July/August 2018

Prediabetes on the Rise — Opportunities to Reduce Cardiovascular and Renal Risk With Early Intervention
By KC Wright, MS, RDN
Today's Geriatric Medicine
Vol. 11 No. 4 P. 18

"We are yet to know what the burden might look like," says Mohammed K. Ali, MD, an associate professor of global health at Emory Rollins School of Public Health in Georgia, referring to the marked increase in incidence and prevalence of prediabetes, considered a worldwide epidemic. Ali is lead author of the study that found a high proportion of patients with prediabetes at substantial risk for cardiovascular disease and chronic kidney disease.1

What is known is that there are more than 30 million people with diabetes in the United States today, almost 10% of the population. What's more, some 84 million adults—1 in 3 people—have prediabetes.2 Of those with prediabetes, 90% don't know they have it, and 23 million are 65 years of age or older.

Individuals with prediabetes may be asymptomatic for years, often until they are diagnosed with type 2 diabetes. According to the Centers for Disease Control and Prevention (CDC), people most at risk for prediabetes are overweight, age 45 or older, have a family history of type 2 diabetes, participate in physical activity fewer than three times a week, had gestational diabetes, and/or have polycystic ovary syndrome.3

According to M. Brooke Herndon, MD, in general internal medicine at Dartmouth-Hitchcock Medical Center and an assistant professor at the Geisel School of Medicine in New Hampshire, certain professions tend to put people at an increased risk for prediabetes, such as long-haul truck driving. "The work is so sedentary, and there's little access to healthy food," Herndon says. "Other vulnerable groups include people who work night shifts, and of course those with food insecurity," who often have limited access to nutrient-dense foods.

Diabetes may be diagnosed in seemingly low-risk individuals who happen to have glucose testing, in individuals tested based on diabetes risk assessment, and in symptomatic patients. Diagnosis of diabetes is determined by a fasting plasma glucose (FPG) test (>126 mg/dL [7 mmol/L]), the two-hour plasma glucose test (>200 mg/dL [11.1 mmol/L]) after a 75-g oral glucose tolerance test (OGTT), or a glycated hemoglobin (HbA1c) test (>6.5% [48 mmol/mol]).4

In prediabetes, blood sugar levels are higher than normal but not high enough to be diagnosed as type 2 diabetes. The diagnostic criteria for prediabetes are FPG levels of 100–125 mg/dL (6.9 mmol/L), two-hour plasma glucose in the 75-g OGTT of 140–199 mg/dL (11 mmol/L), or a HbA1c of 5.7% to 6.4% (39–47 mmol/mol).4

Many people with prediabetes who ignore lifestyle modifications will develop type 2 diabetes within five years. In addition, a person with undiagnosed or untreated prediabetes is also at increased risk for heart disease and stroke due to the degenerative changes that occur when blood glucose levels are poorly controlled.

Microangiopathy, in which the capillary basement membrane becomes thick and hard, causes obstruction or rupture of capillaries and small arteries, resulting in tissue necrosis and loss of function, as in the case of a myocardial infarct or cerebrovascular accident.5 Vascular degeneration in the kidney glomeruli—diabetic nephropathy—eventually leads to chronic renal failure.

Prediabetes: Medicalization or Intervention?
There is controversy over the usefulness of prediabetes as a diagnostic tool, suggesting that the current criteria threshold is too low and that labeling people as having prediabetes leads to medicalization of the condition.1 Some critics argue that the pharmaceutical industry conceived prediabetes, while others point out the large proportion of people with prediabetes who never progress to type 2 diabetes.

Yet proponents of the prediabetes diagnosis defend findings from meta-analyses,6,7 observational studies, and randomized controlled trials8,9 that show people with prediabetes have a three to 12 times faster progression to type 2 diabetes than does the general population. Moreover, although prediabetes is associated with an excess future risk of cardiovascular disease,10 little consideration has been given to the prevalence of cardiovascular and renal risk factors and disease in people with prediabetes, or to whether identifying people with prediabetes presents an opportunity to intervene and treat these risk factors.

To address this, Ali and colleagues of Emory University and fellow researchers at the CDC analyzed data from US National Health and Nutrition Examination Surveys (NHANES) between 1988 and 2014. Their goal was to examine trends in prevalence, treatment, and control of hypertension, dyslipidemia, and smoking; average 10-year risk of cardiovascular disease; and the presence of cardiovascular and renal comorbidities in adults by glycemic status.1 Cross-sectional survey data for almost 28,000 subjects was evaluated from NHANES survey periods of 1988 to 1994, 1999 to 2004, 2005 to 2010, and 2011 to 2014. Subjects defined as having diabetes were those who self-reported that a physician or other primary care provider had previously diagnosed them. The prediabetes population consisted of those defined with FPG of 100–125 mg/dL or HbA1c of 5.7% to 6.4%. Undiagnosed diabetics had an FPG of >126 mg/dL or HbA1c >6.5%, while subjects with a normal glycemic status were identified with an FPG of <100 mg/dL or an HbA1c of less than 5.7%.

