Efficacy and safety of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, alirocumab and evolocumab, a post-commercialization study.

BACKGROUND: Efficacy-safety of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, alirocumab (ALI) and evolocumab (EVO), have previously been evaluated through controlled clinical trials with selective patient groups. Post-commercially, in 69 patients with heterozygous familial hypercholesterolemia (HeFH) and/or cardiovascular disease (CVD) with suboptimal LDL cholesterol (LDLC) lowering on maximal tolerated LDLC therapy, we assessed efficacy and safety of ALI and EVO. METHODS: Post-commercially, we started 29 patients on ALI 75 mg, 18 on ALI 150 mg, and 22 on EVO 140 mg every 2 weeks added to a maximally tolerated LDLC-lowering regimen. Since LDLC lowering did not differ between ALI 150 and EVO 140 mg, ALI 150-EVO 140 data were pooled (ALI-EVO). Changes in LDLC and AHA and NIH calculated 10-year CVD risks were assessed. RESULTS: Of the 69 patients, 25 had HeFH, 25 CVD, and 19 had both. At entry, 23 (33%) took statins and 46 (67%) were statin-intolerant. Mean ± SD and median follow-up were 49 ± 13 and 49 weeks on ALI 75 mg, and 37 ± 12 and 33 weeks on ALI-EVO. In the ALI-EVO group (n = 40), median LDLC fell from 165 mg/dl at entry to 70 mg/dl (median - 59%, p < .0001). AHA 10-year calculated CVD risk fell from 10.2 to 5.5% (median - 28%, p < .0001), and by the NIH calculator from 14.2 to 3.6% (median - 78%, p < .0001). In the ALI 75 mg group (n = 29), entry LDLC fell from 115 to 68 mg/dl (median - 39%, p < .0001). AHA 10-year calculated CVD risk fell from 11.5 to 7.3% (median - 20%, p = .004), and NIH 10-year risk from 12.9 to 5.1% (median 67%, p < .0001). Absolute and percent change in LDLC was independent of statin use. There were flu-like symptoms in 14% of patients. Adverse events did not differ (p > 0.05) between ALI 75 mg and ALI-EVO. CONCLUSION: In patients with HeFH and/or CVD, LDLC decreased from 115 to 68 mg/dl (39%) on ALI 75 mg with mean follow-up of 49 weeks, and from 165 to 70 mg/dl (59%) on ALI-EVO over 37 weeks, p < .0001 for both. Adverse events were minimal and tolerable. ALI and EVO represent paradigm shifts in LDLC lowering.

Efficacy, safety, Low density lipoprotein cholesterol lowering, and calculated 10-year cardiovascular risk reduction of alirocumab and evolocumab in addition to maximal tolerated cholesterol lowering therapy: a post-commercialization study.

BACKGROUND: Efficacy and safety of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, alirocumab (ALI) and evolocumab (EVO) have previously been evaluated through controlled clinical trials with selective patient groups. Post-commercially, in patients with heterozygous familial hypercholesterolemia (HeFH) and/or cardiovascular disease (CVD) with suboptimal LDL cholesterol (LDLC) lowering on maximal tolerated cholesterol lowering therapy, we assessed efficacy and safety of ALI and EVO. METHODS: Post-commercially, we started 25 patients on ALI 75 mg, 15 on ALI 150 mg, and 32 on EVO 140 mg bi-weekly added to entry LDLC lowering regimen, with follow-up for a median 24 weeks. History, physical exam, demographics, and adverse event data were collected. Changes in LDLC and AHA and NIH calculated 10-year CVD risks were assessed on ALI and EVO. RESULTS: Of 72 patients, 25 had HeFH only, 25 CVD only, 22 had both, median age was 65 years, 63% females, 38% males, 86% Caucasian, 11% African-Americans, 17% diabetics, 63% on anti-hypertensives, and 7% smokers. At entry, 30 (42%) were on a statin and 42 (58%) could not tolerate any statins. At 24-weeks, median LDLC decreased on ALI 75 mg from 117 to 62 mg/dL (-54%), on ALI 150 mg from 175 to 57 mg/dL (-63%), and on EVO 140 mg from 165 to 69 mg/dL (-63%), p <0.0001 for all. Absolute and percent LDLC reduction did not differ (p >.05) between ALI 150 and EVO 140 mg, but were less on ALI 75 mg vs ALI 150 mg and EVO 140 mg (p <.05). Percent reductions in 10-year CVD risks by AHA and NIH calculators, respectively were ALI 75 mg -22 and -44%, ALI 150 mg -31 and -50%, and EVO 140 mg -29 and -56%, p ≤.002 for all. The three most common adverse events included flu-like myositis 10%, respiratory tract symptoms 8%, and injection site reaction 6%. CONCLUSION: In patients with HeFH and/or CVD, LDLC was lowered by 63% on EVO and ALI 150 mg, and 54% on ALI 75 mg. Adverse events were minimal and tolerable. ALI and EVO represent paradigm shifts in LDLC lowering. Long term, post-commercial safety and efficacy remain to be determined.

