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EFFECT OF METFORMIN ON LIPOPROTEIN PARTICLE CONCENTRATION
IN PEDIATRIC CARDIOMETABOLIC PATIENTS
Tara L. Dall,1 Madhuri M. Vasudevan,2 Christie M. Ballantyne,2 Ray Pourfarzib,3 1. Advanced Lipidology, Delafield, WI; 2. Baylor College of Medicine and Methodist DeBakey Heart Center, Houston, TX; 3. LipoScience, Inc., Raleigh, NC As the incidence of childhood obesity continues to Patient Selection and Study Design. A total of 78 pediatric
Baseline Characteristics. In the metformin plus TLC and TLC
The obesity epidemic and associated comorbidities in 1. Troiano RP, Flegal KM. Overweight children and adolescents: increase globally to near epidemic proportions, there is an patients were seen in the lipid clinic over the period of January 2006 group, the mean age was 12.5 and 12 years of age, respectively children is particularly concerning as these patients are likely description, epidemiology, and demographics. Pediatrics through May 2008. A retrospective chart review was conducted in (Table 4). For all of the subjects (N= 20) at the initial visit there was associated increase in the prevalence of metabolic syndrome to have long term cardiovascular and diabetes risk. Based on the office and 20 patients met the study criteria and were eligible for discordance between LDL-P versus LDL-C and non-HDL-C (Table and Type 2 diabetes in adolescence. In the past 20 years, the our study findings many of these children were noted to have 2. Dabelea D, Pettit DJ, Jones KL, Arslanina SA. Type 2 Diabetes the analysis (Table 1). The criteria for analysis included patients with 5). Comparing LDL-C less than 110 mg/dL and LDL-P less than Mellitus in Minority Children and Adolescents. Endorinol Metab Clin prevalence of an adolescent with a body mass index (BMI) increased atherogenic risk as defined by high number of LDL increased cardiometabolic risk and at least 2 available NMR lipoprotein 1100 nmol/L, 68% of the subjects had LDL-C less than 110 mg/dL above the 95th percentile has increased by more than 50%.1,2 particles that were not identified by traditional LDL cholesterol data sets in the time course specified. Increased cardiometabolic and 15% of the subjects had LDL-P less than 1100 nmol/L. 3. Wilmshurst P. Heart Protection Study. Lancet 2003;361:528-529.
Although statin therapy has been shown in small studies to risk was defined as having one or more of the following: diabetes, At baseline, there were no significant differences in lipid levels measurements. Treatment of lipid disorders in children has to 4. Ridker PM, Danielson E. Fonseca FAH, Genest J et al. Rosuvastatin improve insulin resistance, recent large randomized trials in obesity, family history of premature cardiovascular disease, impaired between those selected for treatment with TLC alone, versus those date focused on TLC and statin therapy. Statins are proven to to Prevent Vascular Events in Men and Women with Elevated adults showed no benefit.3,4 Metformin therapy in adults with fasting glucose or lipid abnormalities on traditional lipid panel or selected for treatment with metformin plus TLC, except for LDL-C, reduce LDL but do not prevent diabetes. Metformin has been C-Reactive Protein. NEJM 2008;359:2159-2207.
metabolic syndrome has favorable effects on glycemic control, at least 2/3 metabolic markers on NMR lipoproteins (small dense which was higher (p=0.037) in the metformin plus TLC-treated group shown to slow progression to diabetes in previously published 5. Orchard TJ, Temprosa M, Goldberg R, Haffner S, Ratner R, weight and lipid parameters.5 Metformin hydrochloride is an oral Marcovina S, Fowler S. The Diabetes Prevention Program Research LDL-P predominance, reduced large HDL P, excess large VLDL-P). (average LDL-C 114.45 mg/dL) compared to the LDL-C level in the studies. Metformin has also been shown have beneficial effects Group: The effect of metformin and intensive lifestyle intervention antihyperglycemic agent that has been prescribed for over 40 The treating physician abstracted the data from the patient’s medical TLC treated group (average LDL-C 85.75 mg/dL). In the TLC-treated on lipids as well as long term CV event reduction as studied in on the metabolic syndrome: the Diabetes Prevention Program years. It is now available as an inexpensive generic in both short group, small LDL-P decreased by 21% (p=0.022) after an average 5.4 Randomized Trial. Ann Intern Med 2005;142:611-19.
