Management of Prediabetes
The primary goal of prediabetes management is to normalize glucose levels and prevent or delay progression to diabetes and associated microvascular complications (1,2). Management of common prediabetes comorbidities such as obesity, hypertension, dyslipidemia, cardiovascular disease, and chronic kidney disease is also essential.
Therapeutic Lifestyle Management
Given its safety and the strength of evidence for its effectiveness in improving glycemia and reducing cardiovascular disease (CVD) risk factors, the preferred treatment approach for prediabetes is intensive lifestyle management (1,2). Therapeutic lifestyle management should be discussed with all patients with prediabetes at the time of diagnosis and throughout their lifetimes. Therapeutic lifestyle management includes medical nutrition therapy (MNT; the reduction and modification of caloric and saturated/hydrogenated fat intake to achieve weight loss in individuals who are overweight or obese), appropriately prescribed physical activity, avoidance of tobacco products, adequate quantity and quality of sleep, limited alcohol consumption, and stress reduction (2).
While lifestyle modifications may be difficult to maintain, the following strategies have been shown to increase the likelihood of patient success (1,2):
- Patient self-monitoring
- Realistic and stepwise goal setting
- Stimulus control
- Cognitive strategies
- Social support
- Appropriate reinforcement
Primary care providers (PCPs) often take on the responsibility of encouraging behavior changes. The Avoiding Diabetes Through Action Plan Targeting (ADAPT) trial has developed a system that combines evidence-based interventions for behavioral change with existing health record technology to improve primary care providers’ ability to effectively counsel patients on lifestyle behavior changes. The ADAPT system, which is currently being studied, combines shared goal setting and feedback, patient contracts, tailored approaches, reminders, and other strategies to integrate evidence-based behavior change principles into the electronic health record to optimize PCP counseling efficacy during routine visits. The ADAPT system has the potential to be an adaptable and scalable technology-enabled behavior change tool for PCPs (3,4).
The effectiveness of structured lifestyle interventions was conclusively demonstrated in the US Diabetes Prevention Program (DPP), which compared intensive lifestyle change to metformin and placebo. The structured lifestyle interventions included training people with prediabetes to achieve modest weight loss through diet and physical activity. Relative to placebo, lifestyle intervention reduced 3-year diabetes incidence by 58% compared with a 31% reduction in the metformin group (5), and continued benefits were confirmed in a 10-year follow-up of the DPP, which showed a 34% reduction in type 2 diabetes (T2D) incidence relative to placebo (6).
A systematic meta-analysis and review of 28 US-based studies demonstrated that the translation of the lifestyle interventions of the DPP into real-world settings yields significant and sustainable benefits for people at high risk for diabetes (7). Across the 28 studies, the average weight loss was 4% after 1 year. In an analysis limited to 17 studies with a 9-month or greater follow-up assessment, the authors found that for each lifestyle session attended, there was a 0.26% decrease in weight. These findings greatly support the implementation of the DPP lifestyle interventions in the treatment of prediabetes.
Medical Nutrition Therapy (MNT)
MNT is an important aspect of therapeutic lifestyle management that should be discussed with every patient with prediabetes. Recommendations should be personalized and, if possible, patient evaluation and teaching should be conducted by a registered dietitian (RD) or knowledgeable physician (2).
Key MNT recommendations include the following (2):
- Consistency in day-to-day carbohydrate intake
- Limitation of sucrose-containing or high-glycemic index foods
- Adequate protein intake
- Weight management
Aerobic exercise and strength training improve cardiovascular disease (CVD) risk factors, decrease the risk of falls and fractures, and improve functional capacity and well-being. Physical activity is also a key component in weight loss and maintenance and is particularly important in weight maintenance (2). A program of regular moderate-intensity physical activity for 30 to 60 minutes daily, at least 5 days per week, is recommended (1,2).
Key points to remember when counseling patients on exercise are (2):
- Patients must be evaluated initially for contraindications and/or limitations to increased physical activity.
- An exercise prescription should be developed for each patient based on his or her goals and limitations.
- Any new physical activity should be started slowly and built up gradually.
Weight loss is a fundamental tenet of prediabetes management. All patients should be advised on how to achieve and maintain a healthful weight, corresponding to a body mass index (BMI) between 18.5 and 24.9 kg/m2. Recommendations should be personalized on the basis of a patient’s specific medical conditions, lifestyle, and behaviors. Patients unable to maintain a healthy weight on their own should be referred to an RD or weight-loss program with a proven history of success (2).