Cardiovascular and Renal Burdens
Of the 2011 to 2014 population of adults with prediabetes, 36.6% had hypertension, 51.2% had dyslipidemia, 24.3% smoked, 7% had albuminuria, 4.6% had reduced estimated glomerular filtration rate, and a 10-year cardiovascular event risk ranged from 5% to 7%.

From 1988–1994 to 2011–2014, adults with prediabetes showed significant increases in hypertension, no change in dyslipidemia, decreases in smoking, increased use of treatment to lower blood pressure and reduce lipids, and increased goal achievements for blood pressure and lipids. Compared with adults with prediabetes, adults with diagnosed diabetes showed much greater improvements in cardiovascular and renal status because they were more likely to have received blood pressure-lowering and cholesterol-lowering treatments.

The absolute numbers of people with prediabetes grew substantially over 25 years, from 56.2 million to 78.5 million. Yet the prevalence of cardiovascular and renal risks and comorbidities remained the same over time, suggesting that people with prediabetes affected by these comorbidities outnumbered those with diabetes and similar risks or comorbidities. Thus, individuals with diagnosed diabetes have benefited from more treatments to lower blood pressure and lipids and have had a substantial decrease in 10-year risk of having a cardiovascular event. Of further interest, mean body mass index and waist-to-hip ratio increased substantially in every group.

Screening
Regardless of the high prevalence of prediabetes among Americans and data associating the cardiovascular and renal disease risks, many physicians don't regularly screen for prediabetes. Ali states that many of his clinical colleagues are simply not certain what to do when they see prediabetes. "Despite all the literature, many physicians do not see the value of [intervening with] prediabetes," he says. "And if patients are not symptomatic, they don't see it as having a bad endpoint, so they are not interested in addressing their elevated glucose levels."

Ali and his coresearchers point out important considerations their data represent in the ongoing debate about the medicalization of prediabetes. Even if conversion from prediabetes to type 2 diabetes is not particularly high, the number of people with cardiovascular and renal burdens is concerning. And, health care costs for prediabetes are higher than those for the general public; moreover, they increase when people do progress to diabetes.11 Meanwhile, some large gaps were evident in prescribing lipid-lowering drugs that may have reflected either a missed opportunity or, perhaps, physicians' apprehension given the risk of type 2 diabetes with statin use.12

The data also suggest that diagnosed diabetes was associated with significantly greater treatment and achievement of blood pressure and blood lipid goals. As only 1 in 10 people with prediabetes was aware of their increased blood glucose, identifying the condition may prompt earlier treatments, in turn lowering cardiovascular and renal risks.

Perhaps most important, early intervention for prediabetes is beneficial, with randomized controlled research showing that intensive lifestyle modifications—such as eating fiber-rich foods, participating in regular physical activity, and managing weight—for people with impaired glucose can slow their progression to type 2 diabetes.13,14 According to Medha Munshi, MD, director of the Geriatrics Clinic at Joslin Diabetes Center and director of the Outpatient Geriatric Program at Beth Israel Deaconess Medical Center, lifestyle management is considered a standard strategy in her practice. "It's important to push the point that managing prediabetes is not about managing diabetes; rather, it's about managing overall health," she says. "Eating a healthier diet and participating in regular physical activity are activities that most people should be doing anyway," Munshi points out.

For overweight or obese adults ages 40 to 70, the US Preventive Services Task Force (USPSTF) recommends screening for abnormal blood glucose as part of a cardiovascular risk assessment. Clinicians should offer or refer patients with abnormal blood glucose to intensive behavioral counseling interventions to promote a healthful diet and physical activity.15 Research investigating the performance of the full 2015 USPSTF dysglycemia screening recommendation found that approximately one-half of the US population without diagnosed diabetes was identified with dysglycemia.16

Lifestyle Modification
Ali and his colleagues noted that they are not advocating for earlier initiation of glucose-lowering prescriptions to prevent diabetes, as aggregated data have shown that these medications serve only to suppress glucose for a certain period of time, having no effect on the pathophysiology of diabetes.17 Rather, the authors endorse early intervention and lifestyle modifications that may preserve quality of life for longer with associated benefits such as improved blood pressure and cholesterol levels18 and less need for medications.19,20 Ali is confident that "lifestyle modification is effective in both treating prediabetes and reducing the progression of prediabetes to diabetes."