Pharmacoeconomics of PCSK9 inhibitors in 103 hypercholesterolemic patients referred for diagnosis and treatment to a cholesterol treatment center.

BACKGROUND: PCSK9 inhibitor therapy has been approved by the FDA as an adjunct to diet-maximal tolerated cholesterol lowering drug therapy for adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD) with suboptimal LDL cholesterol (LDLC) lowering despite maximal diet-drug therapy. With an estimated ~24million of US hypercholesterolemic patients potentially eligible for PCSK9 inhibitors, costing ~ $14,300/patient/year, it is important to assess health-care savings arising from PCSK9 inhibitors vs ASCVD cost. METHODS: In 103 patients with HeFH, and/or ASCVD and/or suboptimal LDLC lowering despite maximally tolerated diet-drug therapy, we assessed pharmacoeconomics of PCSK9 inhibitor therapy with lowering of LDLC. For HeFH diagnosis, we applied Simon Broome's or WHO Dutch Lipid Criteria (score >8). Estimates of direct and indirect costs for ASCVD events were calculated using American Heart Association (AHA), U.S. DHHS, Healthcare Bluebook, and BMC Health Services Research databases. We used the ACC/AHA 10-year ASCVD risk calculator to estimate 10-year ASCVD risk and estimated corresponding direct and indirect costs. Assuming a 50 % reduction in ASCVD events on PCSK9 inhibitors, we calculated direct and indirect health-care savings. RESULTS: We started 103 patients (58 [56 %] women and 45 [44 %] men), on either alirocumab (62 %) or evolocumab (38 %), median age 63, BMI 29.0, and LDLC 149 mg/dl. Of the 103 patients, 28 had both HeFH and ASCVD, 33 with only ASCVD, 33 with only HeFH, and 9 had neither. Of the 103 patients, 61 had a first ASCVD event at median age 55 and on best tolerated cholesterol-lowering therapy median LDLC was 137 mg/dl. In these 61 patients, total direct costs attributable to ASCVD were $8,904,361 ($4,328,623 direct, $4,575,738 indirect), the median 10-year risk of a new CVD event was calculated to be 13.1 % with total cost $1,654,758. Assuming a 50 % reduction in ASCVD events on PCSK9 inhibitors in our 61 patients, $4,452,180 would have been saved in the past; and future 10-year savings would be $1,123,345. CONCLUSION: In the 61 CVD patients, net costs/patient/year were estimated to be $7,000 in the past, with future 10-year intervention net costs/patient/year being $12,459, both below the $50,000/year quality adjusted life-year gained by PCSK9 inhibitor therapy.

Eligibility for PCSK9 treatment in 734 Hypercholesterolemic patients referred to a regional cholesterol treatment center with LDL cholesterol ≥ 70 mg/dl despite maximal tolerated cholesterol lowering therapy.

