Grace A. Lee

Improved Blood Pressure Control Associated With a Large-Scale Hypertension Program

IMPORTANCE Hypertension control for large populations remains a major challenge. OBJECTIVE To describe a large-scale hypertension program in Northern California and to compare rates of hypertension control in that program with statewide and national estimates. DESIGN, SETTING, AND PATIENTS The Kaiser Permanente Northern California (KPNC) hypertension program included a multifaceted approach to blood pressure control. Patients identified as having hypertension within an integrated health care delivery system in Northern California from 2001-2009 were included. The comparison group comprised insured patients in California between 2006-2009 who were included in the Healthcare Effectiveness Data and Information Set (HEDIS) commercial measurement by California health insurance plans participating in the National Committee for Quality Assurance (NCQA) quality measure reporting process. A secondary comparison group was included to obtain the reported national mean NCQA HEDIS commercial rates of hypertension control between 2001-2009 from health plans that participated in the NCQA HEDIS quality measure reporting process. MAIN OUTCOMES AND MEASURES Hypertension control as defined by NCQA HEDIS. RESULTS The KPNC hypertension registry included 349,937 patients when established in 2001 and increased to 652,763 by 2009. The NCQA HEDIS commercial measurement for hypertension control within KPNC increased from 43.6% (95% CI, 39.4%-48.6%) to 80.4% (95% CI, 75.6%-84.4%) during the study period (P < .001 for trend). In contrast, the national mean NCQA HEDIS commercial measurement increased from 55.4% to 64.1%. California mean NCQA HEDIS commercial rates of hypertension were similar to those reported nationally from 2006-2009 (63.4% to 69.4%). CONCLUSIONS AND RELEVANCE Among adults diagnosed with hypertension, implementation of a large-scale hypertension program was associated with a significant increase in hypertension control compared with state and national control rates. Key elements of the program included a comprehensive hypertension registry, development and sharing of performance metrics, evidence-based guidelines, medical assistant visits for blood pressure measurement, and single-pill combination pharmacotherapy.

The metabolic effects of lopinavir/ritonavir in HIV-negative men.

Background: Therapy with HIV protease inhibitors (PI) has been shown to worsen glucose and lipid metabolism, but whether these changes are caused by direct drug effects, changes in disease status, or body composition is unclear. Therefore, we tested the effects of the PI combination lopinavir and ritonavir on glucose and lipid metabolism in HIV-negative subjects. Methods: A dose of 400 mg lopinavir/100 mg ritonavir was given twice a day to 10 HIV-negative men. Fasting glucose and insulin, lipid and lipoprotein profiles, oral glucose tolerance, insulin sensitivity by euglycemic hyperinsulinemic clamp, and body composition were determined before and after lopinavir/ritonavir treatment for 4 weeks. Results: On lopinavir/ritonavir, there was an increase in fasting triglyceride (0.89 ± 0.15 versus 1.63 ± 0.36 mmol/l; P = 0.007), free fatty acid (FFA; 0.33 ± 0.04 versus 0.43 ± 0.06 mmol/l; P = 0.001), and VLDL cholesterol (15.1 ± 2.6 versus 20 ± 3.3 mg/dl; P = 0.05) levels. There were no changes in fasting LDL, HDL, IDL, lipoprotein (a), or total cholesterol levels. Fasting glucose, insulin, and insulin-mediated glucose disposal were unchanged, but on a 2 h oral glucose tolerance test glucose and insulin increased. There were no changes in weight, body fat, or abdominal adipose tissue by computed tomography. Conclusion: Treatment with 4 weeks of lopinavir/ritonavir in HIV-negative men causes an increase in triglyceride levels, VLDL cholesterol, and FFA levels. Lopinavir/ritonavir leads to a deterioration in glucose tolerance at 2 h, but there is no significant change in insulin-mediated glucose disposal rate by euglycemic hyperinsulinemic clamp.