Individuals with overweight or obesity should strive for a 5% to 10% reduction in weight and should avoid weight gain. Both MNT and physical activity are essential to achieving this goal, but medical or surgical weight loss therapy may be indicated for patients who cannot achieve weight loss goals with lifestyle change alone (1,2,8,9).
Pharmacologic Approaches to Glucose Management in Prediabetes
For patients in whom lifestyle modification fails to produce necessary improvement after 3 to 6 months, pharmacologic intervention may be appropriate (2,8). However, no medications are currently approved by the US Food and Drug Administration (FDA) for the management of prediabetes; thus, any decision to implement pharmacologic therapy for prediabetes, especially in children/adolescents, is off-label and requires careful judgment regarding the risks and benefits of each specific agent for each individual patient.
A risk-benefit assessment should be conducted before starting any medication. Pharmacologic drug therapy should be considered for higher-risk patients rather than lower-risk patients (unless there is evidence for progressive deterioration of blood glucose levels despite lifestyle modification). High-risk patients include those with some combination of impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and/or the metabolic syndrome (ie, ≥2 of these risk factors). Other key considerations in decision making should include worsening glycemia, the presence of CVD and/or nonalcoholic fatty liver disease (NAFLD), or a history of gestational diabetes mellitus (GDM) or polycystic ovary syndrome (PCOS) (2,8).
Weight Loss Agents
The weight loss effects of phentermine/topiramate extended release (ER) are associated with improved glucose tolerance and a reduced incidence of T2D of 79% after 2 years in patients with prediabetes (10,11). Four years of orlistat treatment reduced the incidence of T2D by 34% relative to placebo (12), and 56 weeks of liraglutide 3 mg treatment delayed progression to T2D and significantly improved glucose tolerance (13).
Metformin. Metformin has been shown to have beneficial effects on metabolic syndrome components, including mild to moderate weight loss, lipid profile improvements, and improved fibrinolysis (9). In addition, lifestyle and metformin were both highly effective in delaying or preventing T2D in women with a history of GDM and IGT (14). In the DPP study, metformin alone was not as effective as the intensive lifestyle intervention, which was associated with a 58% reduction in incidence of diabetes, but the metformin group did experience a 31% decrease relative to placebo. At the 10-year follow-up, the metformin group’s risk of T2D remained 18% lower than the placebo group’s (6).
Acarbose. In the STOP-NIDDM (Stop Noninsulin-Dependent Diabetes Mellitus) Trial, acarbose improved CVD outcomes and reduced progression to diabetes in patients with IGT (1,15-17). In this trial, acarbose was associated with a significant reduction in the incidence of both myocardial infarction and hypertension, suggesting a reduced risk of coronary heart disease with this treatment (16). Additionally, the relative risk of progression from IGT to diabetes was reduced by 25% in acarbose-treated patients vs placebo-treated patients. This benefit held even after adjusting for age, sex, and BMI (17).
Thiazolidinediones. The TZDs rosiglitazone and pioglitazone have been shown to prevent T2D in 60% and 72%, respectively, of high-risk patients (18,19). However, because of these drugs’ associated adverse effects, their use in prediabetes is controversial (2,8,9).
Insulin Glargine. In the Outcome Reduction with Initial Glargine Intervention (ORIGIN) study, 3-4 weeks of glargine treatment reduced the incidence of diabetes by 31% in patients without diabetes at baseline (11% of total study population). In the entire cohort of >12,000 patients, glargine therapy had a neutral effect on cardiovascular outcomes and cancer (20).
GLP-1 Receptor Agonists. The glucagon-like peptide 1 (GLP-1) receptor agonist exenatide has been shown to reduce weight and improve glucose tolerance in patients with obesity and prediabetes (21). As mentioned above, liraglutide 3 mg (indicated for the treatment of obesity) has been shown to delay onset of T2D (13). Liraglutide 1.8 mg, the dosage used to treat T2D, has also been shown to reduce T2D risk (22,23).
Management of Children and Adolescents With Prediabetes
The management of children or adolescents at increased risk for T2D should apply many of the same measures recommended to prevent or delay the progression to diabetes in adults at elevated risk (1). In these patients, emphasis must be placed primarily on lifestyle change, which can be beneficial in improving glycemic and cardiovascular risk parameters. Although there have been few interventional studies among children that are directed at reducing diabetes and/or cardiovascular risk, the increased incidence of T2D in this age group parallels an increase in obesity, which has been attributed to increased caloric consumption and diminished exercise/activity.