BACKGROUND: LDL cholesterol (LDLC) lowering has been revolutionized by PCSK9 inhibitors, Alirocumab (Praluent) and Evolocumab (Repatha), approved as adjuncts to maximally tolerated cholesterol lowering therapy in heterozygous (HeFH) or homozygous (HoFH) familial hypercholesterolemia, and/or clinical atherosclerotic cardiovascular disease (CVD) where LDLC lowering is insufficient. METHODS: We applied FDA and insurance eligibility criteria for PCSK9 inhibitor use in 734 hypercholesterolemic patients serially referred over 3 years who then received ≥ 2 months maximally tolerated LDLC lowering therapy with follow up LDLC ≥ 70 mg/dl, and in 50 patients approved by insurance for PCSK9 inhibitors. We documented the percentage of patients with HeFH and/or CVD who met FDA and insurance criteria for PCSK9 inhibitor therapy using LDLC goal-based guidelines. RESULTS: Of 734 patients with LDLC ≥ 70 mg/dl after ≥ 2 months maximally tolerated LDLC lowering therapy, 220 (30%) had HeFH and/or CVD with LDLC > 100 mg/dl, meeting FDA-insurance criteria for PCSK9 inhibitor therapy. Another 66 (9%) patients were statin intolerant, without HeFH or CVD. Of the 50 patients whose PCSK9 inhibitor therapy was approved for insurance coverage, 45 (90%) had LDLC > 100 mg/dl after ≥ 2 months on maximally tolerated LDLC lowering therapy. Seventeen of these 50 patients (34%) had HeFH without CVD (LDLC on treatment 180 ± 50 mg/dl), 15 (30%) had CVD without HeFH (LDLC on treatment 124 ± 26 mg/dl), 14 (28%) had both HeFH and CVD (LDLC on treatment 190 ± 53 mg/dl), and 4 (8%) had neither HeFH nor CVD (LCLC 142 ± 11 mg/dl). CONCLUSION: Of 734 patients referred for LDLC reduction, with LDLC ≥ 70 mg/dl after ≥ 2 months on maximally tolerated therapy, 220 (30%) had HeFH and/or CVD with LDLC > 100 mg/dl, meeting FDA-insurance criteria for PCSK9 inhibitor therapy as an adjunct to diet-maximally tolerated cholesterol lowering therapy in HeFH or CVD. If 30% of patients with high LDLC and HeFH-CVD are eligible for PCSK9 inhibitors, then specialty pharmaceutical pricing models (~$14,300/year) will collide with tens of millions of HeFH-CVD patients. We speculate that if there was a 50 % reduction in CVD, then there would be savings of $245 billion, in the middle of the range of estimated PCSK9 inhibitor costs of $185-342 billion. Whether the health care savings arising from the anticipated reduction of CVD events by PCSK9 inhibitors justify their extraordinary costs in broad population use remains to be determined.

Adolescent and young adult female determinants of visceral adipose tissue at ages 26-28 years.

OBJECTIVE: To assess adolescent and young adult determinants of visceral adipose tissue (VAT) at ages 26-28 years. STUDY DESIGN: Prospective study (ages 9-28 years) of cardiometabolic measures, menarche age, menses irregularities, metabolic syndrome, impaired fasting glucose-type 2 diabetes mellitus, and VAT in 400 girls (248 black, 152 white). RESULTS: Adolescent (age 14-19) independent variables for greater VAT at ages 26-28 included larger mean waist circumference (partial R(2) = 30.8%), earlier age at menarche (0.9%), and white race (1.8%). Young adult (ages 20-28 years) independent variables for greater VAT included larger mean waist circumference (partial R(2) = 61.7%), greater triglyceride levels (3.3%), lower high-density lipoprotein cholesterol (1.0%), and greater insulin resistance (homeostasis model assessment-estimated insulin resistance; 0.4%). Independent variables for greater VAT when both adolescent and young adult variables were used included waist (tertile rank change from adolescence to young adulthood, partial R(2) = 58.3%), greater young adult triglyceride levels (4.4%), white race (1.8%), greater young adult homeostasis model assessment-estimated insulin resistance (age 20-28, 2.4%), and earlier menarche age (0.7%). Menses irregularities were not independently associated with young adult VAT. CONCLUSIONS: Adolescent girls with early menarche and larger waist circumference should be targets for primary prevention of accretion of VAT. In young adulthood, VAT is associated with dysregulated cardiometabolic profiles, which is greater for those with waist circumference increases from adolescence to adulthood. Waist circumference during young adulthood, and to a lesser degree during adolescence, is an inexpensive surrogate for VAT at ages 26-28 years.

Familial Thrombophilia Is Associated With Primary Multifocal Osteonecrosis: A Case-Control Study of 40 Patients.