Defining Treatment Goals. All pediatric patients presenting to
months of therapy. In the metformin plus TLC-treated group, after Strong evidence now exists in the benefit of LDL-P 6. Bailey CJ, Turner R. Metformin. The New England Journal of the lipid clinic received trial of therapeutic lifestyle changes as noted an average 6.7 months of therapy, large HDL-P increased by 47 % Despite the success of cholesterol screening and low- measurement in management of CVD. What we have found in in table 2. Subjects were then assigned to receive either metformin (p=0.037), LDL particle number decreased by 34% (p=0.002), small density lipoprotein cholesterol (LDL-C) lowering therapy in the our adult population is that patients with predominantly small 7. Kenneth J, Silva A, Robert M, et al. Effect of Metformin in Children with diet and exercise (TLC) or TLC alone. The protocol for assigning LDL-P decreased by 57% (p=0.002), LDL particle size increased by diabetic population, it has been recognized that many patients LDL particles and total LDL particles in excess have favorable With Type 2 Diabetes. Current Diabetes Reports 2001;1:9-10.
patients to one of these two groups is detailed in table 3. 5% (p=0.001), LDL-C decreased by 14% (p=0.025), total cholesterol with low or moderate LDL-C levels still experience CHD events.8,9 8. Jeyarajah EJ, Cromwell WC, Otvos JD. Lipoprotein particle analysis The patients were seen at varying frequency, but most were decreased by 8% (p=010), and Non-HDL-C decreased by 16% lipoprotein/lipid changes with treatment of insulin resistance with by nuclear magnetic resonance spectroscopy. Clin Lab Med The limitation of testing LDL-C is that cholesterol is only one seen every 4-8 weeks. Based on criteria listed in table 3 some (p=0.001). In the metformin plus TLC treated group, although there agents such as metformin or pioglitazone in addition to TLC. type of lipid carried within low-density lipoprotein particle patients were placed on metformin therapy in addition to TLC after was a 21% increase in HDL-C, this did not reach clinical significance. If LDL-P, triglycerides, and HDL normalize with this treatment 9. Garvey WT, Kwon S, Zheng D, et al. The effects of insulin resistance (LDL-P) “containers” and its measurement provides only an initial dietary trial. All patients were started on once daily metformin No significant differences were found in TG levels, large VLDL-P, option, a need for additional higher cost lipid lowering agents and Type 2 diabetes mellitus on lipoprotein subclass particle size and approximation of the numbers of LDL particles.10 500 mg with titration to 500 mg twice daily as tolerated, typically glucose, HbA1C or weight before and after therapy in the metformin concentration determined by nuclear magnetic resonance. Diabetes To our knowledge, no study to date has directly addressed the in 2-4 weeks. Goal of treatment was weight loss and improvement Moreover, the discordance in LDL-C and LDL-P as well as question of the effect of metformin on LDL particle concentration in lipoprotein parameters with optimal LDL-P <1100 nmol/L. This is During therapy, total LDL-P decreased 34% in the metformin Non-HDL-C and LDL-P is expected in the setting of metabolic 10. Brunzell, J, Davidson, M, Furberg, C, et al. Lipoprotein Management based on NCEP pediatric lipid guidelines of LDL-C <110 mg/dL.11 treated group (p=0.002). Small LDL-P (p < 0.005), LDL-C (p < 0.05), measured by nuclear magnetic resonance (NMR) in the pediatric syndrome or diabetes.13,14 Metformin plus TLC was very effective in Patients With Cardiometabolic Risk. Diabetes Care 2008;4:811- Laboratory Analysis. All lipid and lipoprotein particle analyses
and Non-HDL-C (p < 0.005) also decreased in the metformin treated population with metabolic syndrome. Hence, the aim of this study in decreasing small LDL-P, increasing large HDL-P and decreasing were conducted on the same plasma specimens by the same patients (-57%, -14%, -16%, respectively). Large HDL-P value 11. Daniels SR, Greer FR. Committee on Nutrition 2008 Lipid screening was to examine the discordance between LDL-C and LDL-P large VLDL-P values which is also associated with a decrease laboratory. Total cholesterol, triglycerides, and HDL cholesterol and cardiovascular health in childhood. Pediatrics 2008;122:198– in adolescent patients with increased cardiometabolic risk and in total LDL-P, weight loss, and often drop in triglycerides and (HDL-C) were measured by standardized automated methods, and In the TLC group at baseline, the mean values for LDL-C, non- to compare the effects of metformin plus TLC therapy versus LDL-C was calculated by the Friedewald equation.12 Concentrations HDL-C, and LDL-P were approximately at the 10th, 30th, and 55% non-HDL-C. With the rising epidemic of pediatric obesity and 12. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the TLC therapy alone on standard lipid profile measurements and concentration of low-density lipoprotein cholesterol in plasma, of LDL-P were determined by automated nuclear magnetic resonance percentile of the population, respectively. As expected, the mean comorbities of metabolic syndrome, diabetes, and dyslipidemia, lipoprotein particle number and size as measured through the without use of the preparative ultracentrifuge. Clin Chem values for LDL-C, non-HDL-C and LDL-P were also lower compared we need to find alternative clinical approaches. Treatment of NMR LipoProfile® test analyzer.