- Garber AJ, Handelsman Y, Einhorn D, Bergman DA, Bloomgarden ZT, Fonseca V, et al. Diagnosis and management of prediabetes in the continuum of hyperglycemia: when do the risks of diabetes begin? A consensus statement from the American College of Endocrinology and the American Association of Clinical Endocrinologists. Endocr Pract. 2008;14:933-46.
- Handelsman Y, Bloomgarden ZT, Grunberger G, Umpierrez G, Zimmerman RS, Bailey TS, et al. American Association of Clinical Endocrinologists and American College of Endocrinology: clinical practice guidelines for developing a diabetes mellitus comprehensive care plan—2015. Endocr Pract. 2015;21:1-87.
- Devine EB, Lee CJ, Overby CL, Abernethy N, McCune J, Smith JW, et al. Usability evaluation of pharmacogenomics clinical decision support aids and clinical knowledge resources in a computerized provider order entry system: a mixed methods approach. Int J Med Inform. 2014;83:473-83.
- Mann DM, Lin JJ. Increasing efficacy of primary care-based counseling for diabetes prevention: rationale and design of the ADAPT (Avoiding Diabetes Thru Action Plan Targeting) trial. Implement Sci. 2012;7:6.
- Diabetes Prevention Program Research Group, Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.
- Diabetes Prevention Program Research Group, Knowler WC, Fowler SE, Hamman RF, Christophi CA, Hoffman HJ, et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study [Erratum in Lancet. 2009;374:2054]. Lancet. 2009;374:1677-86.
- Ali MK, Echouffo-Tcheugui J, Williamson DF. How effective were lifestyle interventions in real-world settings that were modeled on the Diabetes Prevention Program? Health Aff (Millwood). 2012;31:67-75.
- Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, et al. AACE/ACE comprehensive diabetes management algorithm 2015. Endocr Pract. 2015;21:438-47.
- Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, et al. American Association of Clinical Endocrinologists' comprehensive diabetes management algorithm 2013 consensus statement. Endocr Pract. 2013;19:1-48.
- Garvey WT, Ryan DH, Henry R, Bohannon NJ, Toplak H, Schwiers M, et al. Prevention of type 2 diabetes in subjects with prediabetes and metabolic syndrome treated with phentermine and topiramate extended release. Diabetes Care. 2014;37:912-21.
- Garvey WT, Ryan DH, Look M, Gadde KM, Allison DB, Peterson CA, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. 2012;95:297-308.
- Torgerson JS, Hauptman J, Boldrin MN, Sjostrom L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients [Erratum in Diabetes Care. 2004;27:856]. Diabetes Care. 2004;27:155-61.
- Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med. 2015;373:11-22.
- Ratner RE, Christophi CA, Metzger BE, Dabelea D, Bennett PH, Pi-Sunyer X, et al. Prevention of diabetes in women with a history of gestational diabetes: effects of metformin and lifestyle interventions. J Clin Endocrinol Metab. 2008;93:4774-9.
- STOP-NIDDM Trial Research Group, Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, et al. Acarbose for the prevention of type 2 diabetes, hypertension and cardiovascular disease in subjects with impaired glucose tolerance: facts and interpretations concerning the critical analysis of the STOP-NIDDM Trial data. Diabetologia. 2004;47:969-75; discussion 76-7.
- STOP-NIDDM Trial Research Group, Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, et al. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA. 2003;290:486-94.
- STOP-NIDDM Trial Research Group, Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, et al. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet. 2002;359:2072-7.
- DeFronzo RA, Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, et al. Pioglitazone for diabetes prevention in impaired glucose tolerance. N Engl J Med. 2011;364:1104-15.
- DREAM (Diabetes REduction Assessment with rampipril and rosiglitazone Medication) Trial Investigators, Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, et al. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial [Erratum in: Lancet. 2006:368:1770]. Lancet. 2006;368:1096-105.
- Gerstein HC, Bosch J, Dagenais GR, Diaz R, Jung H, Maggioni AP, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367:319-28.
- Rosenstock J, Klaff LJ, Schwartz S, Northrup J, Holcombe JH, Wilhelm K, et al. Effects of exenatide and lifestyle modification on body weight and glucose tolerance in obese subjects with and without pre-diabetes. Diabetes Care. 2010;33:1173-5.
- Kim SH, Abbasi F, Lamendola C, Liu A, Ariel D, Schaaf P, et al. Benefits of liraglutide treatment in overweight and obese older individuals with prediabetes. Diabetes Care. 2013;36:3276-82.
- Astrup A, Rossner S, Van Gaal L, Rissanen A, Niskanen L, Al Hakim M, et al. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet. 2009;374:1606-16.