To characterize pathoetiologic associations of heritable thrombophilia-hypofibrinolysis with idiopathic (primary) multifocal osteonecrosis (ON) (≥3 ON anatomic sites), we prospectively studied 28 women and 12 men with primary multifocal ON compared with 27 women and 24 men with primary nonmultifocal ON (<3 sites) and 110 healthy controls without ON. The 40 cases with primary multifocal ON differed from controls for 3 familial thrombophilias: Factor V Leiden heterozygosity (6 of 40 [15%] vs 2 of 109 [2%], P=.002), G20210A prothrombin gene heterozygosity (6 of 40 [15%] vs 3 of 110 [3%], P=.011), and high (>150%) Factor VIII (8 of 40 [20%] vs 7 of 103 [7%], P=.031). These case-control familial coagulation differences paralleled those in 51 concurrently evaluated cases with primary nonmulti-focal ON, 7 of 51 (14%) of whom had Factor V Leiden heterozygosity vs 2% of controls (P=.005) and 14 of 44 (32%) of whom had high Factor VIII vs 7 of 103 (7%) of controls (P=.0002). Recognition of familial thrombophilia as a common pathoetiology of primary multifocal ON provides an opportunity for early anticoagulation (before joint collapse), allowing both prophylaxis and therapy aimed at relieving pain and slowing or stopping progression of the disease to joint collapse. [Orthopedics. 2023;46(3):164-168.].

The child as proband for future parental cardiometabolic disease: the 26-year prospective Princeton Lipid Research Clinics Follow-up Study.

OBJECTIVE: To evaluate children's cardiovascular disease (CVD) risk factors as predictors of parents' subsequent CVD, type 2 diabetes mellitus (T2DM), and high blood pressure (HBP). STUDY DESIGN: We conducted a 26-year prospective follow-up of 852 5- to 19-year-old black and white schoolchildren (mean age, 12 years; Lipid Research Clinics, 1973-8), and parents (mean age, 40 years) from 519 families in Princeton Schools, Cincinnati, Ohio. Schoolchildren were reassessed in the Princeton Follow-up study 1999-2003 at mean age 39 years; CVD, T2DM, and HBP history of their 1038 parents were reassessed by mean age 66 years. We assessed relationships of childhood risk factors with parental CVD, T2DM, and HBP. Child-probands identified with triglyceride (TG) levels, blood pressure, low-density lipoprotein cholesterol levels, body mass index (BMI), and glucose level greater than and high-density lipoprotein cholesterol levels less than established cutoff points. RESULTS: Pediatric HBP (P=.006) and low high-density lipoprotein cholesterol (P=.018) were predictive of parental CVD at age ≤50 years. Pediatric HBP (P=.02) and high TG (P=.03) were predictive of parental CVD at age ≤60 years. Pediatric high TG (P=.009) and high low-density lipoprotein cholesterol (P=.04) were predictive of parental CVD by age 66 years. Pediatric high BMI (P=.0006) were predictive of parental T2DM. Pediatric high BMI (P=.003) and black race (P=.004) were predictive of parental HBP. CONCLUSIONS: Pediatric risk factors identify families with parents at increased risk for CVD, T2DM, and HBP, emphasizing the usefulness of the child as proband.

Titrating lovaza from 4 to 8 to 12 grams/day in patients with primary hypertriglyceridemia who had triglyceride levels >500 mg/dl despite conventional triglyceride lowering therapy.

BACKGROUND: Omega-3 fatty acids are important in treatment of severe primary hypertriglyceridemia (HTG). In 15 patients with severe primary HTG (TG >500 mg/dl despite conventional TG lowering therapy), we assessed efficacy-safety of sequential monthly treatment with Lovaza, 4 to 8 to 12 g/day. METHODS: With TG >500 mg/dl despite Type V diet, hyperinsulinemia and diabetes control, and fibric acids, Lovaza (4 g/d) was added for 1 month, and if TG remained >500 mg/dl, increased to 8 g/d for 1 month, and then to 12 g/d for 1 month, and subsequently reduced to 4 g/day for 4 months. RESULTS: Primary HTG, median TG 884 mg/dl, 14 men, 1 woman, all white, age 50 ± 7 years, 12 non-diabetic, 3 with stable diabetes control. Weight and diet held stable throughout. In 5 patients, after 1, 2, and 3 months on 4 g/day, TG fell <500, mean 1390 to 234 (-83%, p<.0001), to 135 (-90%, p<.0001), and 158 mg/dl (-89%, p<.0001), with a negative TG slope, p=.0013. Non-HDLC fell from 320 to 177 (-45%, p=.001), to 152 (-53%, p=.0002), and to 163 (-49%, p=.0004), with a negative slope, p=.01. In 10 patients, with Lovaza increased from 4 to 8 to 12 g, 3 failed to respond. In 7 of these 10 patients, TG fell 37% from 1075 to 672 on 4 g (p=.006), to 577 on 8 g (-46%, p=.0009), and to 428 mg/dl (-60%, p<.0001) on 12 g/day, with a negative TG slope, p=.0018. TG on 12 g/day was lower than on 8 g/day, p =.03. Non-HDLC fell from 245 to 217 mg/dl (-11%) on 4 g/day, to 203 (-17%, p=.01) on 8 g/day, and to 192 (-22%, p=.003) on 12 g/day, with a negative slope, p=.016. Compared to pre-Lovaza baseline, no abnormal measures developed in safety tests. The 4, 8, and 12 g/d Lovaza doses were well tolerated. CONCLUSION: Titration of Lovaza from 4 to 8 to 12 g/d safely offers an effective way to lower TG beyond conventional 4 g therapy.

