Discontinuing Lipid-Lowering Agents

Objective: The current study aimed to evaluate the relation between leptin and serum lipids, and to explore whether alcohol consumption modifies the effect of leptin on lipids. Method: We conducted a Mendelian randomization analysis to the baseline data for 3,780 participants of the Framingham Heart Study Generation III cohort. A genetic risk score (GRS) for leptin was generated by summing leptin increasing alleles of 3 single-nucleotide polymorphisms, weighted by their corresponding effect sizes on leptin reported by Kilpelainen et al. For those taking lipid lowering medications, total cholesterol (TC) was adjusted as TC/0.8, and low density lipoprotein (LDL) was imputed by replacing the adjusted TC into the Friedewald equation. Leptin and triglycerides (TG) were log transformed. Associations between the GRS and leptin, leptin and imputed lipids, and GRS and imputed lipids were assessed, respectively, by multivariate linear regression models, controlling for age and sex in basic model and additionally controlling for education, smoking, drinking, and physical activity in the fully adjusted model. Interactions between the GRS and alcohol drinking was evaluated by adding an interaction term, GRS*drinking, in the fully adjusted model. Sensitivity analyses were performed among those not taking lipid or glucose lowering medications. Result: In univariate analyses, the GRS was significantly associated with leptin (Beta=1.44, P =4.55E-4), but not with age ( P =0.33), sex ( P =0.62), education ( P =0.37), smoking ( P =0.59), drinking ( P =0.42), or physical activity ( P =0.80). Leptin was significantly associated with age and sex adjusted LDL (Beta=7.29, P =5.95E-38), high density lipoprotein (HDL) (Beta=-4.30, P =4.35E-62), TG (Beta=0.22, P =1.05E-119), and TC (Beta=8.06, P =1.72E-36). The GRS for leptin was associated with HDL (Beta=-16.72, P =0.01), but not LDL (Beta=2.64, P =0.85), TG (Beta=-0.35, P =0.16), or TC (Beta=-23.34, P =0.15), in partially adjusted model. In the fully adjusted model, association between the GRS and HDL was still significant (Beta=-16.70, P =0.01). When stratified by drinking status, the GRS for leptin was significantly associated with reduced LDL (Beta=-99.26, P =0.02), TG (Beta=-2.4, P =0.002), and TC (Beta=-156.10, P =0.001) among non-current drinkers, and reduced HDL (Beta=-19.98, P =0.005) among current drinkers, adjusting for age and sex. After further adjustment, these associations were still significant. In the fully adjusted model, significant interactions between the GRS and alcohol drinking were identified for LDL ( P =0.02), TG ( P =0.005), and TC ( P =0.008). Sensitivity analyses among those not taking lipid or glucose lowering medications revealed similar associations. Conclusion: Out study provided evidence for a causal relationship between leptin and lipids, and an interaction effect of alcohol drinking on leptin and lipids associations.

Can patterns of medication use explain the increasing incidence of end stage kidney disease among people with diabetes in Australia?

People with diabetes are at high risk for cardiovascular events regardless of known heart disease. Physicians may underrecognize the excess cardiovascular risk conferred by diabetes alone, without a recent cardiovascular event. Other disparities in the receipt of lipid-lowering medications (LLMs) may exist. We studied veterans with diabetes in fiscal years 1998 and 1999 cross-sectionally. We used administrative data (demographic information, International Classification of Diseases, Ninth Revision [ICD-9] codes, utilization information, medications, and laboratory tests) to evaluate associations between use of LLMs and age, ethnicity, sex, marital status, Charlson Index, heart disease ICD-9 codes, oral agents and insulin, hospitalization status, and low-density lipoprotein cholesterol levels. We constructed separate logistic regression models to evaluate associations between low-density lipoprotein cholesterol and similar predictor variables. Odds ratios were similar in both years. For fiscal year 1999, patients without recent ICD-9 codes in their administrative data indicating heart disease were 0.35 times less likely to be given LLMs than those with such codes. Individuals older than 75 years were 0.65 times less likely to be given LLMs than those younger than 65 years. African Americans were 0.72 times less likely than whites to be given LLMs. In fiscal years 1999 and 1998, 27% and 36% of individuals given LLMs had low-density lipoprotein cholesterol levels higher than 130 mg/dL (3.37 mmol/L). Veterans with diabetes but no recently coded heart disease, older individuals, and African Americans could benefit from programs targeted to introduce LLMs. Up to one third of individuals given LLMs remained above the target level of 130 mg/dL for low-density lipoprotein cholesterol.

