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Date of release: 01 June, 2009

Progression from impaired glucose tolerance to diabetes mellitus: association with cardiovascular risk factors, lifestyle and metformin


In a recently published paper [1], the Diabetes Prevention Program randomized trial provides more information from its database considering the effect of progression from impaired glucose tolerance (IGT) to diabetes on cardiovascular risk factors and its amelioration by intensive lifestyle and metformin intervention. 


There is a known increase of cardiovascular disease in subjects with diabetes, but the evolution of this risk in patients progressing from prediabetes to diabetes is not understood. In this study, 3234 patients with IGT were followed for 3.2 years and randomized to intensive lifestyle (ILS) intervention (achieve and maintain a 7% weight reduction in initial body weight using a low-calorie, low-fat diet and 150 min/week of moderate physical activity), metformin (850 mg twice a day) or placebo [2].


This study examines the longitudinal relationship between selected risk factors for cardiovascular disease (blood pressure, triglycerides, high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol, and LDL peak particle density) and glycemia in the three treatment groups in the Diabetes Prevention Program. Values of the risk factors for cardiovascular disease and changes from baseline became more unfavorable as glucose tolerance status deteriorated but improved with reversion to normal glucose tolerance, especially in the ILS intervention group (trend test p < 0.001 for all risk factors except LDL peak particle density (p = 0.02) in the ILS group and HDL cholesterol (p = 0.02) in the placebo group). Also, while the glucose tolerance status was improved in the ILS group, systolic blood pressure and triglyceride levels fell by 25%, whereas HDL cholesterol increased by 8%; the metformin and placebo groups showed less significant improvements. Although there were few significant differences in the transition from IGT to diabetes, there were strong relationships between risk factors and continuous measures of glycemia.  


Progression from IGT to diabetes is associated with mild deterioration, whereas reversion to normal glucose tolerance is associated with improvement in cardiovascular risk factors. Early intervention with intensive lifestyle, but less so with metformin, in participants at high risk for diabetes improves the cardiovascular risk and glucose tolerance profile simultaneously.

Comment

Factors other than worsening hyperglycemia are responsible for the increased cardiovascular risk seen in diabetes, as an adverse pattern of risk factors for cardiovascular disease is already present in normoglycemic patients who develop diabetes compared to those who do not [3]. This study shows that participants who developed diabetes tended toward higher blood pressure and triglyceride levels and lower HDL cholesterol levels. After intervention, in those who remained in IGT or normal glucose tolerance, the risk factor profile among those with ILS was more favorable than in the metformin or placebo groups. Fewer participants developed diabetes and more reverted to normal glucose tolerance in the ILS group. Fasting glucose correlated less with risk factors than 2-h glucose or HbA1c. These findings suggest that reversion to normal glucose tolerance from IGT is associated with long-term improvement in risk factor status, which deteriorates rapidly if glucose tolerance worsens. In progression to diabetes, neither ILS nor metformin were associated with any significant change in risk factors. In other reports from the same study [4], a past history of gestational diabetes mellitus (GDM) confers a very high risk of postpartum development of diabetes, particularly type 2 diabetes. Women with a history of GDM randomized to placebo had a crude incidence rate of diabetes 71% higher than that of women without such a history. Among women reporting a history of GDM, both intensive lifestyle and metformin therapy reduced the incidence of diabetes by approximately 50% compared with the placebo group, whereas these reductions were 49% and 14%, respectively, in parous women without GDM. These data suggest that metformin may be more effective in women with a GDM history as compared with those without. In another publication of the Diabetes Prevention Program randomized study [5], authors found out 53% of the participants (n = 1711) had metabolic syndrome at baseline; the incidence did not vary substantially by age. However, low levels of HDL cholesterol predominated in younger participants (age 2544 years), and high blood pressure predominated in older participants (age 6082 years). The incidence of the metabolic syndrome was reduced by 41% in the lifestyle group (p < 0.001) and by 17% in the metformin group (p = 0.03) compared with placebo. In this study [6], hypertension was present in 30% of the participants at study entry and then increased in the placebo and metformin groups, although it significantly decreased with intensive lifestyle intervention. Triglyceride levels fell in all treatment groups, but fell significantly more with intensive lifestyle intervention. Total cholesterol and LDL cholesterol levels were similar among treatment groups. Intensive lifestyle intervention significantly increased the HDL cholesterol level and reduced the cumulative incidence of the proatherogenic LDL phenotype B. At 3 years of follow-up, the use of pharmacologic therapy to achieve established goals in the intensive lifestyle group was 2728% less for hypertension and 25% less for hyperlipidemia compared with the placebo and metformin groups. In conclusion, if patients have cardiovascular risk factors, they will improve when glucose tolerance is controlled or reversed by intensive lifestyle intervention, but not so much with metformin therapy. In those who progress to diabetes, active intervention for cardiovascular risk factors (intensive lifestyle intervention vs. metformin) will make little difference and might reflect a lack of success.

Comentario

Konstantinos Tserotas
Department of Obstetrics & Gynecology, Complejo Hospitalario Metropolitano, Caja del Seguro Social de Panama

    References

  1. Goldberg RB, Temprosa M, Haffner S, et al. Effect of progression from impaired glucose tolerance to diabetes on cardiovascular risk factors and its amelioration by lifestyle and metformin intervention: The Diabetes Prevention Program randomized trial. Diabetes Care 2009;32:72632. Published April 2009.
    http://www.ncbi.nlm.nih.gov/pubmed/19171717

  2. Knowler WC, Barrett-Connor E, Fowler SE, et al.; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393403.
    http://www.ncbi.nlm.nih.gov/pubmed/11832527

  3. Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK. Cardiovascular risk factors in confirmed prediabetic individuals. Does the clock for coronary heart disease start ticking before the onset of clinical diabetes? JAMA 1990;263:28938.
    http://www.ncbi.nlm.nih.gov/pubmed/2338751

  4. Ratner RE, Christophi CA, Metzger BE, et al.; Diabetes Prevention Program Research Group. Prevention of diabetes in women with a history of gestational diabetes: effect of metformin and lifestyle modification. J Clin Endocrinol Metab 2008;93:47749.
    http://www.ncbi.nlm.nih.gov/pubmed/18826999

  5. Orchard TJ, Temprosa M, Goldberg R, et al.; Diabetes Prevention Program Research Group. The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial. Ann Intern Med 2005;142:61119.
    http://www.ncbi.nlm.nih.gov/pubmed/15838067

  6. Ratner R, Goldberg R, Haffner S, et al.; Diabetes Prevention Program Research Group. Impact of intensive lifestyle and metformin therapy on cardiovascular disease risk factors in the diabetes prevention program. Diabetes Care 2005;28:88894.
    http://www.ncbi.nlm.nih.gov/pubmed/15793191