Sex hormone-binding globulin, oligomenorrhea, polycystic ovary syndrome, and childhood insulin at age 14 years predict metabolic syndrome and class III obesity at age 24 years.

OBJECTIVE: We hypothesized that oligomenorrhea (menstrual cyclicity ≥42 days), hyperandrogenism, low levels of sex hormone-binding globulin (SHBG), childhood insulin, and metabolic syndrome (MetS) at age 14 years would predict MetS and class III obesity (body mass index ≥40 kg/m(2)) at age 24 years. STUDY DESIGN: In this prospective study of schoolgirls, at age 14 years, the girls were categorized as regularly cycling (n = 375), oligomenorrheic (n = 18), or oligomenorrhea plus biochemical hyperandrogenism (polycystic ovary syndrome [PCOS]; n = 12), together designated PCOS. RESULTS: Significant explanatory variables for MetS at age 24 years included childhood insulin, MetS, and PCOS category (all positive) and SHBG (negative) at age 14 years. Using categorical data, top decile of childhood insulin, MetS at age 14, bottom decile of SHBG, and PCOS category were significant positive predictors for MetS at age 24. SHBG (negative), black race (positive), and oligomenorrhea (positive) were significant explanatory variables for class III obesity at age 24. Using categorical data, black race, MetS at age 14, bottom decile of SHBG, PCOS category, and top decile of childhood insulin were positive explanatory variables for class III obesity at age 24 years. CONCLUSIONS: Oligomenorrhea, PCOS (a subcohort of oligomenorrhea), hyperandrogenism, low SHBG, MetS, and childhood insulin at age 14 years may represent a critical, reversible pathway for the development of MetS and class III obesity in young adulthood.

Paradoxically high adiponectin in obese 16-year-old girls protects against appearance of the metabolic syndrome and its components seven years later.

OBJECTIVE: To evaluate the relationships of adiponectin levels at age 16 years in obese schoolgirls to metabolic syndrome and its components at age 23 years. STUDY DESIGN: Seven-year prospective study of 381 females. RESULTS: In 144 white and 129 black non-obese 16-year old girls (body mass index < 24.6 kg/m(2)), race-specific median adiponectin levels (white 12 mg/L, black 11) was used to identify paradoxically high adiponectin levels in obese girls. Of 34 white and 74 black obese girls, 12 (35%) and 19 (26%) had paradoxically high adiponectin levels. In these 108 obese girls, adiponectin levels at age 16 years independently predicted high-density lipoprotein cholesterol (positive) and waist (negative), insulin (negative), and glucose (negative) at age 23 years; paradoxically high adiponectin levels at age 16 years was a negative independent predictor for waist, homeostatic model assessment-insulin resistance, and for the number of abnormal components of the metabolic syndrome at age 23 years. In 31 pairs of obese girls with and without paradoxically high adiponectin levels, matched by race and age 16 body mass index, adiponectin levels at age 16 years was a negative predictor for the number of abnormal metabolic syndrome components at age 23 years. CONCLUSION: Paradoxically high adiponectin levels in obese 16 year old girls protects against metabolic syndrome and its components at age 23 years.

Determinants of persistent obesity and hyperinsulinemia in a biracial cohort: a 15-year prospective study of schoolgirls.

