Prediabetes—Time to Treat to Preempt Diabetes and Related Complications

With all the upsides, how often are you actively implementing a management care plan for the many at-risk patients that present in your practice?

with Elena Christofides, MD, and Jacqueline Lonier, MD

Many individuals are knowingly evading recommendations on physical active and diet at a younger age, according to Heart & Stroke Statistics—2020,1 published in Circulation.

This lax behavior, which is compounded by the realization that current screening criteria for diabetes promulgated by the US Preventive Services Task Force are missing nearly half (49.7%) of the undiagnosed adults with prediabetes and diabetes,2 suggesting an imperative to spotlight the need for more vigilant management of many of your at-risk patients.

It is becoming increasingly necessary that we help patients understand that progression from prediabetes to type 2 diabetes (T2D) is not a foregone conclusion. Equally important, they must be guided to realize that prediabetes is not a benign condition if left to progress to diabetes, thus raising the risk of damage to nearly every major organ and system should they maintain their status quo.

Tackling the Rise in Prediabetes and Diabetes-Related Complications

The American Diabetes Association estimates that 84.1 million American adults aged >20 years have prediabetes, and about 90% of them are unaware of their condition.4 Data based on either fasting glucose or hemoglobin A1c (HbA1c) levels indicate that about 34% of the adult US population and nearly half of individuals who are 65 years or older have prediabetes.4

Given the epic numbers at-risk adults, clinicians must overcome any lingering hesitation to initiate pharmacotherapy when a patient presents with evident signs of obesity, elevated blood glucose, hyperlipidemia, and/or hypertension,5 according to management resources available from the American Association of Clinical Endocrinologists.

Data from the Diabetes Prevention Program (DPP) indicated that intensive lifestyle modifications—specifically, weight loss of at least 7% of initial body weight and (at least moderate) physical activity for at least 150 minutes weekly—achieved a reduction in the incidence of diabetes by 58%, compared with a 31% reduction in incidence associated with metformin as compared to placebo.6

Although no medications are currently approved by the US Food and Drug Administration (FDA) for prediabetes, a variety of medications are commonly being prescribed off-label.7 In addition to metformin, among the most commonly prescribed medications for prediabetes are:

  • thiazolidinediones (such as pioglitazone among the class of glitazones)
  • acarbose
  • glucagon-like peptide-1 receptor agonists (GLP-1RA) such as exenatide and liraglutide
  • dipeptidylpeptidase-4 (DPP-4) inhibitors such as linagliptin and other so-called gliptins
  • anti-obesity/weight loss-inducing medications including orlistat, lorcaserin, and phentermine/topiramate ER

Growing Clarity of Pathways Involved in Diabetes Initiation

Persons with T2D have an impairment in the incretin system as characterized by a reduced responsiveness to glucose-dependent insulinotropic polypeptide (GIP) and substantially lower GLP-1 concentration.8

Administration of GLP-1RA has shown improvement in glycemic control with weight loss. so the use of an agnoist is necessary as the native homorne is rapidly degraded by DPP-4. This reflects the potential benefit of DPP-4 inhibitors, in the prediabetic patient to enhance incretin effects, albeit weaker than with pharmaologic agents.9

Patients with prediabetes already have insulin resistance, pancreatic β-cell and α-cell dysfunction, and a reduced incretin effect.8,9 DPP-4 inhibitors target these physiological and pathological defects. Linagliptin is a DPP-4 inhibitor that is metabolized mainly by the liver and has previously been shown to be safe and effective. 9

Consequently, investigators in the PRELLIM project (Diabetes Prevention with Linagliptin Lifestyle and Metformin) chose to evaluate the effect of adding the DPP-4 inhibitor linagliptin to a combination with metformin and lifestyle changes as compared with metformin and lifestyle changes alone.10

PRELIMM was originally a 12-month double-blind, randomized parallel clinical trial in patients with impaired glucose tolerance with or without impaired fasting glucose (IFG) and at least 2 T2D risk factors (as per the American Diabetes Association) that evaluated the effect of the combination of the DPP-4 inhibitor linagliptin (5 mg) with metformin (1700 mg/day) and lifestyle changes on glucose tolerance, pancreatic β-cell function, and incidence of T2D in patients with prediabetes;9 This current study reports on the 24-month extension of PRELLIM.10

As in the initial PRELIMM trial, the comparator group in the extension study received metformin (1700 mg/day) and lifestyle directives only. A total of 144 patients meeting the study criteria were included in the study; 74 were randomized to the linagliptin/metformin/lifestyle (LML) group and 70 to the metformin/lifestyle group. A total of 52 participants in each group completed 12 months of treatment; 36 participants in the LM and 27 in the M group completed 24 months of treatment.9