Statistical Analysis. Nine subjects were selected to
to the metformin plus TLC group (86 mg/dL, 129 mg/dL, 1457 nmol/L, dyslipidemia in children currently is focused on TLC and statins. 13. Cromwell WC, Otvos JD, Keyes M, Pencina M, Sullivan L, Vasan receive TLC, and 11 subjects were selected to receive metformin respectively). Furthermore, there was no significant change in the However, the underlying cause of dyslipidemia in these children R, Wilson P, D’Agostino R. LDL Particle Number and Risk of Future plus TLC. Homoscedastic student’s t-test was used to compare the TLC group for all lipid and lipoprotein values except a significant is often insulin resistance. Therefore, we believe this condition Cardiovascular Disease in the Framingham Offspring Study- differences in lipoprotein parameters between TLC-treated subjects drop in the small LDL-P (-21%, p < 0.05).
can be cost effectively treated with TLC and Metformin to lower Implications for LDL Management. J of Clinical Lip 2007;1:583-592.
and metformin plus TLC-treated subjects at baseline visit. A paired their lipids and improve their weight loss.
14. Otvos, J Collins D, Freedman D, Shalaurova I, Schaefer E, McNamara student’s t-test was used to compare the differences in lipoprotein J, Bloomfield H, Robins S. VA-HIT: Low Density Lipoprotein and parameters in TLC-treated patients before and after therapy, and High Density Lipoprotein Particle Subclasses Predict Coronary compare metformin plus TLC-treated subjects before and after Events. Circulation 2006;113:1556-1563.
TABLE 3 : Criteria for Patient Selection for Treatment with TABLE 5 : Percent of Subjects with Discordance Between LDL-C, Non-HDL-C, and LDL-P Goals and their Perspective Percent Population Distribution During Initial Visit • Pediatric population- ages 4 to 18 years of age • low HDL, <40 mg/dL males <50 mg/dL females and elevated • Baseline and follow-up NMR LipoProfile test results available for LDL-C < 110 mg/dL .68% . 102 mg/dL . ~ 20% • elevated small particles where the majority of the total LDL-P were • Diagnosis of increased cardiometabolic risk defined as having any LDL-P < 1100 nmol/L .15% . 1650 nmol/L . ~ 70% one of the following: diabetes, obesity, impaired fasting glucose or lipid abnormalities on traditional lipid panel or at least 2/3 metabolic • age (children were not started on metformin strictly because < 10 markers on NMR (small dense LDL-P predominance, reduced TABLE 6 : Percent Change of Various Values Between the Metformin + TLC vs. TLC Group from Baseline to Follow-Up visit large HDL P, excess large VLDL-P), family history of premature • physical exam showing acanthosis nigricans, a clinical sign of insulin TABLE 2 : TLC - Patient Management Protocol (Specific TLC Recommendations) First Visit:
• Exercise: based on an assessment of each individual patient • Parents and patients were informed that this was family program and according to likes, current activity levels, family schedules and it was expected that everyone in the family make changes and child • Limit sedentary activities including television, computer not being • Read labels on every item purchased; patients were given a detailed used for homework, video games limited to no more than 1 hour on handout on reading labels that was specific to looking for added sugar, school nights and no more than 2 hours on weekend days high fructose corn syrup, sat fat and partially hydrogenated oil Second Visit:
• Avoid High fructose corn syrup, limit added sugar to no more than 4-6 • Limit portions- used division of 9” plate into fourths; half with non- starchy vegetable; ¼ protein 6 oz; ¼ grain or starchy vegetable • Avoid partially hydrogenated oils and limit sat fats to no more than 3 • Insoluble fiber intake: age plus 5 grams minimum and soluble fiber 10 • Increase vegetable intake: Assignments for trying one new vegetable • Incorporating legume type beans into diet every week and reporting back what the vegetable was, how it was cooked and whether child liked it or not.

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