To determine the effects of lipid-lowering agent (LLA) class and drug plan design option on persistence with LLAs among elderly patients enrolled in a managed care plan. A retrospective cohort study was conducted among 310 older adult members enrolled in a health maintenance organization operating in New England who were dispensed an LLA between July 1, 1994, and June 30, 1996. Survival analysis was used to examine differences in discontinuation of LLAs between different classes of LLAs and drug benefit plans as well as patient sex, age, prior hospitalization for coronary heart disease (CHD), hypertension, diabetes mellitus, and the number of other medications. The overall LLA discontinuation rate increased with time from 18% (95% confidence interval [CI], 13.8%-22.4%) at 6 months to 46% (95% CI, 39.7%- 52.5%) at 12 months and 66% (95% CI, 59.2%-73.0%) at 18 months. The likelihood of discontinuation increased from 54% (95% CI, 44.8%-63.6%) at 12 months to 77% (95% CI, 67.5%-85.5%) at 18 months in nonstatin users and from 39% (95% CI, 30.4%-47.6%) at 12 months to 57 % (95% CI, 47.3%-66.9%) at 18 months in statin users (P = 0.001). Among patients prescribed a statin at initial prescription (n = 182), the 12-month discontinuation rates were 33% (95% CI, 23.0%-43.6%) for those with full drug benefit coverage and 50% (95% CI, 34.8%-65.1%) for those with 1,000 dollars per year maximum coverage, while the 21-month discontinuation rates were 60% (95% CI, 46.3%-72.9%) for those with full coverage and 86% (95% CI, 73.7%-98.7%) for those with 1,000 dollars per year maximum coverage (P = 0.023). Adjusting for plan design and hypertension, statin users were less likely to discontinue compared with users of other LLAs (rate ratio [RR] = 0.58; 95% CI, 0.40-0.82; P = 0.002). Among patients dispensed a statin, full-coverage members were less likely to discontinue compared with members having an annual 1,000 dollars maximum drug coverage, adjusting for diabetes and hypertension (RR = 0.58; 95% CI, 0.34-0.98; P = 0.041). This finding was among a small sample after subanalyses, and further research is warranted. Plan design was not determined to be significantly associated with discontinuation of other LLAs. Our findings suggest that persistence with LLAs is low among older patients regardless of scope of drug benefit coverage or the drug class. Addressing the challenges of maintaining adherence to prescribed therapeutic regimens in the elderly will require a multifaceted approach; deficiencies will not be eliminated simply through the provision of prescription drug benefit coverage.

Predictors, Barriers, and Facilitators of Lipid-Lowering Medication Use Among African Americans in a Primary Care Clinic

Several single-nucleotide polymorphisms (SNPs) are associated with both plasma low-density lipoprotein cholesterol (LDL-c) level and coronary artery disease in the general population. It is unclear whether these associations also apply to patients with vascular disease and whether the associations are independent of lipid-lowering therapy. Single-nucleotide polymorphisms associated with plasma LDL-c and vascular risk in the general population (rs11206510 (PCSK9), rs1122608 (LDLR), rs579459 (ABO) and rs599839 (SORT1)) were genotyped in a prospective cohort study of 5482 patients with vascular disease. We determined the association between LDL-c-associated alleles and plasma LDL-c levels and the risk of new vascular events. All tested SNPs were associated with LDL-c plasma levels with a magnitude between +0·06 (95% CI 0·02-0·10)mM and +0·14 (95% CI 0·09-0·18)mM per LDL-c-increasing allele. The associations were independent of the use of lipid-lowering medication, except for rs579459, for which the association was not present in patients using lipid-lowering medication. In patients with 7-8 risk alleles for these SNPs, 59% of the patients treated with lipid-lowering medication did not reach the LDL-c target of <2·5mM compared with 45% in patients with 3 or fewer risk alleles. LDL-c-increasing alleles were not associated with increased risk of vascular events in patients not using lipid-lowering medication (HRs: 1·01; 95% CI: 0·93-1·09). In patients using lipid-lowering medication, the risk of myocardial infarction increased with 14% (HRs: 1·14; 95% CI: 1·01-1·28) per allele. In patients with established vascular disease, the studied SNPs increase LDL-c plasma levels. LDL-c-increasing alleles may be associated with increased risk of myocardial infarction in patients treated with lipid-lowering medication, but not in patients not treated with lipid-lowering medication.

