20 Feb GenXys Picks: The Best Precision Medicine Articles We Read in 2018
These fascinating peer-reviewed papers from 2018 keep building the foundation for the implementation of precision prescribing in the clinic. From mental health to cardiovascular disease and diabetes, this compilation shows that precision medicine is much more than genomics. The degree of precision relies on accounting for the complex interplay of multiple variables including pharmacogenetics.
Prevalence of potentially inappropriate prescribing in older people in primary care and its association with hospital admission: longitudinal study.
In this study of 38,000 patients followed over a period of three years, the prevalence of potentially inappropriate prescribing in patients aged 65 or older was 51%. Inappropriate prescribing was associated with a 24% increase (Adjusted Hazard Ratio 1.24) rate of hospital admission. This was even after adjusting for other factors such as patient age, number of diseases the patient had, and the number of prescriptions they were taking. It indicates how difficult it is to prescribe safely and the serious impact this may have for older individuals. (PMID: 30429122)
Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis.
A meta-analysis of 522 studies found that anti-depressants were more effective than placebo in short-term treatment of acute depression. The analysis also found that some antidepressants were better tolerated or more effective than others. Could patient response be better predicted using pharmacogenetics? There is an abundance of ongoing research in this area. (PMID: 29477251)
Pharmacogenetics in Psychiatry: A Companion, Rather Than Competitor, to Protocol-Based Care
CPIC members Chad Bousman and Daniel Muller published an opinion article supporting the use of pharmacogenetics for enhancing the care of patients with psychiatric illnesses. “Pharmacogenetic-based dosing guidelines have been developed for 57 medications. Notably, 30% of the medications with pharmacogenetic-based dosing guidelines are relevant to psychiatry. As such, it is our opinion that the field should begin to embrace pharmacogenetic testing but should do so thoughtfully.” Currently, several commonly used antidepressants have pharmacogenetic dosing guidelines and include pharmacogenetic information in their FDA label. (PMID: 30167635)
Pharmacogenomic Approach to Selecting Antiplatelet Therapy in Patients With Acute Coronary Syndromes: The PHARMCLO Trial
This study in ACS (acute coronary syndrome) patients evaluated whether selecting antiplatelet therapy by using pharmacogenetics in combination with clinical characteristics leads to better outcomes compared to clinical characteristics alone. The study was stopped prematurely after the primary composite endpoint of cardiovascular death and the first occurrence of nonfatal myocardial infarction, nonfatal stroke, and major bleeding occurred in 15.9% of patients in the pharmacogenetic arm vs 25.9% in the standard arm (hazard ratio: 0.58; 95% confidence interval: 0.43 to 0.78; p < 0.001). Despite some potential confounders and bias, and a much larger effect size than anticipated, this study provides a compelling case for implementing pharmacogenetic results into antiplatelet prescribing. (PMID: 29540324)
Pharmacogenetics of inhaled long-acting beta2-agonists in asthma: A systematic review
In May 2018, a systematic review of 33 studies examining genetic variants associated with LABA (long-acting beta-amongst) response in patients with asthma found an association between the ADRB2 rs1042713 variant and response to LABA in children but not adults. The authors suggest that compared to adults, the contribution of genetics to variability in LABA response is larger in children with asthma, which underlines that children should not just be considered “small adults”. (PMID: 29992699)
Effects of aspirin on risks of vascular events and cancer according to body weight and dose: analysis of individual patient data from randomized trials
This fascinating analysis of the modifying effects of body weight and height on the effects of low dose and high dose aspirin for primary and secondary prevention suggests that the one-size-fits-all approach to aspirin dosing could be improved with a more personalized prescribing strategy. The authors found that low-dose aspirin (75-100 mg/day) prevented cardiovascular events only in individuals with low body weight (<70 kg), whereas higher doses of aspirin (≥300 mg/day) were effective only in individuals weighing 70 kg or more. This is a great example of how precision medicine is more than using genetics. (PMID: 30017552)
6-month versus 12-month or longer dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome (SMART-DATE): a randomised, open-label, non-inferiority trial.
The question of how long dual antiplatelet therapy (DAPT) should be continued after percutaneous coronary intervention (PCI) has never been satisfactorily answered, but this study in an Asian population adds more information to the mix. In patients with acute coronary syndrome who underwent PCI, shorter DAPT (approximately 6 months) increased the risk of recurrent MI (NNH 100) without any clear reduction in bleeding versus a standard DAPT duration of 12 or more months. (PMID: 29544699)
SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.
We now have a major cardiovascular outcome study for three SGLT2 inhibitors: canagliflozin (CANVAS), empagliflozin (EMPA-REG), and dapagliflozin (DECLARE). A meta-analysis of these major studies was published in the Lancet in November 2018, showing that, “by and large the results were consistent between the three different trials when analysed within similar patient subgroups”. Their greatest and most consistent effect is reducing risk of hospitalization for heart failure and progression of renal disease. However, in patients with atherosclerotic cardiovascular disease, the effect of empagliflozin on cardiovascular death was more pronounced than that of canagliflozin or dapagliflozin, and an increased risk of amputations and fractures was only seen with canagliflozin. (PMID: 30424892)
Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular and Renal Risk: The CARMELINA Randomized Clinical Trial
We are always trying to find ways to differentiate between the multitude of antidiabetic agents available for treatment of type 2 diabetes, and the CARMELINA trial seems to confirm that DPP-4 inhibitors do not offer any cardiovascular risk protection. As diabetes is a major risk factor for cardiovascular disease, this may be a compelling reason to choose another agent with demonstrated CV risk reduction, such as a GLP-1 agonist or SGLT2 inhibitor. (PMID: 30418475)
Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial
In patients with diabetes, an 800Kcal food replacement diet for three months led to significant rates of remission of diabetes. This was an open-label cluster randomized controlled trial in 49 GP practices in Scotland. The intervention comprised withdrawal of antidiabetic and antihypertensive drugs, total diet replacement (825–853 kcal/day formula diet for 3–5 months), stepped food reintroduction (2–8 weeks), and structured support for long-term weight loss maintenance. Diabetes remission was achieved in 68 (46%) participants in the intervention group and six (4%) participants in the control group (odds ratio 19·7, 95% CI 7·8–49·8; p<0·0001). The UK has now set up a 5,000 intervention evaluation of this program. (PMID: 29221645)