2DM and were similarly efficacious but not additive.23 No medications are currently approved to treat “prediabetes” in Canada. A recommendation of metformin to reduce risk of developing T2DM among people with impaired FPG or A1c 6.0 to 6.4% is considered Grade D evidence by Diabetes Canada.4    

Does treating people with borderline hyperglycemia reduce bad clinical outcomes important to patients? This is less clear. Two long-term observational follow-up studies of the DPP trial (about 20 years each) found no difference in future risk of major CV events, CV death, or total mortality between people originally randomized to receive metformin (continued open label), or intensive lifestyle intervention (offered metformin post-trial) compared with standard lifestyle advice only.24,25  

Evidence that newer drugs (SGLT2 inhibitors and GLP-1 agonists) improve patient-important clinical outcomes in T2DM at achieved A1c >7% suggests that large RCTs combining lifestyle interventions with these drug classes could potentially identify more promising drug treatments.26,27

The health context, values and goals of individual patients (age, life expectancy, co-morbidities, treatment burden) pose an essential question: will acting on borderline hyperglycemia make sense for your patient?

Conclusions

  • Many people with borderline hyperglycemia will not progress to type 2 diabetes.
  • Borderline hyperglycemia is associated with adverse health outcomes, but other risk factors for cardiovascular disease may be more important.
  • Use borderline hyperglycemia as a “wake up call”: an opportunity to discuss options. Emphasize lifestyle optimization with improved diet and physical activity.
Multiple experts and primary care clinicians reviewed the draft of this Therapeutics Letter for factual accuracy, and to ensure it is relevant to clinicians.
The UBC TI is funded by the BC Ministry of Health to provide evidence-based information about drug therapy. We neither formulate nor adjudicate provincial drug policies.
ISSN: 2369-8691 (Online) || ISSN: 2369-8683 (Print)
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References

  1. Zhang X, Gregg EW, Williamson DF, et al. A1C level and future risk of diabetes: a systematic review. Diabetes Care. 2010; 33(7):1665-73. DOI: 10.2337/dc09-1939
  2. Davidson MB. Metformin should not be used to treat prediabetes. Diabetes Care. 2020; 43(9):1983-87. DOI: 10.2337/dc19-2221
  3. Heianza Y, Arase Y, Fujihara K, et al. Screening for pre-diabetes to predict future diabetes using various cut-off points for HbA(1c) and impaired fasting glucose: the Toranomon Hospital Health Management Center Study 4 (TOPICS 4). Diabetic Medicine. 2012; 29(9):e279-85. DOI: 10.1111/j.1464-5491.2012.03686.x
  4. Diabetes Canada Clinical Practice Guidelines Expert Committees. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Canadian Journal of Diabetes. 2018; 42(Supplement 1):S1-325. https://guidelines.diabetes.ca/docs/cpg-2018-full-en.pdf
  5. Yudkin JS. “Prediabetes”: Are there problems with this label? Yes, the label creates further problems! Diabetes Care. 2016; 39(8):1468-71. DOI: 10.2337/dc15-2113
  6. Yudkin JS, Montori VM. The epidemic of pre-diabetes: the medicine and the politics. BMJ. 2014; 349:g4485. DOI: 10.1136/bmj.g4485
  7. Twohig H, Hodges V, Mitchell C. Pre-diabetes: opportunity or overdiagnosis? British Journal of General Practice. 2018; 68(669):172-73. DOI: 10.3399/bjgp18X695369
  8. Echouffo-Tcheugui JB, Selvin E. Prediabetes and what it means: The epidemiological evidence. Annual Review of Public Health. 2021; 42:59-77. DOI: 10.1146/annurev-publhealth-090419-102644
  9. ADA Professional Practice Committee. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2022. Diabetes Care. 2022; 45(Suppl 1):S17-S38. DOI: 10.2337/dc22-S002
  10. Ackermann RT, Cheng YJ, Williamson DF, Gregg EW. Identifying adults at high risk for diabetes and cardiovascular disease using hemoglobin A1c National Health and Nutrition Examination Survey 2005-2006. Am J of Prev Med. 2011; 40(1):11-7. DOI: 10.1016/j.amepre.2010.09.022
  11. Weisman A, Fazli GS, Johns A, Booth GL. Evolving trends in the epidemiology, risk factors, and prevention of type 2 diabetes: a review. Canadian Journal of Cardiology. 2018; 34(5):552-64. DOI: 10.1016/j.cjca.2018.03.002
  12. Hosseini Z, Whiting SJ, Vatanparast H. Type 2 diabetes prevalence among Canadian adults — dietary habits and sociodemographic risk factors. Applied Physiology, Nutrition, and Metabolism. 2019; 44(10):1099-1104. DOI: 10.1139/apnm-2018-0567
  13. Tenkorang EY. Early onset of type 2 diabetes among visible minority and immigrant populations in Canada. Ethnicity & Health. 2017; 22(3):266-84. DOI: 10.1080/13557858.2016.1244623
  14. Ludwig J, Sanbonmatsu L, Gennetian L et al. Neighborhoods, obesity, and diabetes –a randomized social experiment. NEJM 2011; 365(16):1509-19. DOI: 10.1056/NEJMsa1103216
  15. Warren B, Pankow JS, Matsushita K, et al. Comparative prognostic performance of definitions of prediabetes: a prospective cohort analysis of the Atherosclerosis Risk in Communities (ARIC) study. The Lancet Diabetes & Endocrinology. 2017; 5(1):34-42. DOI: 10.1016/S2213-8587(16)30321-7
  16. Rodríguez-Gutiérrez R, Montori VM. Glycemic control for patients with type 2 diabetes mellitus: Our evolving faith in the face of evidence. Circulation. Cardiovascular Quality & Outcomes. 2016; 9(5):504-12. DOI: 10.1161/CIRCOUTCOMES.116.002901
  17. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. NEJM. 2016; 375(4):311-22. DOI: 10.1056/NEJMoa1603827
  18. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. NEJM. 2015;3 73(22):2117-28. DOI: 10.1056/NEJMoa1504720
  19. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. NEJM. 2017; 377(7):644-57. DOI: 10.1056/NEJMoa1611925
  20. Cai X, Zhang Y, Li M, et al. Association between prediabetes and risk of all cause mortality and cardiovascular disease: updated meta-analysis. BMJ. 2020; 370:m2297. DOI: 10.1136/bmj.m2297
  21. Diabetes Canada Clinical Practice Guidelines Expert Committee, Prebtani APH, Bajaj HS, Goldenberg R, Mullan Y. Reducing the risk of developing diabetes. Canadian Journal of Diabetes. 2018; 42(Suppl 1):S20-S26. DOI: 10.1016/j.jcjd.2017.10.033
  22. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. NEJM. 2002;346(6):393-403. DOI: 10.1056/NEJMoa012512
  23. Madsen KS, Chi Y, Metzendorf MI, et al. Metformin for prevention or delay of type 2 diabetes mellitus and its associated complications in persons at increased risk for the development of type 2 diabetes mellitus. Cochrane Database of Systematic Reviews. 2019; Issue 12. Art. No.: CD008558. DOI: 10.1002/14651858.CD008558.pub2
  24. Lee CG, Heckman-Stoddard B, Dabelea D, et al. Effect of metformin and lifestyle interventions on mortality in the Diabetes Prevention Program and its Outcome Study. Diabetes Care. 2021; 44(12):2775-82. DOI: 10.2337/dc21-1046
  25. Goldberg RB, Orchard TJ, Crandall JP, et al. Effects of long-term metformin and lifestyle interventions on cardiovascular events in the Diabetes Prevention Program and its Outcome Study. Circulation. 2022; 145(22):1632-41. DOI: 10.1161/CIRCULATIONAHA.121.056756
  26. Caffrey M. Is prevention the future of SGLT2s? Inzucchi offers data that suggest “Yes.” Published: 2020. https://www.ajmc.com/view/is-prevention-the-future-of-sglt2s-inzucchi-offers-data-that-suggest-yes
  27. Garvey WT, Holst-Hansen T, Laursen PN et al. Semaglutide 2.4 mg reduces the 10-year T2D risk in people with overweight/obesity. Diabetes. 2022; 71(Suppl 1). DOI: 10.2337/db22-2-LB
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2 Comments
  • James A Dickinson
    Posted at 17:10h, 08 February Reply