Lipid-Lowering Medications Are Associated with Lower Risk of Retinopathy and Ophthalmic Interventions among United States Patients with Diabetes

Background: Homozygous familial hypercholesterolemia (HoFH) is characterized by very premature atherosclerotic cardiovascular disease due to profoundly elevated levels of LDL-C. Attempts to lower LDL-C in patients with HoFH often require multiple lipid-lowering medications (LLMs). Evinacumab, an angiopoietin-like protein 3 inhibitor, has been shown to reduce LDL-C in patients with HoFH by approximately 50% when added to maximally tolerated background LLMs. Objective: In this post-hoc analysis we assessed efficacy of evinacumab in patients with HoFH according to background LLM type. Methods: This was a double-blind, placebo-controlled, 24-week phase 3 trial (NCT03399786) that randomized patients 2:1 to receive intravenous (IV) evinacumab 15 mg/kg (n=43) or IV placebo (n=22) every 4 weeks. The effect of background LLMs on the efficacy of evinacumab to lower LDL-C was assessed for the following subgroups: high intensity-statin, low-intensity statins, lomitapide, triple therapy (ezetimibe + PCSK9 inhibitor + statin), and quadruple therapy (triple therapy + lomitapide). Primary endpoint was % LDL-C reduction from baseline to week 24. Results: At baseline, 55.4% (evinacumab, 58.1%; placebo, 50.0%) of HoFH patients were on triple therapy. Overall, 93.8% were on statins (76.9% on high intensity statins). Across LLM subgroups, mean baseline LDL-C levels ranged from 166.8 mg/dL to 281.8 mg/dL (Table). From baseline to week 24, marked reductions in LDL-C occurred with evinacumab treatment, which were observed in all groups: quadruple therapy (66.8%), triple therapy (56.0%), lomitapide (49.6%), high-intensity statins (48.6%) and low-intensity statins (41.0%). Evinacumab was generally well-tolerated. Conclusions: Evinacumab substantially lowers LDL-C levels in patients with HoFH irrespective of background LLM.