The Effects of Recombinant Human Leptin on Visceral Fat, Dyslipidemia, and Insulin Resistance in Patients with Human Immunodeficiency Virus-Associated Lipoatrophy and Hypoleptinemia

CONTEXT Leptin deficiency is associated with dyslipidemia and insulin resistance in animals and humans with lipoatrophy; leptin replacement ameliorates these abnormalities. OBJECTIVE The objective of the study was to evaluate the effects of leptin therapy in lipoatrophic HIV-infected patients with dyslipidemia and hypoleptinemia. DESIGN This was a 6-month, open-label, proof-of-principle pilot study. SETTING Metabolic ward studies were performed before and 3 and 6 months after leptin treatment. PARTICIPANTS Participants included eight HIV-infected men with lipoatrophy, fasting triglycerides greater than 300 mg/dl, and serum leptin less than 3 ng/ml. INTERVENTION Recombinant human leptin was given by sc injection (0.01 mg/kg and 0.03 mg/kg twice daily for successive 3 month periods). OUTCOME MEASURES Measures included fat distribution by magnetic resonance imaging and dual-energy X-ray absorptiometry; fasting lipids; insulin sensitivity by euglycemic hyperinsulinemic clamp; endogenous glucose production, gluconeogenesis, glycogenolysis, and whole-body lipolysis by stable isotope tracer studies; oral glucose tolerance testing; liver fat by proton magnetic resonance spectroscopy; and safety. RESULTS Visceral fat decreased by 32% (P = 0.001) with no changes in peripheral fat. There were significant decreases in fasting total (15%, P = 0.012), direct low-density lipoprotein (20%, P = 0.002), and non-high-density lipoprotein (19%, P = 0.005) cholesterol. High-density lipoprotein cholesterol increased. Triglycerides, whole-body lipolysis, and free fatty acids decreased during fasting and hyperinsulinemia. Fasting insulin decreased. Endogenous glucose production decreased during fasting and hyperinsulinemia, providing evidence of improved hepatic insulin sensitivity. Leptin was well tolerated but decreased lean mass. CONCLUSIONS Leptin treatment was associated with marked improvement in dyslipidemia. Hepatic insulin sensitivity improved and lipolysis decreased. Visceral fat decreased with no exacerbation of peripheral lipoatrophy. Results from this pilot study suggest that leptin warrants further study in patients with HIV-associated lipoatrophy.

Single-Dose Lopinavir-Ritonavir Acutely Inhibits Insulin-Mediated Glucose Disposal in Healthy Volunteers

Previously, we found that 4 weeks of treatment with lopinavir-ritonavir did not decrease insulin sensitivity but did increase adiponectin levels. In the present study, a single dose of lopinavir-ritonavir decreases insulin sensitivity but does not alter adiponectin levels. Insulin resistance from protease inhibitors may decrease with prolonged use; an increase in adiponectin levels may mediate this effect.

Effects of ritonavir and amprenavir on insulin sensitivity in healthy volunteers.

Background:Some HIV protease inhibitors (PIs) have been shown to induce insulin resistance in vitro but the degree to which specific PIs affect insulin sensitivity in humans is less well understood. Methods:In two separate double-blind, randomized, cross-over studies, we assessed the effects of a single dose of ritonavir (800 mg) and amprenavir (1200 mg) on insulin sensitivity (euglycemic hyperglycemic clamp) in healthy normal volunteers. Results:Ritonavir decreased insulin sensitivity (−15%; P = 0.008 versus placebo) and non-oxidative glucose disposal (−30%; P = 0.0004), whereas neither were affected by amprenavir administration. Conclusion:Compared to previously performed studies of identical design using single doses of indinavir and lopinavir/ritonavir, a hierarchy of insulin resistance was observed with the greatest effect seen with indinavir followed by ritonavir and lopinavir/ritonavir, with little effect of amprenavir.

Indinavir increases glucose production in healthy HIV-negative men.

In the absence of HIV infection, changes in adipose tissue and lipid levels, HIV protease inhibitor therapy increases fasting glucose levels,suggestive of hepatic insulin resistance. After 4 weeks of indinavir treatment in nine HIV-negative healthy men, fasting glucose production and glycogenolysis were significantly increased. During the euglycemic hyperinsulinemic clamp, indinavir blunted the ability of insulin to suppress glucose production. Therefore, indinavir worsens hepatic insulin sensitivity, increasing endogenous glucose production.

The Effects of Low-Dose Growth Hormone in HIV-Infected Men with Fat Accumulation: A Pilot Study

Pharmacologic doses of growth hormone (GH) reduce HIV-associated fat accumulation but may worsen glucose metabolism. We investigated the effects of a low dose of GH (1 mg per day) in HIV-infected men with fat accumulation and found that such treatment reduced total fat and increased lean body mass without significant changes in glucose tolerance or insulin sensitivity. Visceral adipose tissue (VAT) levels did not change significantly for the group as a whole, although a reduction in the VAT level was seen in patients with a greater VAT level at baseline.

Boosting dose ritonavir does not alter peripheral insulin sensitivity in healthy HIV-seronegative volunteers.

