Treating Prediabetes With Medications … or Not

Abstract

There is abundant evidence about the impact of physical activity on health. Many of the clinical guidelines include physical activity as a strong recommendation in treatment plans to optimize health outcomes; however it is necessary to consider the interaction between medications and physical activity. There are certain medical conditions, including cardiovascular disease, diabetes, pain and urinary incontinence that may directly impact physical activity as well as medications for those conditions can affect how a person can be physically active. Having individualized conversations with patients to determine ways to incorporate physical activity into their lives may lead to healthier outcomes.

“This approach may also include prescribing metformin, which is potentially beneficial for individuals at higher risk.”

Introduction

Prediabetes is a condition that is under-recognized, underdiagnosed, undertreated, and under-prioritized. There have been arguments and counterarguments about recognizing prediabetes as a defined medical condition that needs to be addressed and treated by health care providers and patients. Even the experts disagree; for example, at this time, the World Health Organization does not use the term prediabetes, instead categorizing the hyperglycemia that occurs prior to the diabetes diagnosis threshold as “impaired glucose regulation” based on fasting glucose and/or glucose tolerance values. There are different reasons cited for the controversy with prediabetes; these include but are not limited to (1) the defined thresholds continue to change over time, and with the glucose thresholds becoming lower to encompass prediabetes, the number of people with this diagnosis is staggering and overwhelming; (2) the evidence for interventions in the prediabetes populations does show positive outcomes; however, there are many nuances including the rate of progressing to diabetes or how impactful the interventions were on long-term diabetes complications or mortality; (3) ??? understanding that the complexity of type 2 diabetes going beyond a glucocentric approach even though the current diagnosis is based on glucose values; and (4) the need for more well-designed studies that test the various thresholds and continue to look at patient-related outcomes. At the same time, there is ample evidence that is without argument of the impact of hyperglycemia on micro- and macrovascular outcomes. DOES THIS MEAN THERE IS AMPLE EVIDENCE BEYOND DISPUTE THAT HYPERGLYCEMIA HAS AN IMPACT ON MICRO- AND MACROVASCULAR OUTCOMES.^1,2 In general, the controversy is not necessarily whether or not prediabetes is a condition that can lead to negative patient outcomes. Rather, the questions are: what are the optimal glucose thresholds; which patients beyond those categorized as high-risk due to multiple risk factors might also benefit from treatment options such as the diabetes prevention program and/or medications; what are the long-term outcomes for all patients with prediabetes; do providers need to prioritize having this conversation with all patients with prediabetes considering time constraints; and what are the current recommendations to address prediabetes. While experts and researchers continue to explore these questions, this paper will summarize the current pharmacologic approach to prediabetes, while acknowledging and reaffirming that lifestyle medicine based interventions have the strongest evidence to prevent the progression of prediabetes to diabetes and other medical conditions. ³

Prediabetes: Definition and Pathophysiology

Per the American Diabetes Association (ADA) Standards of Care in Diabetes—2024, prediabetes in non-pregnant people is defined as meeting one of the following three criteria: (1) A1C 5.7 to 6.4%; OR (2) fasting blood glucose of 100 to 125 mg/dL; OR (3) a 2-hour prandial glucose during 75-g OGTT of 140 to 199 mg/dL.

Guideline-Based Recommendations

The ADA has several recommendations for prediabetes. ⁴ Adults at high risk of diabetes due to being overweight or obese should be referred to an intensive lifestyle behavior change program, which should promote a healthy reduced calorie diet and ≥150 minutes/week of moderate intensity physical activity to achieve/maintain a 7% loss of body weight. Metformin should be considered in adults at high risk of type 2 diabetes including those who are 25–59 years of age with BMI ≥35 kg/m², higher fasting plasma glucose (≥110 mg/dL), and/or individuals with a history of gestational diabetes. ⁵