    This is thoughtful and useful. I would like to express concern about the introduction, in which you describe tests being done as part of an annual health review. I commend you for not writing “Annual Physical” since that is inappropriate, but would suggest that doing a health review annually is still overdoing the process. Unless someone is at specially high risk, or already has a disease that needs regular follow-up, such health reviews should be done less often, perhaps every 3 to 5 years. This obtains the benefit of catching problems early enough, while reducing the possibility of harm from over-diagnosis and its consequent overtreatment.
    In addition given the difficulty we now have with shortages of primary care, we would provide greater value to the community by spending our effort on treating people with current symptomatic health problems rather than trying to find small variations that may become a problem in a small number of people some time in the future.
    Dr. James A Dickinson, MD, PhD, CCFP
    Professor of Family Medicine
    University of Calgary
    Calgary, Alberta, Canada
    —
    Dr. James Dickinson has submitted the ICJME disclosure form and has no conflict of interest to declare.

    • Anshula Ambasta
      Posted at 09:27h, 10 February Reply

      Thank you Dr. Dickinson for this insightful comment. We are in agreement with your statement and wrote the case vignette as an example of exactly the scenario that you describe, wherein hunting for small variations in asymptomatic people may not be helpful. We agree that testing itself should be purposeful and directed, so as to best utilize our existing healthcare personnel and health resources and reduce the burden of over-testing and over-diagnosis in the population. In future, we will address some of these concepts of over-testing in upcoming Therapeutics Letters and ongoing webinars in our regular webinar series and methods series. A forthcoming webinar on February 22nd explores some of these issues in radiology: https://www.ti.ubc.ca/2023/01/25/rapid-methods-develop-diagnostic-imaging-referral-guidelines/
      Dr. Anshula Ambasta, MD, MPH, FRCPC
      Assistant Professor
      Department of Anesthesiology, Pharmacology & Therapeutics
      Faculty of Medicine
      University of British Columbia
      Vancouver, British Columbia, Canada
      —
      Dr. Anshula Ambasta has submitted the ICJME disclosure form and has no conflict of interest to declare.

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