Prediabetes: Time for More Aggressive Treatment to Prevent Progression

STOP Diabetes trial results suggest significant benefits in patients deemed at higher risk for type 2 diabetes who receive more aggressive pharmacotherapy, against lifestyle and metformin to reverse diabetes and associated complications.

With Ralph A. DeFronzo, MD, and David M. Nathan, MD

While there is substantial interest in identifying strategies to prevent the progression of prediabetes to type 2 diabetes (T2D), no therapeutic means has been shown to uniformly preserve β-cell function or prevent diabetes in those at greatest risk.

However, the underlying pathophysiology that insulin resistance originated from glucose dysregulation in the muscle, liver, and β-cells, has evolved with a recognition that the onset of diabetes also arises due to glucose dysregulation in the brain, gastrointestinal tract, alpha cells (hyperglucagonemia), and kidneys.1 This, in turn, has advanced our understanding that beta cell failure is likely to occur earlier with greater severity than previously anticipated.

Preserving beta cell function with aggressive treatment will reverse diabetes risk.

Diabetes Outcomes Impacted By Multiple Organ Involvement

Involvement of these eight organ systems, termed the “ominous octet,” according to Ralph A. DeFronzo, MD, professor of medicine and chief of the Division of Diabetes at the University of Texas Health Science Center in San Antonio, and one of the investigators of the STOP DIABETES study, suggests the need for a more pharmacologically aggressive treatment strategy in order to slow or possibly prevent conversion of prediabetes to T2D.2

We know that an estimated 86 million people are living with prediabetes; yet, about 90% of these individuals are unaware of the risks they face should they develop type 2 diabetes given the risks associated with common complications.3

As the prevalence of diabetes rises, so has the urgency to find effective management strategies. Of greatest concern are individuals whose impaired glucose tolerance (IGT) falls into the top tertile as it appears that this subgroup will have lost more than 80% of their β-cell function,1 rendering them nearly insulin resistant.

To improve the outcomes of those with prediabetes, just such a methodology has been proffered as an effective strategy over lifestyle and metformin for individuals at greatest risk for type 2 diabetes, as supported by results of the Successful Treatment of Prediabetes in Clinical Practice Using Physiological Assessment (STOP Diabetes) study.2

STOP Diabetes: Treat Prediabetes More Aggressively 

Dr. DeFronzo and colleagues conducted a seven-year, prospective, observational real-world study of adults considered to be at elevated risk for developing type 2 diabetes, and its myriad complications.2

Of the 1,769 patients enrolled in the trial who were diagnosed as prediabetic, the investigators identified 747 people considered at intermediate or high risk, based on the presence and severity of their insulin resistance, impaired β-cell function, and glycemia.2

A three-tier preventive treatment approach was conducted based on a risk assessment:2

  • For patients assessed as having the highest risk (n=81), triple therapy was prescribed including metformin, pioglitazone and GLP-1 receptor agonist therapy with lifestyle therapy.
  • Patients deemed to be at intermediate risk (n=141) were prescribed dual therapy with metformin and pioglitazone with lifestyle therapy. 
  • Participants at intermediate or high risk who refused pharmacotherapy (n= 200) were assigned to lifestyle therapy only.
  • Oral glucose tolerance tests were repeated at six months and then every two years or so.

Lifestyle Changes or Aggressive Pharmacotherapy 

Participants who only received lifestyle intervention had a non-significant change in mean body weight, 42% of patients lost weight (average of 10.6 lbs.) and 54% gained weight (~8 lbs) over the approximately 32-month follow-up period.2 Individuals in the dual therapy group also had a non-significant change in mean body weight, with an average 1.3 lbs loss in weight, whereas those in the triple therapy treatment group lost a significant mean of 3.7 lbs.2

Of significance, a total of 28 patients (7%) progressed to T2D over the 32 months, including 21 (11%) in the lifestyle intervention only group, 28 (7%) in the dual therapy group, and zero in the triple therapy group.2

Both fasting and two-hour plasma glucose concentrations were significantly reduced in participants receiving pharmacotherapy compared with lifestyle intervention alone; in fact, the latter group reported a significantly elevated two-hour plasma glucose concentration.2

Ultimately, participants receiving dual therapy had a 71% decrease in future T2D risk and those receiving triple therapy had an 88% reduction in risk compared with patients on lifestyle therapy alone, according to the investigators.

In an interview with EndocrineWeb regarding the study results, Dr. DeFronzo said, “Evidence that a pathophysiologic approach works are overwhelming– no participants receiving triple therapy progressed to diabetes over the nearly three-year study period.” He emphasized that this was a real world versus clinical study, indicating that similar results could be expected and were achievable in clinical practice. 

When asked about the barriers to integrating this approach into clinical practice, Dr. DeFronzo identified the primary barriers as:

  • Lack of clinical knowledge about the pathophysiology of diabetes
  • Clinician inertia4,5
  • Cost of diabetes medications

In response to a question regarding how likely patients with prediabetes might be to initiate a dual or triple therapy program that may require patients to self-inject medication, Dr. DeFronzo said, “it would depend on how concerned the patient is about the complications of diabetes.”

