Diabetes: Medications as Adjunct Therapy for Prediabetes
By Jill Weisenberger, MS, RDN, CDCES, CHWC, FAND
Today’s Dietitian
Vol. 25 No. 4 P. 14

In the United States, more than one-third of adults have prediabetes, the leading risk factor for type 2 diabetes and a major risk factor for coronary artery disease. Unfortunately, only 19% of people with prediabetes are aware they have the disorder.1 Of those who have been diagnosed, only a fraction is taking meaningful steps to prevent the progression to type 2 diabetes.

Problem With Prediabetes
Many consumers and health care professionals are blind to the problems associated with prediabetes. “Prediabetes is not benign,” says Sam Dagogo-Jack, MD, DSc, author of Prediabetes: A Fundamental Text and chief of the division of endocrinology, diabetes, and metabolism at the University of Tennessee Health Science Center. He says most people with prediabetes will advance to type 2 diabetes within a decade, but even without progression to diabetes, persistent prediabetes is a toxic state. One issue is that people with prediabetes are at risk of both microvascular and macrovascular complications.

Various studies find alarming rates globally of microvascular complications among people with prediabetes. According to the research, about 14% of people with prediabetes have retinopathy, nearly 18% have chronic kidney disease, and 11% to 25% are noted to have neuropathy.2 These microvascular complications are likely related to glycemic exposure, Dagogo-Jack says.

In addition, people with prediabetes have increased risk of cardiovascular, cerebrovascular, and peripheral vascular complications compared with people with normoglycemia. Although hyperglycemia may play a role, more likely contributors are insulin resistance and associated risk factors, such as hypertension, dyslipidemia, proinflammatory markers, and endothelial dysfunction, Dagogo-Jack says.

Goals for People With Prediabetes
When working with clients with prediabetes, dietitians will have to field questions about the best course of action. Clients will want to know how to prevent type 2 diabetes and whether they can reverse prediabetes. Dagogo-Jack argues that the primary goal should be a return to normoglycemia because remission of prediabetes offers the greatest protection from diabetes and its complications. In addition, even a temporary return to normoglycemia is associated with a lower risk of diabetes and microvascular complications.

The American Diabetes Association’s (ADA) Standards of Care in Diabetes—2023 discusses individualized care goals for the prevention or delay of type 2 diabetes in Chapter 3, “Prevention or Delay of Type 2 Diabetes and Associated Comorbidities,” but doesn’t specifically call out remission in that chapter.2 The guidelines address weight loss or prevention of weight gain, minimizing the progression of hyperglycemia, and cardiovascular risk factors such as high blood pressure and dyslipidemia. The primary treatment recommendations center around lifestyle changes, although medications are encouraged under certain conditions.

The guidelines are based on results from major randomized controlled trials, including the Diabetes Prevention Program (DPP), that have found lifestyle intervention to be a successful strategy for the prevention of type 2 diabetes, as well as for improvement of blood pressure, lipids, inflammation, and other cardiometabolic risk factors. The DPP used a goal-based lifestyle intervention in which participants were asked to lose at least 7% of their starting body weight within six months and engage in at least 150 minutes of moderate-intensity exercise each week.

The results of the DPP and the long-term DPP Outcomes Study have been impressive, showing that intensive lifestyle intervention reduced the risk of incident diabetes by 58% over three years and by 27% after 15 years. Thus, the ADA’s current recommendations for anyone overweight or obese at high risk of developing type 2 diabetes follow the same exercise and weight loss goals of the DPP.2

Medications in Prediabetes
The DPP and other studies also have looked at medications typically used in the treatment of type 2 diabetes, examining their efficacy for diabetes prevention. Specifically, researchers have found metformin, alpha-glucosidase inhibitors, liraglutide, semaglutide, and thiazolidinediones beneficial.2 During the three-year DPP study, metformin performed less effectively than lifestyle intervention but still showed impressive results with a 31% reduction in the conversion to diabetes compared with placebo. After 15 years, metformin reduced type 2 diabetes by 18%.2

Because of the DPP and DPP Outcomes Study results and the long-term safety profile of metformin, the ADA recommends considering metformin in adults most likely to benefit, such as those between the ages of 25 and 59, with BMI > 35 kg/m2, who have an A1c > 6, or who have a history of gestational diabetes.