Background: Some HIV protease inhibitors (PIs), including full-dose ritonavir (800 mg) and ritonavir-boosted lopinavir, acutely induce insulin resistance in the absence of HIV infection and changes in body composition. Boosting dose ritonavir (100-200 mg) is the most commonly prescribed PI, yet its effects on glucose metabolism have not been described in the absence of another PI. Methods: In this randomized, double-blind, cross-over study, a single dose of ritonavir 200 mg or placebo was given to healthy HIV-seronegative volunteers before assessment of insulin sensitivity by euglycemic hyperinsulinemic clamp. Results: Boosting dose ritonavir had no effect on insulin-mediated glucose disposal (M/I, placebo: 8.59 ± 0.83 vs. ritonavir: 8.51 ± 0.64 mg/kg per minute per μU/mL insulin, P = 0.89). Conclusions: A single boosting dose of ritonavir does not alter insulin sensitivity, suggesting lopinavir is likely responsible for the induction of insulin resistance demonstrated in prior short-term studies of lopinavir/ritonavir. There is a dose-dependent effect of ritonavir on insulin sensitivity.

The protease inhibitor combination lopinavir/ritonavir does not decrease insulin secretion in healthy, HIV-seronegative volunteers.

Background: HIV protease inhibitors have been shown to worsen glucose and lipid metabolism. Recent studies have suggested that protease inhibitors can impair insulin secretion in HIV-infected patients. We studied the effects of the protease inhibitor combination lopinavir and ritonavir on insulin secretion, insulin sensitivity, and lipid metabolism in HIV-negative persons. Methods: A combination dose of lopinavir 400 mg and ritonavir 100 mg was given twice daily to eight HIV-seronegative men for 4 weeks. Fasting glucose, insulin, lipid, and lipoprotein profiles; oral glucose tolerance; insulin secretion and insulin-mediated glucose disposal by hyperglycemic clamp; and body composition by dual energy X-ray absorptiometry were determined before and after lopinavir/ritonavir administration. Results: There was no change in first-phase insulin secretion (2.82 ± 0.30 versus 2.71 ± 0.31 nmol/l; P = 0.60), as well as fasting insulin and glucose levels, oral glucose tolerance, or insulin-mediated glucose disposal after 4 weeks administration of lopinavir/ritonavir. However, there were significant increases in fasting triglycerides (1.02 ± 0.13 versus 2.20 ± 0.31 mmol/l; P = 0.001), total cholesterol (4.42 ± 0.30 versus 5.70 ± 0.60 mmol/l; P = 0.007), and apo B-100 levels (0.86 ± 0.07 versus 1.07 ± 0.11 g/l; P = 0.0009). High-density lipoprotein cholesterol decreased (0.99 ± 0.11 versus 0.82 ± 0.10 mmol/l; P = 0.005). There were no changes in body composition, weight, or body fat. Conclusion: Although administration of lopinavir/ritonavir to healthy, HIV-seronegative volunteers for 4 weeks resulted in increased triglyceride and decreased high-density lipoprotein cholesterol levels, there was no change in first-phase insulin secretion during the hyperglycemic clamp. The reported effects of protease inhibitor on insulin secretion in HIV-infected individuals may be due to changes in HIV-related factors and not a direct drug effect.

The acute effects of HIV protease inhibitors on insulin suppression of glucose production in healthy HIV-negative men.

Background:The effects of different HIV protease inhibitors (PIs) on peripheral insulin resistance have been described, but less is known about their effects on insulin suppression of endogenous glucose production (EGP). Methods:We tested the acute effects of 3 PIs, indinavir, ritonavir, and amprenavir, on EGP quantified by stable isotope techniques during the hyperinsulinemic, euglycemic clamp in 3 similar placebo-controlled protocols. Results:EGP was higher with indinavir in the hyperinsulinemic state than with placebo (4.1 ± 1.3 vs. 2.2 ± 0.8 μg·kg−1·min−1, P = 0.04). A trend toward higher EGP was seen with ritonavir (3.6 ± 0.3 vs. 3.0 ± 0.5 μg·kg−1·min−1, P = 0.08). There was no evidence that amprenavir blunted insulin suppression of EGP compared with placebo (2.9 ± 0.04 vs. 3.2 ± 0.7 μg·kg−1·min−1, P = 0.63). Conclusions:Some PIs can acutely blunt the ability of insulin to suppress EGP, but, as with insulin resistance, the effects of PIs on EGP are drug-specific, not class-specific.