Pharmacotherapy

Metformin

Metformin is the most widely studied medication in the treatment of prediabetes, and many of the studies that evaluate the efficacy of various interventions for prediabetes include metformin as an intervention. The recommendation to prescribe metformin in patients with prediabetes came from the Diabetes Prevention Program (DPP) and Diabetes Prevention Program Outcomes Study (DPPOS). While lifestyle modifications were more effective than metformin, the differences between the groups attenuated over time as seen in the DPPOS. ⁵ A review that included 40 articles published between 1998 and 2017 evaluating metformin use for the primary indication of diabetes prevention concluded that metformin was associated with a reduced relative risk of incident diabetes. This evidence was strongest for those at highest risk, including age ≤60 years, BMI ≥35 kg/m², and women with history of gestational diabetes. The study designs included in this review were randomized controlled trials (including the Diabetes Prevention Program, the largest RCT including metformin as an intervention), observational analyses, and real-world assessments. ⁶

On the other hand, the arguments against the broad use of metformin in people with prediabetes include the substantial number of people with prediabetes either returning to normal glucose regulation or not progressing to diabetes, and people with prediabetes may not be at a risk for microvascular complications, and one of metformin’s main mechanism is increasing insulin sensitivity, targeting glucose levels. ⁷ If there is not strong correlation between targeting blood glucose solely in prediabetes with a medication and if sometimes people become normoglycemic anyway, why start a medication that may be continued forever. In general, it is important to look at the patient with prediabetes holistically—ensuring lifestyle modifications are emphasized, and, as appropriate, considering metformin based on the unique, individualized factors present in a given patient with prediabetes.

Metformin is FDA-approved for the treatment of diabetes mellitus type 2; however, it is also used for other indications including antipsychotic-induced weight gain; prevention of type 2 diabetes; gestational diabetes mellitus (treatment); and ovarian hyperstimulation syndrome prevention in patients with polycystic ovary syndrome undergoing in vitro fertilization/intracytoplasmic sperm injection. It is available as an oral solution, tablet, and extended release tablet.

People who are taking metformin should be periodically evaluated for vitamin B12 deficiency, especially if they have anemia or peripheral neuropathy or if they have been taking metformin for a longer period of time (deficiencies may be seen around year 4 or 5 of metformin use). If other factors are present for B12 deficiency, people should be evaluated yearly while taking metformin. Gastrointestinal-related adverse effects include diarrhea, flatulence, and nausea/vomiting (occurring more often with the immediate release formulation), and are typically transient in nature. It is imperative to start at a lower dose, typically once a day with a meal; this dose then can be titrated to efficacious doses as tolerated. Less common adverse effects (1 to 10%) include but are not limited to other abdominal distress, distension, dyspepsia, asthenia, and headache. In addition, while rare, it is worth nothing that another adverse effect linked to metformin is lactic acidosis. Dosing is based on kidney function where use of metformin in a person with a eGFR of <30 mL/minute/1.73m² is contraindicated, and a dose reduction is necessary in a person with an eGFR of 30 to 45 mL/minute/1.73 m² if they are already taking metformin; if they are not, then it should not be initiated. Additionally, people with a liver impairment may need dosages adjusted as well. ⁸

Traditional Chinese Medicine

A review article included 26 randomized controlled trials from 2007 to 2017 with at least 60 participants, all of whom had a diagnosis of prediabetes, diabetes, diabetes nephropathy (DN), diabetes retinopathy (DR), or diabetes peripheral neuropathy (DPN), and an intervention of either TCM, western medicine, or placebo. There were seven studies in the prediabetes group with the primary outcome being the development of diabetes. The TCM herbs included: Radix Astragali seu Hedysari, Rhizoma Coptidis, Radix Trichosanthis, Fructus Ligustri Lucidi, Herba Dendrobii, Herba Ecliptae, Radix Ginseng, Cortex Lycii, Galla Chinensis, and Fructus Corni. Many of the trials had a capsule that contained a combination of these herbs, that is, Tianqi Jiangtang Capsule which works by promoting transport/use of glucose by increasing insulin secretion from beta cells in the pancreas, downregulation of Apolipoprotein E, and other proposed mechanisms. Each of the studies showed that there was a delay in the progression to diabetes in the TCM group. ⁹

