Practice Update: Endocrinology | Volume 1. Number 2. 2016

METABOLIC & ENDOCRINE DISORDERS

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EXPERT COMMENTARY Is lower better for LDL-C? By Dr Peter Lin For over a decade, the mantra in the lipid world has been “lower is better” and that statins are the cornerstone of therapy. This has been supported by large randomised studies like PROVE-IT and TNT trials. T his research group used observational data to see if lower is truly better. They looked at over 31,000 patients

LDL levels and major adverse cardiac events in ischaemic heart disease treated with statins JAMA Internal Medicine Take-home message

age was 67.3 (9.8) years. Of this population, 27% were female and 29% had low, 53% moderate, and 18% high LDL-C when taking sta- tin treatment. Overall, there were 9035 patients who had an adverse outcome during a mean 1.6 years of follow-up (6.7 per 1000 persons per year). The adjusted incidence of adverse outcomes was not dif- ferent between low and moderate LDL-C (hazard ratio [HR], 1.02; 95% CI, 0.97–1.07; P = 0.54), but it was lower with moderate vs high LDL- C (HR, 0.89; 95% CI, 0.84–0.94; P<0.001). Among 54 884 patients with at least 50% statin adherence, the adjusted HR was 1.06 (95% CI, 1.02–1.10; P = 0.001) in the low vs moderate groups and 0.87 (95% CI, 0.84–0.91; P=0.001) in the moder- ate vs high groups. CONCLUSIONS AND RELEVANCE Pa- tients with LDL-C levels of 70 to 100 mg/dL taking statins had lower risk of adverse cardiac outcomes com- pared with those with LDL-C levels between 100 and 130 mg/dL, but no additional benefit was gained by achieving LDL-C of 70 mg/dL or less. These population-based data do not support treatment guidelines recommending very low target LDL-C levels for all patients with preexisting heart disease. Association between achieved low-density lipoprotein levels and major adverse cardiac events in patients with stable ischemic heart disease taking statin treatment. JAMA Intern Med 2016 Jun 20;[Epub ahead of print], Leibowitz M, Karpati T, Cohen-Stavi CJ, et al.

• The authors of this observational, cohort study evaluated the associa- tion between LDL levels and major adverse cardiac events (MACE) in 31,619 patients with ischaemic heart disease who were compliant with statin therapy. They found that patients with LDL levels of 70.1 to 100 mg/dL had significantly lower risk of major adverse cardiac events compared with patients with LDL levels of 100.1 to 130 mg/dL (HR, 0.89). They found no difference in risk between patients with LDL levels of 70.1 to 100 mg/dL and those with LDL levels ≤70 mg/dL. • In patients with ischaemic heart disease who are compliant with statin therapy, LDL levels ≤100 mg/dL are associated with reduced risk of MACE, and there does not appear to be additional benefit with LDL levels ≤70 mg/dL. Abstract

There are a few complications in this study. The three groups did not have the same number of patients, and the moderate group had more than double the number of patients compared with the other two groups. Also, the low LDL-C group had many more diseases such as diabetes, congestive heart failure, chronic kidney disease, atrial fibrillation, angioplasty. Also many patients in the low-level group were taking at least eight medications per day. So, effectively, the lower LDL-C group was a sicker population, which explains why they did not do so well. The researchers did try propensity matching, but it is difficult to match that many different variables simul- taneously. Perhaps the simple conclusion that a lower LDL-C level had no benefit might not be accurate, considering the differences in the patient comorbidities. Perhaps the PCSK9 inhibitor trials will provide us with a more definitive answer. These trials will have LDL-C levels in the 45 mg/dL range, and the data generated will show us if these low LDL-C levels are safe and if they help reduce CV events. So, stay tuned as we boldly go where no doctor has gone before in terms of LDL-C.

who were at least 80% adherent to their statin therapy. These patients were divided into three groups based on their LDL-C levels. The high-level group were patients with LDL-C levels between 100 and 130 mg/dL, the moderate-level group were between 70 and 100 mg/dL, and the low- level group had LDL-C below 70 mg/dL. The researchers then looked at the MACE outcomes of the groups.

or, in a sensitivity analysis, at least 50% adherent. Patients with active cancer or metabolic abnormalities were excluded. EXPOSURES Index LDL-C was de- fined as the first achieved serum LDL-C measure after at least 1 year of statin treatment, grouped as low (≤70.0 mg/dL), moderate (70.1–100.0 mg/dL), or high (100.1– 130.0 mg/dL). MAIN OUTCOMES AND MEASURES Major adverse cardiac events included acute myocardial infarc- tion, unstable angina, stroke, angioplasty, bypass surgery, or all- cause mortality. The hazard ratio of adverse outcomes was estimated using 2 Cox proportional hazards models with low vs moderate and moderate vs high LDL-C, adjusted for confounders and further tested using propensity score matching analysis. RESULTS The cohort with at least 80% adherence included 31 619 patients, for whom the mean (SD)

