Prediabetes is a state in which the blood glucose levels are not high enough to qualify as hyperglycemia but are well above the normal parameters. By WHO parameters, prediabetes is defined as a fasting plasma glucose of 6.1 to 6.9 mmol/L and impaired glucose tolerance as a 2-hour plasma glucose of 7.8 to 11.0 mmol/L after a 75g oral glucose load.
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These are more or less similar to other criteria such as the American Diabetes Association. However, the degree of clinical utility, to predict the future development of diabetes or even to capture the prediabetic state, is still undesirably low. Even the use of HbA1C as a screening indicator is flawed by the substantial genetic contribution to its serum levels.
The importance of prediabetes lies in its high risk for full-blown diabetes, which develops in 5%-10% of cases each year. The prediabetic state is also associated with diabetic complications such as early development of nephropathy, retinopathy, small fiber neuropathy, and cardiovascular disease.
Prevention of diabetic progression in prediabetes
Lifestyle modifications are found to reduce the risk of diabetes in adults with prediabetes, by 40% to 70%. Other interventions include pharmacological management, such as metformin, for high-risk patients.
There are several modifiable risk factors in prediabetes treatment, most of which target excessive energy intake by two key steps: reducing the ingestion of high-energy foods and increasing the expenditure of energy by physical activity.
If practiced constantly and meticulously, such interventions can reduce the relative risk of diabetes (compared to other prediabetics who do not undergo this intervention) by almost 60%. They also result in long-term effects including maintenance of weight and lower food intake, improvement of blood glucose and lipid parameters, and reduction of diabetic risk, which persist for at least 10 years.
Weight loss is the biggest single factor leading to risk reduction, at 16% lowering of risk for each kilogram of weight lost from the body. The Diabetes Prevention Study set goals as:
- Weight loss of more than 5%
- Fat intake less than 30% of total energy intake
- Saturated fat less than 10% of total energy intake
- Dietary fiber of 15g/1000 kcal or more
- Exercise for more than 4 hours a week
Fructose restriction plays a role in preventing hypertriglyceridemia and metabolic syndrome, which has underlying insulin resistance.
Soft drinks, which are commonly sweetened with sucrose and high-fructose corn syrup, are especially associated with weight gain and insulin resistance due to excessive energy intake, the high percentage of fructose absorbed, and the lack of dietary fiber in this dietary component.
The most commonly used drug for prediabetes is metformin, because of its associated beneficial effects on weight loss and dyslipidemia, amounting to a 45% reduction of risk for diabetes. Some studies have shown its use to be as effective as lifestyle modifications, and especially in obesity or high lipid levels. However, its effects level out at about 12 months.
The glitazone group of drugs (thiazolidinediones) act to increase peripheral glucose uptake and utilization and to reduce gluconeogenesis in the liver. This improves insulin sensitivity. They were found to reduce the risk of diabetes by 60% to 70% but increased weight gain and heart failure rates were undesirable concomitant side effects.
Combinations of lower doses of metformin with a glitazone has led to a risk reduction but with an increase in the incidence of diarrhea. The thiazolidinediones in general are associated with numerous safety concerns such as cardiovascular adverse events and liver toxicity.
Other drugs which have been explored include the alpha-glucosidase inhibitor acarbose, which do reduce the risk by 25% but cause a high rate of gastrointestinal discomfort.
This issue has been significantly addressed by voglibose which brought about a 40% reduction in progression to diabetes over one year. GLP-1 analogs such as exenatide and liraglutide are also used in injectable form only to help reduce weight loss in obese individuals, but they do cause vomiting and nausea.
Orlistat is a gastrointestinal inhibitor of lipase which reduces fat absorption by 30%, and in combination with reduced energy intake it causes satisfactory weight loss.
Bariatric surgery is a term which includes several procedures which are aimed at reducing the energy intake by malabsorption or restricting the amount of food that can be ingested at one time, or both together. Some commonly used procedures include the Roux-en-Y bypass, laparoscopic adjustable gastric banding, and sleeve gastrectomy.
This reduces the weight and diabetes relative risk by 75%, as well as cardiovascular events and deaths in obese individuals. Normoglycemia is achieved in a very high percentage (approximately 80-100%) of individuals after a gastric bypass.
In short, all patients with prediabetes are not equal. Those with prediabetes should aim for:
- lifestyle modification
- 7% weight loss if BMI exceeds 25 kg/m2
- 150 minutes or more per week of physical activity
For obese or overweight individuals with high-risk factors, pharmacologic interventions and surgery may be required in addition if the above goals are not met. There is evidence that individuals who attain normal glucose levels for even a short period have a drastically reduced risk of progressing to diabetes.
Bromocriptine has been investigated as an anti-diabetic agent because it acts centrally on the circadian rhythm to reduce hepatic glucose production and lipid synthesis as well as to mobilize fats from central storage to reduce obesity and insulin resistance. Lorcaserin is another agent used for its agonist action on the central serotonin 2C receptors on the hypothalamic neurons. It reduces food intake and promotes satiety.
It is important to emphasize that early and intensive intervention is crucial in reducing the risks associated with prediabetes. The type of intervention preferred may vary, since regaining weight, for instance, can nullify the effect of lifestyle modification, especially since it may be difficult for many individuals to change their food habits permanently.
However, if a patient shows a persistent prediabetic state despite such lifestyle changes, it may signal the need for other strategies to avert the high risk of progression. Achieving normoglycemia is key in prevention, even if it is for a short season.