OBJECTIVE: To identify childhood-adolescent determinants of persistent hyperinsulinemia and obesity. STUDY DESIGN: We conducted a 15-year prospective study of 296 African-American and 260 Caucasian girls. RESULTS: Childhood insulin level (partial R2=40.4%) and 14-year change in body mass index (BMI; partial R2=20.2%) were major predictors for average insulin Z score during the 15-year follow-up. Waist circumference at age 19 years, 10-year mean percentage of calories from carbohydrates, 15-year change in insulin Z score, the interaction of race with 8-year change in waist, and 14-year change in glucose level were major predictors of a 14-year change in BMI, explaining 66.7% of variability. In girls with all 9 insulin measurements in 15 years persistently in the top 25% versus girls with all measures in the bottom 75%, variables predicting the persistent insulin category included waist circumference at age 11 years (odds ratio [OR], 1.25; 95% CI, 1.11-1.40; P=.0003), 14-year change in BMI (OR, 1.26; 95% CI, 1.01-1.57; P=.037), and 8-year change in waist circumference (OR, 1.16; 95% CI, 1.01-1.32; P=.038). CONCLUSIONS: Childhood interventions to reduce occurrence of hyperinsulinemia and obesity in early adulthood should focus on childhood-adolescent hyperinsulinemia, obesity, central adiposity, and adolescent increases in these factors.

A likelihood model that accounts for censoring due to fetal loss can accurately test the effects of maternal and fetal genotype on the probability of miscarriage.

OBJECTIVE: Heritable maternal and fetal thrombophilia and/or hypofibrinolysis are important causes of miscarriage. Under the constraint that fetal genotype is observed only after a live birth, estimating risk is complicated. Censoring prevents use of published statistical methodology. We propose techniques to determine whether increases in miscarriage are due to the fetal genotype, maternal genotype, or both. METHODS: We propose a study to estimate the risk of miscarriage contributed by an allele, expressed in either dominant or recessive fashion. Using a multinomial likelihood, we derive maximum likelihood estimates of risk for different genotype groups. We describe likelihood ratio tests and a planned hypothesis testing strategy. RESULTS: Parameter estimation is accurate (bias <0.0011, root mean squared error <0.0780, n = 500). We used simulation to estimate power for studies of three gene mutations: the 4G hypofibrinolytic mutation in the plasminogen activator inhibitor gene (PAI-1), the prothrombin G20210A mutation, and the Factor V Leiden mutation. With 500 families, our methods have approximately 90% power to detect an increase in the miscarriage rate of 0.2, above a background rate of 0.2. CONCLUSION: Our statistical method can determine whether increases in miscarriage are due to fetal genotype, maternal genotype, or both despite censoring.

Long-term Anticoagulation Prevents Progression of Stages I and II Primary Osteonecrosis of the Hip in Patients With Familial Thrombophilia.

The authors prospectively assessed long-term anticoagulation outcomes (≥3 years) for 9 patients meeting 4 inclusion criteria: pretreatment Ficat stage I or II primary hip osteonecrosis (ON), factor V Leiden or prothrombin G20210A heterozygosity, no contraindication to anticoagulation, and 90-day participation in an initial enoxaparin 60 mg/d protocol. The primary endpoint was prevention of hip collapse (Ficat stage III or IV). The secondary endpoint was pain relief. After 90 days of enoxaparin 60 mg/d, anticoagulation was continued for 8 patients: 4 receiving warfarin (international normalized ratio targeted to 2 to 2.5; 11.5, 13, 14.5, and 21 years), 1 receiving enoxaparin 120 mg/d (11.5 years), and 3 receiving novel oral anticoagulants (5, 6, and 8 years). Radiographs were obtained before treatment; at 3 to 4, 6 to 8, and 12 to 14 months; and then annually. By selection, 8 patients had factor V Leiden heterozygosity and 1 had prothrombin G202010A heterozygosity. Of their 13 hips (Ficat I or II at entry), 12 remained Ficat I or II after 12±5 years (range, 5.5-21 years) of continuous anticoagulation and follow-up; 1 hip radiographically normalized. None of the 13 hips progressed to collapse (Ficat III or IV). Six patients became symptom free after the first 3 months of receiving enoxaparin, 1 after 6 months of anticoagulation, and 1 after 10 months of anticoagulation; all 8 patients remained symptom free with anticoagulation. Anticoagulation for primary hip ON before hip collapse in patients with familial thrombophilia may change the natural history of ON because most untreated patients with ON have joint collapse and total joint replacement within 2 years of original symptoms. [Orthopedics. 2020;43(4):e208-e214.].