IMPORTANCE International guide- lines recommend treatment with statins for patients with preexisting ischaemic heart disease to prevent additional cardiovascular events but differ regarding target levels of low-density lipoprotein cholesterol (LDL-C). Trial data on this question are inconclusive and observational data are lacking. OBJECTIVE To assess the relation- ship between levels of LDL-C achieved with statin treatment and cardiovascular events in adherent patients with preexisting ischemic heart disease. DESIGN, SETTING, AND PARTICIPANTS Population-based observational cohort study from 2009 to 2013 using data from a health care or- ganisation in Israel covering more than 4.3 million members. Included patients had ischaemic heart dis- ease, were aged 30 to 84 years, were treated with statins, and were at least 80% adherent to treatment

THE MACE EVENTS

Moderate vs high LDL-C HR, 0.89

(CI, 0.84–0.94; P < 0.001)

Low vs moderate LDL-C HR, 1.02

(Cl, 0.97–1.07; P = 0.54) The researchers concluded that getting the LDL-C level between 70 and 100mg/dL (moderate level) was better than between 100 and 130 mg/dL (high level), and was close enough to below70mg/dL (low level); hence, their recommendation is that we should not be aiming for “lower is better” but to aim for somewhere between 70 and 100 mg/dL.

JOURNAL SCAN Statins are associatedwith decreased risk of IBD The American Journal of Gastroenterology Take-home message • Using data from a US health claims database, the authors of this ret- rospective, matched case-control study evaluated the association between statins and risk of inflammatory bowel disease (IBD) in adults. The risk of new-onset IBD, including both ulcerative colitis and Crohn’s disease, was significantly lower in individuals with any statin use, even after controlling for multiple confounders. • Statin exposure appears to be associated with reduced risk of IBD, especially among older patients. Abstract OBJECTIVES Prior studies suggest that medication exposures may be associ- ated with new onset inflammatory bowel disease (IBD). The aim of this study was to determine the effect of statins on the risk of new onset IBD in a large United States health claims database. METHODS We conducted a retrospective matched case-control study with a national medical claims and pharmacy database fromSource Healthcare Analyt- ics LLC. We included any patient aged 18 or older with ICD-9 code 555.x for Crohn’s disease (CD) or 556.x for ulcerative colitis (UC) between January 2008 and December 2012. IBD patients diagnosed in 2012 were compared with the age group, gender, race, and geographically matched controls. Controls had no ICD-9 codes for CD, UC, or IBD-associated diseases and no prescriptions for IBD-related medications. New onset IBD patients were defined as having at least three separate CD or UC ICD-9 codes and no IBD-related ICD-9 or prescription before first IBD ICD-9. Statin exposure was assessed by Uniform Systemof Classification level 5 code. To account for diagnostic delay, exposures within 6 months of first ICD-9 were excluded. Exposures within 12 and 24 months were excluded in sensitivity analyses. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for new onset IBD, CD, and UC. RESULTS A total of 9,617 cases and 46,665 controls were included in the analysis. Any statin exposure was associated with a significantly decreased risk of IBD (OR 0.68, 95% CI 0.64–0.72), CD (0.64, 95% CI 0.59–0.71), and UC (OR 0.70, 95% CI 0.65–0.76). This effect was similar for most specific statins and regardless of intensity of therapy. The protective effect against new onset CD was strongest among older patients. Statins’ association with a lower risk of IBD was similar after adjusting for antibiotics, hormone replacement therapy, oral contraceptives, comorbidities, and cardiovascular medications. CONCLUSIONS Statins may have a protective effect against new onset IBD, CD, and UC. This decreased risk is similar across most statins and appears to be stronger among older patients, particularly in CD. Statins associated with decreased risk of new onset inflammatory bowel disease. Am J Gastroenterol 2016 Jun 14;[Epub ahead of print], Ungaro R, Chang HL, Cote-Daigneaut J, et al.

JOURNAL SCAN Blood pressure targets should be individualised in elderly patients with diabetes Diabetes Care Take-home message • The authors evaluated the evidence regarding blood pressure (BP) targets for elderly patients with hypertension and type 2 diabetes. Hypertensive control is challenging in this cohort due to the high prevalence of isolated systolic hypertension, comorbidities, organ damage, cardiovascular disease, and renal failure as well as the risk of orthostatic and postprandial hypotension. An individualized approach is ideal. • Further research regarding optimal BP targets is needed in this popula- tion. Aggressive lowering of BP may reduce the risk of stroke at the expense of more cardiac events and unpleasant side effects.

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hypertension, comorbidities, organ damage, cardiovascular disease, and renal failure and have a high rate of orthostatic and postprandial hypotension. On the basis of the available evidence, we provide arguments supporting the individualized approach in these patients. Target BP should be based on concomitant diseases, orthostatic BP changes, and the general condition of the patients. It is recommended to lower BP in the elderly patient with diabetes to < 140–150/90 mmHg, providing the patient is in good condition. In patients with isolated systolic hypertension, the same target is reasonable providing the diastolic BP is > 60 mmHg. In patients with coronary artery disease and in patients with orthostatic hypotension, excessive BP lowering should be avoided. In elderly hypertensive patients with diabetes, BP levels should be monitored closely in the sitting and the standing position, and the treatment should be tailored to prevent excessive fall in BP. What should be the target blood pressure in elderly patients with diabe- tes? Diabetes Care 2016;39 Suppl 2(1):S234-S243, A Solini, E Grossman.

VOL. 1 • No. 2 • 2016