Cinnamon

A meta-analysis that included 16 randomized controlled studies showed that cinnamon reduced fasting blood glucose; however, further studies are necessary to ascertain the cinnamon formulations and impact. ¹⁰ In a recent study published in 2024, authors evaluated the effect of daily cinnamon spice supplementation (dose similar to what one may use for seasoning) in 18 people with prediabetes and obesity over 4 weeks. Compared to placebo, 24-hour glucose concentrations were significantly lower in the cinnamon group [mixed-models; effect size (ES) = 0.96; 95 % confidence interval (CI): −2.9, −1.5; P < 0.001]. There were no significant differences in terms of adverse effects, specifically digestive symptoms. ¹¹

Additional Herbal Remedies

There are many other herbal medications that have been evaluated for the treatment of prediabetes. These include fenugreek, aloe vera, emblica officinalis (gooseberry), green tea, and momordica charantia (bitter melon).^12-14 While these studies show beneficial effects of lowering blood glucose, most of the studies do not have adequate power and most of these herbal medications do not have appropriate oversight to ensure the product is safe and efficacious.

Medications Prescribed for Obesity/Overweight

People who are diagnosed with overweight or obesity have an increased risk of diabetes; a patient with prediabetes who loses 10% of body weight lowers their risk of diabetes. Current guidelines for overweight/obesity management recommend the use of pharmacologic agents as an adjunct to comprehensive lifestyle interventions when BMI is ≥30 kg/m² with or without risk factors or when BMI is ≥27 kg/m² with at least one comorbidity such as hypertension or diabetes. Medications such as phentermine, orlistat, phentermine/topiramate, naltrexone/bupropion, liraglutide, semaglutide, or tirzepatide may be prescribed to treat overweight/obesity. These medications should not be given to patients solely for prediabetes; however, when prescribed for the appropriate indication, they may lead to weight loss that can mitigate the progression of prediabetes to diabetes.^15-18

Conclusion

Interprofessional and multifactorial patient care is fundamental to addressing prediabetes holistically. While some individuals with prediabetes may never progress to diabetes or the multitude of complications impacting most organs in the body, there is ample evidence that shows the impact of hyperglycemia and renal-cardio-metabolic connection on morbidity and mortality-related patient outcomes. While this review focuses on the adult population, there is evidence emerging about prediabetes in children, including risk factors, consequences, and consideration of similar strategies discussed in this paper. ¹⁹

As health care providers, we need to work together with patients to implement a holistic approach that brings evidence and recommendations to our patients after taking into account objective data such as glucose and A1C values; contributing risk factors; and treatment goals from the perspective of the provider and the patient. Oftentimes, people may not be aware that they have multiple risk factors because they have not necessarily met the thresholds for the actual diagnosis. However, we know that there are ways to address these risk factors with lifestyle interventions so that perhaps they do not ever need to progress to that official diagnosis; even those patients who do progress to a diabetes diagnosis can mitigate complications by employing these same lifestyle interventions.

With prediabetes especially, many people are not aware that they meet the glucose thresholds for prediabetes and that there are interventions they can incorporate in their lives to optimize health. Lifestyle medicine, emphasizing all its pillars, involves collaborating with a team of interprofessional health care practitioners who educate on physical activity and healthy eating, while also addressing sleep, stress, substance use, and social connections. Strong evidence shows that such interventions may significantly impact prediabetes and the patient’s health. This approach may also include prescribing metformin, which is potentially beneficial for individuals at higher risk. The other medications discussed in this review have some evidence; however, more robust clinical data is necessary to truly appreciate the risk/benefit and role these medications play in addressing prediabetes.