Results from the US Diabetes Prevention Program (DPP)—a randomized clinical study of more than 3,000 nondiabetic subjects with elevated fasting and postload plasma glucose concentrations—demonstrated that lifestyle intervention reduced diabetes incidence by 58%, whereas the prescription drug metformin reduced it by 31% compared with a placebo.8 The lifestyle intervention was significantly more effective than was metformin—with one case of diabetes prevented per seven persons adhering to modifications in lifestyle for three years. Of particular interest to geriatric practitioners, in both the DPP 10- and 15-year outcome studies, twice as many subjects aged 60 to 85 years participated in quarterly lifestyle sessions than did those aged 25 to 44 years.13,21

Herndon agrees that lifestyle modification can be effective in deterring prediabetes in most patients, but observes some common barriers to change: depression, social strain, and financial strain. "There are also some who get caught in a vicious cycle that begins with a chronic condition such as back pain, which leads to decreased activity and underemployment, followed by weight gain," says Herndon. "And sometimes it's hard to unravel this once it gets going." Many people who've been told they have prediabetes either don't have the motivation or feel that lifestyle changes are too challenging to pursue. In a survey to assess treatment preferences for high blood pressure, respondents were more likely to choose a daily cup of tea or a pill over recommended lifestyle changes such as exercise as first line to prolong their life.22

Yet a lifestyle change program offered through the CDC-led National DPP (see resource box) can help patients reduce their risk of developing type 2 diabetes by as much as 58%, or 71% for patients older than age 60.3 Compared with no intervention, lifestyle modification for prediabetes might also offer a promising opportunity to preserve quality of life for longer.

According to Munshi, "The problem with defining prediabetes as a condition [is that it] makes people automatically think of prescription medication, which is probably the fault of the medical community. We need to liberalize the guidelines for treatment." She first asks her patients what they are currently doing for exercise. For sedentary individuals, she asks her patients to consider walking around the house for five minutes after using the bathroom and before each meal. "I've probably put Fitbits on more patients than anyone! If a patient tells me they are doing 100 steps, I ask them to build upon that, go for 200." Munshi takes the same approach to help patients improve their diets, referring them to a registered dietitian nutritionist for some initial, simple tweaks from their current food intake.

Prediabetes in the Geriatric Clinic
Munshi notes that helping her geriatric patients manage their diabetes requires additional considerations, such as assessing cognitive function: "Are they forgetting to eat or take their medications?" She continues, "In geriatrics, we need to try to determine what are the results of aging and what are the results of the diabetes as a disease." She also advises that "we can't rely on A1c to diagnose or as a treatment goal as aging systems can also impact glycation of hemoglobin," considering the risk vs benefit associated with tight glycemic control. Benefits of therapy in an effort to lower HbA1c should be weighed against the greater risk of hypoglycemia, as the geriatric population is less likely to benefit from reducing the risk of microvascular complications and more likely to suffer serious adverse effects from hypoglycemia.23

Munshi urges specific caution with prediabetic older patients, for example, who may have acute incidents and get admitted to the hospital with urinary tract infections. "Their FPG goes high and they are treated but then discharged on a prescription to lower their blood sugar and end up in the emergency room with an FPG of 30."

Summary
For individuals with prediabetes, lifestyle modification is the cornerstone of diabetes prevention, with evidence pointing to a 40% to 70% relative risk reduction.9,24 The findings of Ali and colleagues show that of the 1 in 3 people who have diabetes, one-half have comorbidities such as hypertension and dyslipidemia, leading to excess cardiovascular and renal disease risk. As the opportunities and benefits to intervene with lifestyle modifications outweigh the concern for the medicalization of prediabetes, this research calls for targeting intervention for cardiometabolic health as an investment in the broader population, substantially reducing a widespread burden.

— KC Wright, MS, RDN, the principal at Wildberry Communications, has clinical, academic, and research experience. She advocates for healthy lifestyles and sustainable food systems at www.wildberrycommunications.com.

Resources
• National Diabetes Prevention Program: www.cdc.gov/diabetes/prevention/index.html

• Prediabetes Screening: How and Why: www.niddk.nih.gov/health-information/communication-programs/ndep/health-professionals/game-plan-preventing-type-2-diabetes/prediabetes-screening-how-why

• How to Talk With Patients About Their Prediabetes Diagnosis: www.niddk.nih.gov/health-information/communication-programs/ndep/health-professionals/game-plan-preventing-type-2-diabetes/how-talk-patients-about-prediabetes-diagnosis

• National Registry of Recognized Diabetes Prevention Programs: https://nccd.cdc.gov/DDT_DPRP/Registry.aspx

References
1. Ali MK, Bullard KM, Saydah S, Imperatore G, Gregg EW. Cardiovascular and renal burdens of prediabetes in the USA: analysis datea from serial cross-sectional surveys, 1988-2014. Lancet Diabetes Endocrinol. 2018;6(5):392-403.