Ocular vascular thrombotic events: a diagnostic window to familial thrombophilia (compound factor V Leiden and prothrombin gene heterozygosity) and thrombosis.

In a 12-member, 3-generation kindred with conjoint inheritance of G1691A factor V Leiden (FVL) and G20210A prothrombin gene (PTG) mutations, identified through a proband with amaurosis fugax and his father with nonarteritic ischemic optic neuropathy (NAION), the authors' hypothesis was that ocular thrombosis was a diagnostic window to familial thrombophilia-thrombosis. The authors used polymerase chain reaction (PCR) measures for thrombophilia (FVL, PTG, C677T-A1298C methylenetetrahydrofolate reductase [MTHFR], platelet glycoprotein PLA1A2) and hypofibrinolysis (plasminogen activator inhibitor-1 4G4G). The 39-year-old white male proband, with amaurosis fugax and transient ischemic attacks (TIA), was found to be a compound heterozygote for FVL and PTG mutations. His symptoms resolved only after coumadin. His 44-year-old brother (deep venous thrombosis [DVT]) and 46-year-old sister (DVT, pulmonary embolus [PE]) were compound FVL-PTG gene heterozygotes. Of 4 asymptomatic children born to these 3 siblings, 2 were FVL heterozygotes and 2 PTG heterozygotes. The proband's 69-year-old father, with NAION and ischemic stroke, had PTG heterozygosity, familial high factor VIII, and compound MTHFR C677T-A1298C mutation with homocysteinemia. The proband's 61-year-old aunt had PTG heterozygosity, recurrent DVT, and mesenteric artery thrombosis. The proband's 67-year-old mother, free of thrombotic events, was a FVL heterozygote, had high factor VIII, and PAI-1 4G4G homozygosity. In this extended kindred, ocular thrombotic events (amaurosis fugax, NAION) were associated with variegated thrombotic events, including TIA, ischemic stroke, DVT, PE, and mesenteric artery thrombosis, and opened a diagnostic window to family screening and treatment for complex thrombophilias, which had previously been undiagnosed.

Metformin-diet ameliorates coronary heart disease risk factors and facilitates resumption of regular menses in adolescents with polycystic ovary syndrome.

BACKGROUND: In 20 adolescents age < or = 17 (16 +/- 1 yr) with polycystic ovary syndrome (PCOS), we assessed efficacy and safety of metformin-diet for 1 year in treatment of endocrinopathy and coronary heart disease (CHD) risk factors. METHODS: Calories were targeted to 1,500-1,800/ day if body mass index (BMI) was < 25 or to 1,200-1,500/day if BMI was > or = 25, along with 2,550 mg metformin. RESULTS: Median weight fell from 85.5 to 78.4 kg (p = 0.004), waist circumference from 91 to 84 cm (p = 0.017), triglyceride from 108 to 71 mg/dl (p = 0.008), insulin from 20.5 to 15 microU/ml (p = 0.018), HOMA-IR from 2.0 to 1.5 (p = 0.026), and testosterone from 45.5 to 31.5 ng/dl (p = 0.03). The percentage of cycles with normal menses rose from a pre-treatment median of 8% to 100%, p < 0.0001. CONCLUSIONS: In adolescents (< or = age 17 yr) with PCOS, metformin-diet safely ameliorates CHD risk factors and endocrinopathy while facilitating resumption of regular menses.

VKORC1 variant genotypes influence warfarin response in patients undergoing total joint arthroplasty: a pilot study.

