Stating the Case for Early, Aggressive Intervention in Prediabetes

ORLANDO — Strong evidence of increased cardiovascular disease (CVD) risk in patients with prediabetes makes a compelling case for aggressive treatment to prevent progression to diabetes, a primary care diabetes specialist said here.

An estimated 84 million adults in the U.S. have prediabetes, defined as a fasting glucose level of 100-124 mg/dL, hemoglobin A1C (HbA1c) of 5.7-6.4%, or 2-hour oral glucose tolerance test of 140-199 mg/dL. Anywhere from 5-10% of patients with prediabetes develop frank diabetes each year, and as many as 70% of people with prediabetes will eventually develop diabetes, said Lori O’Toole, MSN, APRN, of LCO Nursing Consultants in Las Vegas, during the American Association of Nurse Practitioners meeting. One diabetes prevention study in China found that more than 90% of individuals with prediabetes developed diabetes over a 20-year period.

“I’m going to be a little more optimistic,” said O’Toole.

“A majority of people with prediabetes will eventually have diabetes, usually within 5 years,” she said. “The prevalence of prediabetes is increasing worldwide, and it is projected that 470 million people will have prediabetes by 2030. This is an impending tsunami, and it will be very taxing on the healthcare system.”

The good news, she continued, is that early intervention can reduce the incidence of complications associated with prediabetes, thereby reducing the cost of caring for the patients and improving their long-term quality of life. Primary care practitioners, who already provide 90% of care for prediabetes and diabetes, will play a critical role in trying to hold back the tsunami.

Risk factors for prediabetes are similar to those for type 2 diabetes: excess weight, poor diet, sedentary lifestyle, older age, family history of type 2 diabetes, race (Blacks, Hispanic, and Native American individuals, as well as those of Asian/Pacific Island heritage are at higher risk), gestational diabetes, polycystic ovarian syndrome, sleep apnea, smoking, and low birth weight. Also like type 2 diabetes, prediabetes has a strong association with hypertension, low levels of HDL cholesterol, elevated triglycerides, and metabolic syndrome.

Patients with prediabetes are maximally or near-maximally insulin resistant. In most cases, patients with prediabetes have lost 80% of their beta cell function.

“Sometimes I sugarcoat it a little bit and say 50%, because 80% sounds terrible,” said O’Toole. “I don’t want to say you’ve only got 20% for the rest of your life. If you’re in your 40s, that’s a long time to have to take care of your sugar.”

Insulin resistance and development of frank diabetes are preceded by a long period of glucose intolerance, and screening tests can identify patients at high risk of developing diabetes. During that time lag, potentially effective interventions can address multiple modifiable risk factors, including obesity, body fat distribution, physical inactivity, and high blood glucose.

Multiple studies conducted since the mid-1980s show that diet, exercise, other lifestyle modifications, and medication can reduce the risk of progression from prediabetes to diabetes by 25-72% during follow-up periods ranging from 2 to 6 years.

Unfortunately, many clinicians apparently do not take prediabetes seriously. A review of more than 1 million office visits with family and internal medicine clinicians showed that a third of the patients had prediabetes, but fewer than a fourth of the patients received treatment, which consisted primarily of lifestyle modification advice.

The findings reflected missed opportunities for diabetes prevention in the primary care, the authors concluded. They hypothesized that clinicians felt “it’s not yet bad enough to need medication.” The authors also concluded that patients do not pay attention to advice about lifestyle modification.

Missed opportunities for diabetes prevention can translate into clinical consequences for patients with prediabetes, according to O’Toole. The landmark Diabetes Prevention Program Study showed that 7.9% of individuals with prediabetes had diabetic retinopathy at the end of year 3, increasing to 12.6% in patients who progressed to diabetes. Among prediabetic individuals with retinopathy, the eye pathology occurred against a background HbA1c range of 5.9-6.1%

Other studies have shown that 5-10% of patients with prediabetes have peripheral neuropathy, O’Toole continued. Data from the National Health and Nutrition Examination Survey showed a 17% prevalence of chronic kidney disease in prediabetic individuals versus 10.6% in people without diabetes.

CVD accounts for about 80% of all deaths among diabetic patients, primarily coronary artery disease. CVD and myocardial infarction can occur in patients whose HbA1c values are in the prediabetes range.

A frequently referenced analysis has identified a more specific HbA1c cutoff for increased risk in prediabetes. The data showed a consistent association between an HbA1c of 5.5% and an increased risk of progression to diabetes, development of CVD, stroke, and death from any cause.

“Once patients become prediabetic, [the risk increase] is a very high curve and it goes up very fast,” said O’Toole.

The American Association of Clinical Endocrinologists and the American College of Endocrinology (AACE/ACE) have published recommendations for managing type 2 diabetes, including an algorithm for patients with prediabetes. The algorithm covers weight-loss interventions, treatment for CVD risk factors (including dyslipidemia and hypertension), and strategies for reducing hyperglycemia.

Targets for lipid modification vary by an individual patient’s CVD risk (high, very high, and extreme). Ranges are <100 to <55 mg/dL for LDL, <130 to <80 for non-HDL, and <150 for triglycerides. The standard blood pressure goal is <130/80 mm Hg.

With respect to targeting hyperglycemia, the AACE/ACE guideline recommends intensified weight-loss therapies, including medication and bariatric surgery as indicated. Physical activity should have a goal of 30 to 60 minutes, 5 days a week. Short amounts of brisk walking (such as three 10-minute walks) often fit well with personal schedules. The Mediterranean and DASH diets have the most supporting evidence for improving hyperglycemia and reducing CVD risk, said O’Toole.

Smoking cessation is an essential component, but pushing interventions before patients are ready to quit often is not productive.

“Most of my patients who are smokers tend to quit cold turkey,” she said.

Among medical interventions for prediabetic patients, metformin is safe, inexpensive, and weight neutral, although many patients lose weight during treatment, said O’Toole. In patients with diabetes, the drug is associated with fewer microvascular complications. Metformin also has demonstrated efficacy for delaying progression to diabetes, improving gestational diabetes, and reducing hyperglycemia associated with polycystic ovarian syndrome.

The alpha-glucosidase inhibitor acarbose retards digestion and absorption of carbohydrates to reduce blood-glucose levels after a carbohydrate load. The drug may also reduce CVD risk. A major downside is drug-related flatulence, which can be severe in some cases, O’Toole noted. If more intensive antiglycemic therapy is indicated, pioglitazone and GLP-1 agonists inhibitors have proven efficacy in prediabetes, including CVD risk.

Occasionally, she prescribes SGLT2 inhibitors, which help modulate glucose levels, lower blood pressure, and are helpful in patients with heart failure. The drug class is not yet approved for use in prediabetes.

“So how early should we start medical therapy [for prediabetes]?” O’Toole asked. “Remember, even in prediabetes there is cardiovascular risk.”

“Prediabetes carries an increased risk of cardiovascular disease,” she added. “Significant physiological, metabolic, and biochemical features are dysregulated in prediabetes. Extensive randomized controlled trials have demonstrated that lifestyle modification can decrease the rate of progression from prediabetes to diabetes in short term. Early detection and intervention is vitally important for prevention of prediabetes progression to diabetes and to help decrease micro- and macrovascular complications.”