2. National Diabetes Statistics Report. Centers for Disease Control and Prevention website. https://www.cdc.gov/diabetes/data/statistics/statistics-report.html. Updated February 24, 2018. Accessed April 25, 2018.

3. Prediabetes. Centers for Disease Control and Prevention website. https://www.cdc.gov/
diabetes/basics/prediabetes.html. Updated July 25, 2017. Accessed April 30, 2018.

4. American Diabetes Association. Standards of Medical Care in Diabetes — 2016. Diabetes Care. 2016;39(Suppl1):S13-S22.

5. Gould BE. Pathophysiology for the Health-Related Professions. Philadelphia, PA: W.B. Saunders;1997:387.

6. Gerstein HC, Santaguida P, Raina P, et al. Annual incidence and relative risk of diabetes in people with various categories of dysglycemia: a systematic overview and meta-analysis of prospective studies. Diabetes Res Clin Pract. 2007;78(3):305-312.

7. Morris DH, Khunti K, Achana F, et al. Progression rates from HbA1c 6.0-6.4% and other prediabetes definitions to type 2 diabetes: a meta-analysis. Diabetologia. 2013;56(7):1489-1493.

8. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393-403.

9. Tuomilehto J, Lindström J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344(18):1343-1350.

10. Emerging Risk Factors Collaboration, Di Angelantonio E, Khan H, et al. Glycated hemoglobin measurement and prediction of cardiovascular disease. JAMA.2014;311(12):1225-1233.

11. Dall TM, Yang W, Halder P, et al. The economic burden of elevated blood glucose levels in 2012: diagnosed and undiagnosed diabetes, gestational diabetes mellitus, and prediabetes. Diabetes Care. 2014;37(12):3172-3179.

12. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomized statin trials. Lancet. 2010;375(9716):735-742

13. Diabetes Prevention Program Research Group. Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. Lancet Diabetes Endocrinol. 2015;3(11):866-875.

14. Li G, Zhang P, Wang J, et al. Cardiovascular mortality, all-cause mortality, and diabetes incidence after lifestyle intervention for people with impaired glucose tolerance in the Da Qing Diabetes Prevention Study: a 23-year follow-up study. Lancet Diabetes Endocrinol. 2014;2(6):474-480.

15. Final recommendation statement: abnormal blood glucose and type 2 diabetes mellitus: screening. U.S. Preventive Services Task Force website. https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/
screening-for-abnormal-blood-glucose-and-type-2-diabetes. Updated October 2015. Accessed April 27, 2018.

16. O'Brien MJ, Bullard KM, Zhang Y, et al. Performance of the 2015 US Preventive Services Task Force Screening Criteria for Prediabetes and Undiagnosed Diabetes. J Gen Intern Med. 2018;33(7):1100-1108.

17. Haw J, Galaviz KI, Straus AN, et al. Long-term sustainability of diabetes prevention approaches: a systematic review and meta-analysis of randomized clinical trials. JAMA Intern Med. 2017;177(12):1808-1817.

18. Mudaliar U, Zabetian A, Goodman M, et al. Cardiometabolic risk factor changes observed in diabetes prevention programs in US settings a systematic review and meta-analysis. PLoS Med. 2016;13(7):e1002095.

19. Uusitupa M, Peltonen M, Lindstrom J, et al. Ten-year mortality and cardiovascular morbidity in the Finnish Diabetes Prevention Study—secondary analysis of the randomized trial. PLoS One. 2009;4(5):e5656.

20. Balk EM, Earley A, Raman G, Avendano EA, Pittas AG, Remington PL. Combined diet and physical activity promotion programs to prevent type 2 diabetes among persons at increased risk: a systematic review for the Community Preventive Services Task Force. Ann Intern Med. 2015;163(6):437-451.

21. Diabetes Prevention Program Research Group. 10-year follow-up diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 2009;374(9702):1677-1686.

22. Spatz ES, Shahu A, Kliot T, et al. Antihypertension treatment disutility among U.S. adults. Paper presented at: American Heart Association Quality of Care and Outcomes Research Scientific Sessions; April 7, 2018; Arlington, VA.

23. Alam T, Weintraub N, Weinreb J. What is the proper use of hemoglobin A1c montoring in the elderly? J Am Med Dir Assoc. 2005;6(3):200-204.

24. Tabák AG, Herder C, Rathmann W, Brunner EJ, Kivimäki M. Prediabetes: a high-risk state for developing diabetes. Lancet. 2012;379(9833):2279-2290.