Aims:This study examined the relationship of baseline characteristics and medication use in patients with type 2 diabetes who were prescribed sitagliptin versus other oral antihyperglycemic agents in clinical practice settings in the United States.Methods:The General Electric Healthcare’s Clinical Data Services electronic medical record (EMR) database, covering 12 million US patients of all ages from 49 states, was used to identify patients with type 2 diabetes, aged ≥30 years, who received their first sitagliptin, metformin, sulfonylurea, or thiazolidinedione prescription between October 2006 and June 2008 (index period) as part of new mono-, dual, or triple therapy regimens. Patient demographics, diagnoses, prescriptions, and laboratory results were extracted for the 12-month period (baseline) prior to the index date (i.e., date of first prescription). Data were stratified by mono-, dual, or triple therapy and compared between sitagliptin regimens and non-sitagliptin regimens with other oral agents (metformin, sulfonylureas, or thiazolidinediones). Adjusted logistic regression analyses were used to estimate odds ratios (OR) associated with prescribing sitagliptin versus other oral monotherapy in relation to patient baseline characteristics.Results:Among 41,836 patients new to oral monotherapy, 876 (2.1%) received sitagliptin. Compared to patients initiating non-sitagliptin monotherapy, patients on sitagliptin monotherapy were older (64 vs. 60 years) and had lower body mass index (33 kg/m2 vs. 34 kg/m2), higher serum creatinine (1.2 vs. 1.0 mg/dL), higher prevalence of chronic renal disease (7.2% vs. 1.9%), greater use of lipid-lowering agents (42% vs. 38%), and higher prevalence of cardiovascular conditions (CVD: 12.7% vs. 8.3%) and microvascular complications (MVD: 13.4% vs. 5.8%) (all p < 0.05). Of 22,683 patients new to dual therapy, 1885 (8.3%) were on sitagliptin regimens. Relative to patients on non-sitagliptin dual therapy regimens, patients prescribed sitagliptin as part of dual therapy regimens were older and had higher serum creatinine, higher prevalence of CVD, MVD, or chronic renal disease, and greater use of lipid-lowering and antihypertensive agents (all p < 0.05). Among 9967 patients new to triple therapy, 2828 (28.4%) were on triple therapy regimens with sitagliptin. Relative to patients on non-sitagliptin triple therapy regimens, patients on sitagliptin as part of triple therapy regimens were older, and had higher serum creatinine and greater use of antihypertensive or lipid-lowering agents (all p < 0.05). Adjusted logistic regression showed that significant predictors of being prescribed sitagliptin monotherapy were older age (OR 1.01, 95% CI 1.00, 1.02), higher HbA1c level (OR 1.10, 95% CI 1.04, 1.17), higher serum creatinine level (OR 1.22, 95% CI 1.08, 1.39), presence of MVD (OR 1.50, 95% CI 1.08, 2.09), and presence of chronic renal disease (OR 2.22, 95% CI 1.41, 3.49).Limitations:Diabetes care delivered by non-participating physicians is not captured in the GE CDS EMR database and, therefore, the prevalence of the diseases identified based on ICD-9 diagnosis/procedure and CPT codes provided in the Appendix may be underestimated. Duration of diabetes was not consistently recorded and some measures were not available.Conclusion:Patients with type 2 diabetes who were prescribed sitagliptin regimens in clinical practice were older and more likely to have pre-existing co-morbid conditions compared to patients receiving non-sitagliptin regimens with other common oral antihyperglycemic agents. These findings have important implications for observational studies in that estimated clinical and health outcome measures may be biased due to channeling of patients to different therapies based on different baseline characteristics.

The literature is inconclusive regarding the association between adherence and the number of concurrent prescribed medications. Among patients with type 2 diabetes (T2D), low medication adherence is linked with inadequate glycemic management and increased diabetes-related complications. Adherence to glucose-lowering, lipid-lowering, and antihypertensive medications may be impacted by the number of cardiometabolic medications taken by adults with T2D, including American Indian adults. To examine the association between medication adherence and the number of cardiometabolic medications among American Indian adults with T2D using Tribal health services, a health care system where all medical care and medications are provided free of charge. We used 2019 medication dispensing data and patient data from the electronic health records of the Choctaw Nation Health Services Authority. Our sample included 6,774 American Indian adults aged 20years and older, previously diagnosed with T2D, who received at least 1 cardiometabolic medication from a Choctaw Nation Health Services Authority pharmacy. We measured medication adherence as the proportion of days covered (PDC; possible range 0-1). Analysis of variance and chi-square tests were used to examine the association between the number of medications and patient characteristics. Multiple linear regression was used to estimate the association of adherence with patient characteristics. The sample mean age was 58.4 (SD = 13.2) years; 63.4% were aged 55years or older; 47.8% were male; 49.6% were single; 36.9% had comorbidities. 30.9% were prescribed 2 or fewer medications, 43.1% were prescribed greater than 2 to 4 medications, and 26.0% were prescribed more than 4 medications. 71.7% had noninsulin glucose-lowering medications, 68% had lipid-lowering medication, and 90% had antihypertensive medications. Overall, 60.6% of the sample were adherent (PDC ≥ 0.80), including 49% of those with 2 or fewer medications, 62% of those with greater than 2 to 4 medications, and 72% with more than 4 medications. In a multiple regression model, adherence was positively associated with the number of medications (b = 0.026, P < 0.001), age 55years or older (b = 0.062, P < 0.001), male sex (b = 0.009, P = 0.046), and presence of comorbidities (b = 0.033, P < 0.001) but negatively associated with being single (b = -0.034, P < 0.001) and insulin usage (b = -0.019, P < 0.001). To our knowledge, this is the first study demonstrating the association between a higher number of cardiometabolic medications and better adherence in American Indian adults diagnosed with T2D whose medications were provided without cost to the patients. Medication cost is a well-known medication adherence barrier. Future studies should further examine factors associated with nonadherence in this population, such as younger age and fewer medications.