UNLABELLED: Warfarin dosing algorithms do not account for genetic mutations that can affect anticoagulation response. We retrospectively assessed to what extent the VKORC1 variant genotype would alter the likelihood of being a hyperresponder or hyporesponder to warfarin in patients undergoing total joint arthroplasty. We used the international normalized ratio (INR) on the third postoperative day of 3.0 or greater to define warfarin hyperresponders and 1.07 or less to define hyporesponders. A control group of normal responders was identified. From a cohort of 1125 patients receiving warfarin thromboprophylaxis, we identified 30 free of predisposing factors that could affect warfarin response: 10 hyperresponders, eight hyporesponders, and 12 normal responders. Homozygous carriers of the VKORC1 mutant AA genotype were more likely (compared with carriers of GA or GG genotypes) to be hyperresponders (odds ratio, 7.5; 95% confidence interval, 1.04-54.1). Homozygous carriers of the GG (normal) genotype were more likely (compared with carriers of AA or GA genotypes) to be hyporesponders (odds ratio, 9; 95% confidence interval, 1.14-71). Preoperative screening for the VKORC-1 genotype could identify patients with a greater potential for being a hyperresponder or hyporesponder to warfarin. This may allow an adjusted pharmacogenetic-based warfarin dose to optimize anticoagulation, reducing postoperative risks of bleeding and thrombosis or embolism. LEVEL OF EVIDENCE: Level III, diagnostic study.

Characteristics of obesity in polycystic ovary syndrome: Etiology, treatment, and genetics.

Polycystic ovary syndrome (PCOS) has multiple etiologies including ovarian and adrenal hyperandrogenism, neuro-endocrine and hypothalamic-pituitary dysfunction, and disorders of peripheral insulin resistance. Obesity is neither necessary nor sufficient for the PCOS phenotype, and the association of PCOS with obesity is not universal, with national, cultural, and ethnic differences. Obesity, particularly visceral adiposity which is common in obese and non-obese women with PCOS, amplifies and worsens all metabolic and reproductive outcomes in PCOS. Obesity increases insulin resistance and compensatory hyperinsulinemia, which in turn increases adipogenesis and decreases lipolysis. Obesity sensitizes thecal cells to LH stimulation and amplifies functional ovarian hyperandrogenism by upregulating ovarian androgen production. Obesity increases inflammatory adipokines which, in turn, increase insulin resistance and adipogenesis. Lifestyle interventions focused on diet-weight loss and concurrent exercise are central to therapy which also commonly subsequently needs to include pharmacologic therapy. PCOS symptoms commonly improve with 5% to 10% weight loss, but 25% to 50% weight loss, usually achievable only through bariatric surgery, may be required for morbid obesity unresponsive to lifestyle-medical treatment. Bariatric surgery is a valuable approach to weight loss in PCOS where BMI is ≥40 kg/m2 when non-surgical treatment and/or induction of pregnancy have failed, and can be an initial treatment when BMI is ≥50 kg/m2. Further research in PCOS is needed to better understand the fundamental basis of the disorder, to ameliorate obesity, to correct hyperandrogenism, ovulation, hyperinsulinemia, and to optimize metabolic homeostasis.

Metabolic syndrome in childhood predicts adult metabolic syndrome and type 2 diabetes mellitus 25 to 30 years later.

OBJECTIVE: To prospectively assess the association of the metabolic syndrome in childhood with adult metabolic syndrome and type 2 diabetes mellitus (T2DM) 25 to 30 years later. STUDY DESIGN: Data from the National Heart Lung and Blood Institute Lipid Research Clinics (LRC) Princeton Prevalence Study (1973-1976) and the Princeton Follow-up Study (PFS, 2000-2004) were used. Body mass index (BMI = kg/m(2)) was used as the obesity measure in childhood because waist circumference was not measured at the LRC. The adult T2DM status of participants and their parents was obtained by participant report or fasting blood glucose >/=126 mg/dL. A logistic analysis for clustered samples was used to predict adult metabolic syndrome and T2DM, taking into account sibling correlations in the cohort. Pediatric metabolic syndrome, age at PFS, sex, race, change in BMI percentile, parental history of diabetes, and the interaction of pediatric metabolic syndrome and parental diabetes were explanatory variables. RESULTS: Ages ranged from 5 to 19 years in the LRC and from 30 to 48 years in the PFS. Pediatric metabolic syndrome, parental diabetes, age at follow-up, and change in age-specific BMI percentile were significant predictors of metabolic syndrome in adulthood, and pediatric metabolic syndrome, age at follow-up, black race, and parental diabetes were significant predictors of T2DM. CONCLUSIONS: Evaluating 5- to 19-year-old children for metabolic syndrome and family history of diabetes could identify children at increased risk of adult metabolic syndrome and T2DM, allowing prospective primary prevention of these outcomes.