The combination of linagliptin, metformin, and lifestyle led to significantly greater improvements in glucose levels and disposition index in OGTT, with a significantly lower incidence of T2D in the patients receiving LML compared with just metformin (P = 0.02). Patients in the LML group also had a greater probability of achieving normoglycemia than those in the lifestyle/metformin group.9

Evidence Encourages Initiating Treatment at Prediabetes

Elena Christofides, MD, FACE, Chief Executive Officer of Endocrinology Associates in Columbus Ohio, and clinical associate professor of endocrinology at Ohio University College of Medicine said: We’ve known that “the structure of incretin physiology is such a key component of the diabetic process, that it deserves greater attention, especially to gain a clearer understanding of its role earlier in the prediabetes process. This proof of concept study addresses the incretin pathway as disease prevention for diabetes,” in discussing the findings with EndocrineWeb.

The study, while small, was well-designed and what was chosen to be measured was very appropriate, including the use of metformin and evaluating lifestyle changes as the comparator, Dr. Christofides said.

“We have believed the mechanism of action of DPP-4 may be an appropriate pathway for treating prediabetes; this study affirms what we deemed to be true. The findings support our expectations based on the physiology of diabetes and the action of these drugs,” she said. “As such, this proof of concept study confirms the value of DPP-4s for patients with prediabetes.”

“This study should provide sufficient insight to afford clinicians more ease with the idea of treating prediabetes with these antidiabetes medications–and it supports the need for a larger confirmatory study,” said Dr. Christofides.

Not so fast, said Jacqueline Lonier, MD, an adult endocrinologist and assistant professor of medicine at the Naomi Berrier Diabetes Center at Columbia University Irving Medical Center in New York City. “This was a relatively small, single-center trial,” she said, adding that the “results were not surprising given that we know treating patients with two medications versus 1 drug leads to a greater reduction in adverse T2D outcomes.”

Dr. Lonier reiterated the importance of the findings from the Diabetes Prevention Program Outcomes research findings, which demostrates that intensive lifestyle interventions proved more effective than metformin in preventing type 2 diabetes.

The high cost associated with DPP-4 inhibitors is likely to prohibit many clinicians from recommending this drug over metformin for patients who have maxed out the benefit of lifestyle interventions, she told EndocrineWeb. “However, if there was a study demonstrating that this dual-medication treatment was cost-effective and beneficial,” only then might I consider recommending this to patients.

In concert with Dr. Christofides, Dr. Lonier acknowledged the strength of the methodology undertaken to investigate beta cell function, gaining confirmation of the mechanism of action of DPP-4 inhibitors.

Ultimately, there is still a need for more aggressive approaches to prevent progression of rising glucose to type 2 diabetes among patients with prediabetes. Likely, the greatest imperative remains finding an effective model for guiding patients to adopt and maintain intensive lifestyle changes. According to DPP findings, patients who lose weight often regain normal glucose regulation.

At least by adding metformin, even individuals with prediabetes may gain an added level of protection, and from this initial small study, there is a suggestion that in adding a DPP-4 inhibitor, such as linagliptin, patients may be afforded additional preventive benefits, said Dr. Brito. Both experts see significant benefit from additional research with regard to managing patients in prediabetes.

Risk of Diabetes Complications Support Treating Overweight and Other Risks Early

The ACE/AACE consensus statement recommends a two-pronged approach to treating prediabetes: intensive lifestyle intervention, followed by the prevention of cardiovascular (CV) complications using CV risk reduction medications for abnormal blood pressure and hyperlipidemia, independent of glucose control medications.5

Diabetes management guidelines from the American Diabetes Association (ADA) suggest that patients who are diagnosed with prediabetes be referred to an effective ongoing support program, with a weight loss goal of 5% to 10% of their current body weight, as well as a call for an increase in moderate physical activity of at least 150 minutes per week.4


More specifically, given the relationship between diabetes and increased risk of cardiovascular disease, coronary heart disease, stroke, and all-cause mortality in many studies, it is imperative to identify patients with prediabetes so as to reverse or slow progression to type 2 diabetes.3

However, the challenge will be to prescribe lifestyle modifications as the most effective means to prevent frank diabetes for most everyone,3 while many may also benefit from medications, such as metformin, sooner than later. It may be by recommending medication, the seriousness of the message may convince more patients of the urgency to revisit making lifestyle changes.

Furthermore, there is sufficient evidence to suggest that encouraging patients to become open to lifestyle intervention is advantageous in the long-term with broader benefits than drug therapies, and without the side effect profile, according to John B. Buse, MD, PhD, professor of medicine and endocrinology chief at the University of North Carolina at Chapel Hill.

Neither of the endocrinolgists offering commentary had any financial conflicts with regard to the studies discussed.

Continue Reading:
Diabetes Prevention Possible If All Available Clinical Tools Employed
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