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ADA: Moving from Prediabetes to Normal Just Once Cuts Risk

Achieving normal glucose regulation even once predicted a lower risk of progression to diabetes for prediabetic patients. The evidence points to working hard at prediabetes to get rewarded both now and later….

Follow-up data from the Diabetes Prevention Program (DPP) showed that patients who achieved normal glucose regulation on any annual measurement during the DPP were three times as likely to achieve normal glucose regulation at follow-up as patients who remained prediabetic.

Leigh Perreault, MD, from the University of Colorado in Aurora, and colleagues reported that, in particular, patients who remained prediabetic after intensive lifestyle intervention had a significantly higher risk of progressing to diabetes and a significantly lower likelihood of achieving normal glucose regulation than did patients originally randomized to placebo.

"We conclude that prediabetes is a high-risk state for diabetes, especially in patients who remain with prediabetes despite intensive lifestyle intervention," Perreault and colleagues wrote in conclusion in an article published simultaneously online in The Lancet.

"Reversion to normal glucose regulation, even if transient, is associated with a significantly reduced risk of future diabetes, independent of previous treatment group."

Impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and type 2 diabetes are characterized by elevated blood glucose concentrations associated with an increased risk of several serious health outcomes.

Several large randomized controlled trials have shown that diabetes can be prevented or delayed in people with IFG or IGT by diet, physical activity, and various drugs. Less well understood is the clinical significance of regression of these conditions to normoglycemia, which has been noted in several trials.

Perreault and colleagues sought to determine whether regression to normoglycemia predicted a reduced risk of incident metabolic and vascular diseases or simply reflected glucose fluctuations over time.

Their analysis included 1,990 DPP participants who continued follow-up in the DPP Outcomes Study (DPPOS). The study population comprised 736 patients initially randomized to intensive lifestyle intervention, 647 randomized to metformin, and 607 to placebo. The primary outcome was the proportion of patients who progressed to diabetes during the DPPOS.

Patients who had a confirmed diagnosis of diabetes during DPP were excluded from the analysis.

The following definitions were used:

  • Diabetes: fasting plasma glucose (FPG) ≥126 mg/dL or a 2-hour glucose ≥200 mg/dL after a 75-g oral glucose challenge
  • Normal glucose regulation: FPG <100 mg/dL or a 2-hour glucose <140 mg/dL on at least one annual oral glucose tolerance test (OGTT) during the DPP
  • Prediabetes: FPG 100 to 126 mg/dL or 2-hour plasma glucose 140 to 200 mg/dL after OGTT throughout the DPP

The study population included 894 patients who achieved normal glucose regulation at least once during DPP. Those patients had a 56% lower risk of progression to diabetes than did the patients who remained persistently prediabetic (P<0.0001). The finding was unaffected by DPP treatment assignment.

Three factors had significant associations with achievement of normal glucose regulation during the DPPOS:

  • Increased beta-cell function (OR 1.28, 95% CI 1.18 to 1.39, P<0.0001)
  • Normal glucose regulation during the DPP (OR 3.18, 95% CI 2.71 to 3.72, P<0.0001)
  • Insulin sensitivity (OR 1.16, 95% CI 1.08 to 1.25, P<0.0001)

Among DPP participants who remained persistently prediabetic, those assigned to intensive lifestyle intervention had 31% greater risk of progression to diabetes (HR 1.31, 95% CI 1.03 to 1.8, P=0.0304) and a 41% lower risk of achieving normal glucose regulation during the DPPOS (HR 0.59, 95% CI 0.42 to 0.82, P=0.0014) than did participants randomized to placebo.

"Even when overt diabetes is delayed or prevented, both microvascular and macrovascular disease are more prevalent in those with prediabetes compared with their normoglycemic peers," Natalia Yakubovich, MD, and Hertzel C. Gerstein, MD, from the McMaster University in Hamilton, Ontario, wrote in an accompanying editorial.

"Whether a reduced incidence of diabetes after regression translates into a reduced incidence of diabetes-related health consequences, such as blindness and vascular disease, is unknown, and can be assessed by ongoing follow­-up of this cohort, and by future clinical trials," they added.

Although some issues remain unresolved, "the findings clearly suggest that transient regression of impaired glucose tolerance to normoglycemia that is either spontaneous or in response to treatment is of clinical relevance."

Practice Pearls:
  • Achieving normal glucose regulation even once predicted a lower risk of progression to diabetes for prediabetic patients, according to data from the Diabetes Prevention Program (DPP).
  • Note that the three factors significantly associated with achievement of normal glucose regulation included normal glucose regulation during the Diabetes Prevention Program, increased beta-cell function, and insulin sensitivity.
  • Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Perreault L, et al "Effect of regression from prediabetes to normal glucose regulation on long-term reduction in diabetes risk: Results from the Diabetes Prevention Program Outcomes Study" Lancet 2012; DOI: 10.1016/S0140- 6736(12)60525-X.

Yakubovich N, et al "Is regression to normoglycaemia clinically important?" Lancet 2012; DOI: 10.1016/S0140- 6736(12)60828-9.