In the DPP and other studies, weight loss was the most important factor associated with the prevention of type 2 diabetes and the return to normoglycemia. Every kilogram of weight loss conferred a 16% reduction in risk of progression to type 2 diabetes over 3.2 years in the DPP. Because weight loss through lifestyle changes alone is hard to maintain long term, the ADA Standards of Care include antiobesity medications in its recommendations for weight loss.2

Both liraglutide (Victoza) and semaglutide (Ozempic) are antidiabetes medications that are FDA approved at different doses to treat obesity—and are called Saxenda and Wegovy, respectively. Other FDA-approved antiobesity medications include orlistat and phentermine-topiramate. Each of these has been shown to decrease the incidence of diabetes among people with prediabetes and may be considered an adjunct to prediabetes treatment.2 The antiobesity medications work in various ways and may improve adherence to dietary recommendations. For example, liraglutide and semaglutide act to slow digestion from the stomach, increase the feelings of fullness, and modulate action of the brain’s satiety center.

Weighing Medication Risks and Benefits
Though no medication is FDA approved for the treatment of prediabetes, metformin is sometimes used in high-risk individuals. Even with clinical evidence to support efficacy, “we also need to think about the risks and costs of the medications vs the benefits,” says Sneha Srivastava, PharmD, BCACP, CDCES, DipACLM, FADCES, of the Rosalind Franklin University of Medicine and Science in North Chicago, Illinois, and a spokesperson for the Association of Diabetes Care and Education Specialists.

Metformin is relatively low in cost because it’s in generic form, but many people experience significant gastrointestinal side effects, including discomfort, diarrhea, and loss of appetite, Srivastava says. Many patients will build tolerance to metformin’s side effects by starting at a low dose and taking the medication with meals. Long-term use is associated with vitamin B12 deficiency, so patients should be screened for this annually after taking metformin for four years.2

Liraglutide and semaglutide are more expensive because they’re available only as brand names. Srivastava explains that even though many insurance companies include them on formulary, the copays are sometimes quite high, and the insurance companies often require prior authorization. Side effects of these drugs include nausea, vomiting, diarrhea, and constipation. “These gastrointestinal-related side effects can be managed by starting at a low dose and eating smaller meals,” she says.

Medications for CVD Prevention
Because prediabetes confers a high risk of CVD, both lifestyle and medication interventions should be considered to achieve and maintain targets for blood pressure and lipids. Statin drugs are commonly used to lower LDL-cholesterol levels, inflammation, and CVD risk. This class of drugs is associated with a modest increased risk of type 2 diabetes. However, in primary prevention studies, both cardiovascular and mortality benefits of statin therapy are greater than the risk of diabetes, suggesting an overall benefit to statin use.2

Tobacco use also must be considered, as smoking is a risk factor for type 2 diabetes and CVD. RDs can refer clients to smoking cessation programs and suggest they discuss the use of smoking cessation medications with their providers.

Understanding the role medications may play as an adjunct to lifestyle and behavioral changes in people with prediabetes can help dietitians empower their clients to have meaningful conversations with their physicians. “Lifestyle medicine is incredible,” Srivastava says. Some people with prediabetes or diabetes can achieve normoglycemia and lowered CVD risk without the use of medications, but medication is a useful tool in the toolbox.

— Jill Weisenberger, MS, RDN, CDCES, CHWC, FAND, is the author of several books, including Prediabetes: A Complete Guide, Second Edition. She’s a freelance writer, nutrition and diabetes consultant to the food industry, and the creator of online courses for people with prediabetes and others.

1. Prevalence of prediabetes among adults. Centers for Disease Control and Prevention website. https://www.cdc.gov/diabetes/data/statistics-report/prevalence-of-prediabetes.html. Updated September 30, 2022. Accessed January 5, 2023.

2. ElSayed NA, Aleppo G, Aroda VR, et al. 3. Prevention or delay of type 2 diabetes and associated comorbidities: standards of care in diabetes—2023. Diabetes Care. 2023;46(1):S41-S48.