Statin Use Associated with Lower Incidence of Developing Thyroid Eye Disease in Newly-Diagnosed Graves' Disease

Objective: To evaluate the lipid-lowering effect and safety of Gynostemma pentaphyllum (GP) used alone or as adjunctive therapy for dyslipidemia. Methods: Eight databases and three clinical trial registries were searched until January 2022. Randomized controlled trials (RCTs) assessing the effectiveness of GP for dyslipidemia were included. Trial quality was assessed using the Cochrane Risk of Bias Tool 2.0. Data were analyzed by RevMan 5.4 with effects estimated as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). Results: Twenty-two RCTs involving 2,407 dyslipidemia participants were included. Regarding the risk of bias, 14 RCTs had some concerns, seven RCTs were high, and one trial was low. GP was comparable to n-3 fatty acids (RR 0.89, 95% CI 0.62–1.28) and red yeast rice (RR 0.33, 95% CI 0.1–1.12) on normalization of serum lipids. GP plus n-3 fatty acid was superior in normalization of triglycerides (TG) and total cholesterol (TC) than n-3 fatty acids (RR 1.34, 95% CI 1.01–1.77). GP was similar to lipid-lowering agents (statins, fibrates, and n-3 fatty acids) in regulating TG, TC, and high-density lipoprotein cholesterol (HDL-C). GP plus lipid-lowering agents were superior to lipid-lowering agents in TG (MD −0.65 mmol/L, 95% CI −1.03 to −0.28), LDL-C (MD −0.57 mmol/L, 95% CI −1.07 to −0.08), and HDL-C (MD 0.15 mmol/L, 95% CI 0.11–0.20). GP was inferior to red yeast rice in TC (MD 0.64 mmol/L, 95% CI 0.15–1.13), TG (MD 0.43 mmol/L, 95% CI 0.15–0.71), and HDL-C (MD −0.25 mmol/L, 95% CI −0.47 to −0.04). GP had fewer adverse events than lipid-lowering drugs. Conclusion: Very low certainty evidence showed that GP’s effects on TC, TG, and HDL-C were comparable to that of lipid-lowering agents. Low certainty evidence showed that red yeast rice was superior to GP in TC, TG, and HDL-C. Low to moderate certainty evidence showed that the effects of GP plus lipid-lowering agents were superior to that of lipid-lowering agents on TG, LDL-C, and HDL-C. GP use for more than 8 weeks appears safe. Systematic Review Registration: https://inplasy.com/, identifier INPLASY202210135.

To examine the prescribing of lipid-lowering medications during general practitioner encounters with Indigenous and non-Indigenous Australians from 2001 to 2013. Observational time trend study, using data from the Bettering the Evaluation and Care of Health (BEACH) survey, of 9594 primary care encounters with Indigenous patients and 750 079 encounters with non-Indigenous patients aged 30 years or over. Prescription of at least one lipid-lowering medication. The age-sex standardised proportion of encounters that resulted in at least one lipid-lowering medication being prescribed was 5.5% (95% CI, 4.7%-6.3%) for Indigenous patients and 4.6% (95% CI, 4.5%-4.7%) for non-Indigenous patients. The proportion of encounters with Indigenous patients at which a lipid-lowering medication was prescribed increased significantly from 4.1% during 2001-2005 to 6.4% during 2009-2013 (P = 0.013 for trend). For encounters with non-Indigenous patients, the proportion increased significantly from 3.8% during 2001-2005 to 5.2% during 2009-2013 (P < 0.01). For encounters during which GPs managed diabetes, hypertension or ischaemic heart disease, the proportion of Indigenous encounters during which lipid-lowering medication was prescribed was similar to that for non-Indigenous patients. For encounters in which GPs managed a lipid disorder, however, the age-sex standardised proportion was significantly greater for Indigenous (78.4%; 95% CI, 72.6%-84.2%) than for non-Indigenous patients (65.2%; 95% CI, 64.5%-65.8%). We detected substantial increases in the prescribing of lipid-lowering medications from 2001 to 2013 for both Indigenous and non-Indigenous patients seen in Australian general practice. Providers were more likely to prescribe lipid-lowering medications for Indigenous than for non-Indigenous patients, suggesting some measure of success in expanding access to medications and reducing cardiovascular risk among Indigenous people.