Move to More Concerted Pathophysiological Approach

A more pharmacologically-aggressive approach appears feasible.2 Given their findings,2 DeFronzo and his colleagues recommend that clinicians take a risk-based therapeutic approach such that individuals with prediabetes receive the level of treatment in accordance with a calculated risk for progression to T2D based on the presence and severity of specific pathophysiological abnormalities.2

People with what Dr. DeFronzo has termed the "ominous octet" [see figure] are likely to require multiple drugs to correct the numerous underlying pathophysiological defects; they also require earlier initiation of treatment targeted to not only reduce hemoglobin A1c (HbA1c).6

Ominous octet reflects the multifactorial nature of type 2 diabetes. Concept & Figure by Ralph DeFronzo.Ralph DeFronzo, MD, coined the "Ominous Octet" to demonstrate the multifactorial nature of type 2 diabetes.


Consequently, they have recommended that clinicians assess patients for insulin resistance, impaired β-cell function, and hyperglycemia (defined as a one-hour plasma glucose concentration greater than 8.6 mmol/L during oral glucose tolerance test [GTT]), and then stratify individuals (based on a proposed formula) into mild, moderate or severe risk to inform an appropriate preventive strategy.2,6

The aim would be to correct for the presence of any underlying pathophysiological defects in patients diagnosed with prediabetes to slow progression to T2D or even prevent its onset.

Is Current Approach Early in Diabetes Sufficient?

The data on the efficacy of a lifestyle approach under the auspices of the Diabetes Prevention Program Outcomes Study (DPPOS) demonstrated that losing a modest amount of weight given sustainable dietary changes and increased physical activity, might prevent or delay the progression of prediabetes to type 2 diabetes with the hope that anticipated complications will be reduced,7,8 said Dr. Nathan.

In particular, metformin was shown to reduce the development of diabetes, albeit to a lesser degree than lifestyle changes.7 Overall, participants in the DPP Lifestyle Change Program lowered their chances of developing T2D by 58% over nearly 3 years, compared with participants taking a placebo; and older participants (> 60 years) fared better, reducing their chances of developing diabetes by 71%.9

In addition, metformin was demonstrated to reduce diabetes by 31% compared to placebo and was particularly beneficial in women with a history of gestational diabetes (GDM), younger adults (25-44 years), and people with body mass index (BMI) >35 kg/m2.7

The anti-diabetes benefits persisted, although at lower rates, at both 10-year and 15-year follow-up, by which point patients in the DPP Lifestyle Change Program delayed the development of diabetes by 27% versus those in the placebo group, and individuals taking metformin saw a delay in diabetes onset by 18% against placebo.8

More than half of the participants in each group developed diabetes: 55% in Lifestyle Change Program, 56% taking metformin, and 62% taking placebo. During the 10-year follow-up, diabetes incidence rates were 4.8 cases/100 person-years in the intensive lifestyle group, 7.8 cases/100 person-years in the metformin group, and 11.0 in the placebo group.7

Stick with Standard of Care or Evolve  

David M. Nathan, MD, professor of medicine at Harvard Medical School, as well as the Chair of the NIDDK Diabetes Prevention Program (DPP), discussed his concerns about both the reporting of the STOP Diabetes study and its results with EndocrineWeb

“It is important to note that a large percentage of participants failed to complete one full year of the study: specifically, 51 of the 200 participants in the lifestyle group, 35 of the 141 in the dual therapy group, and 27 of the participants in the triple therapy group received less than one year of treatment,”   said Dr. Nathan. “And, the investigators failed to address how they treated those who dropped out.”

In addition, Dr. Nathan suggested that those self-selected participants in the lifestyle intervention arm were likely different in some possibly important ways than those willing to take two or three medications. It would be critical going forward to gain clarity regarding how these groups differed in order to fully assess the STOP Diabetes findings.

Of particular concern, Dr. Nathan, who is also director of the Diabetes Center and Clinical Research Center at Massachusetts General Hospital said, “participants in the lifestyle intervention arm did not lose weight, whereas participants in the DPP trial had substantial weight loss—of more than 15 lbs in the first year—with lifestyle interventions alone.”7

He said, further, the study did not clearly delineate what specific strategies were imparted to individuals in the lifestyle interventions. Further, the prediabetic participants in the DPP study were at even greater risk for progression to diabetes than those in the severe risk category in STOP Diabetes.

Dr DeFronzo emphasized that “the results of the STOP Diabetes study demonstrated substantial protection with pharmacotherapy aimed at correcting the underlying pathophysiological defects of those at progressively higher risk,” while Dr. Nathan suggested that there is no doubt that there is need for interventions that stop or delay progression from prediabetes to T2D; however, the optimal approach remains controversial.

Dr. Nathan also questioned whether more conventional phenotyping might be as effective (and less costly) as the metabolic parameters used in the STOP Diabetes Trial, and whether or not initiating dual or triple pharmacotherapy in patients with prediabetes–particularly when there is evidence supporting more economically feasible approaches using lifestyle interventions and metformin—is efficacious.

In all, the bottom line remains: There likely isn’t only one correct route or right therapy for every individual with prediabetes, and maybe risk stratification and patient tolerance are necessary considerations in formulating a treatment plan.

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