Background: Although current cholesterol performance measures define good quality as low density lipoprotein cholesterol (LDL-C) levels &lt; 100mg/dl in cardiovascular disease (CVD) patients, they provide a snap shot at one time point and do not inform whether an appropriate action was taken to manage elevated LDL-C levels. We assessed frequency and predictors of this appropriate response (AR). Methods: We used administrative data to assess 22,902 CVD patients receiving care in a Veterans Affairs network of 7 hospitals and affiliated clinics. We determined the proportion of CVD patients at LDL-C goal &lt;100 mg/dl, and the proportion of patients with uncontrolled LDL-C levels (&gt;100 mg/dl) who had an AR [defined as the initiation or dosage increase of a lipid lowering medication (LLM), addition of a new LLM, receipt of maximum dosage or &gt;1 LLM, or LDL-C reading &lt;100 mg/dl] at 45 days follow-up. Logistic regression was performed to evaluate facility, provider and patient characteristics associated with AR. Results: LDL-C levels were at goal in 16,350 (71.4%) patients. An additional 2,110 (9.2%) had an AR at 45 days of follow-up. Controlling for clustering between facilities and patient's illness severity, history of diabetes (OR 1.18, 95% CI 1.03-1.35), hypertension (OR 1.21, 95% CI 1.02-1.44), patients showing good medication adherence (medication possession ratio &gt; 0.8) [OR 2.29, 95% CI 1.99-2.64] were associated with AR. Older CVD patients (age &gt;75 years) were less likely to receive AR (OR 0.60, 95% CI 0.52-0.70). Teaching vs. non-teaching facility (p=0.40), physician vs. non-physician provider (p=0.14), specialist vs. non-specialist primary care provider (p=0.12), and patient's race (p=0.12) were not predictors of AR. Conclusion: Among patients with CVD and LDL-C above guideline recommended levels, only one-third receive AR. Diabetic and hypertensive CVD patients are more likely to receive AR, whereas older Veterans with CVD receive AR less often likely reflecting providers' belief of lack of efficacy from treatment intensification in older CVD patients. Our findings are important for quality improvement and policy making initiatives as they provide more actionable information compared with isolated LDL-C goal attainment as a quality indicator.

To estimate the prevalence of dyslipidemia and to describe its management in Canadian primary care. Retrospective cohort study using primary care electronic medical record data. Canada. Adults aged 40 years or older who saw a Canadian Primary Care Sentinel Surveillance Network contributor between January 1, 2018, and December 31, 2019. Presence or absence of dyslipidemia as identified by a validated case definition and the treatment status of patients identified as having dyslipidemia based on having been prescribed a lipid-lowering agent (LLA). In total, 50.0% of the 773,081 patients 40 years of age or older who had had a primary care visit in 2018 or 2019 were identified as having dyslipidemia. Dyslipidemia was more prevalent in patients 65 or older (61.5%), in males (56.7%) versus females (44.7%), and in those living in urban areas (50.0%) versus rural areas (45.2%). In patients with documented dyslipidemia, 42.8% had evidence of treatment with an LLA. Stratifying patients by Framingham risk score revealed that those in the high-risk category were more likely to have been prescribed an LLA (65.0%) compared with those in the intermediate-risk group (48.7%) or the low-risk group (22.8%). The strongest determinants of receiving LLA treatment for dyslipidemia include sex, with males being 1.95 times more likely to have been treated compared with females (95% CI 1.91 to 1.98; P<.0001); and body mass index, with those with obesity having a significantly increased likelihood of being treated with an LLA (adjusted odds ratio of 1.36, 95% CI 1.32 to 1.41; P<.0001). This study provides an updated look at the prevalence and treatment of dyslipidemia among Canadians. Half of patients aged 40 years or older have dyslipidemia, with an even higher prevalence observed among adults aged 65 years or older, males, and those with obesity or other chronic conditions. There are still gaps in treatment among those with documented dyslipidemia, principally among those calculated to have high or intermediate Framingham risk scores. Particular attention should also be paid to those at higher risk for not receiving treatment, including female patients and those within normal body mass index ranges.