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Chuck Dushman

Improving Outcomes and Reducing Healthcare Costs for Diabetes and Its Comorbidities With Pharmacogenetics Guided Medication Therapy

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'Pharmacogenomics, the study of genetic mediators of medication response, has demonstrated success in improving pharmacotherapy outcomes across a range of medical conditions.'Click To Tweet
Volume 5 White Paper – Improving Outcomes and Reducing Healthcare Costs for Diabetes and Its Comorbidities with Pharmacogenetics Guided Medication Therapy

 

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Pharmacogenetics in Practice

Volume 5

 

Improving Outcomes and Reducing Healthcare Costs for Diabetes and Its Comorbidities With Pharmacogenetics Guided Medication Therapy

 

Introduction

 

Diabetes continues to be a growing epidemic in the United States and one of the more costly conditions to treat long-term. Data from the 2017 Centers for Disease Control (CDC) report on diabetes indicates that 30.3 million people (9.4%) in the United States, and over 25% of those aged 65 or older, had diabetes in 2015, with an estimated 1.5 million new cases each year.1 Moreover, an estimated 33.9% of US adults had prediabetes, including nearly half of those aged 65 years or older. The social and economic burden of diabetes is likewise staggering. Diabetes was the seventh leading cause of death in the United States in 2015. Total direct and indirect estimated costs of diagnosed diabetes was $245 billion, accounting for over 20% of health care dollars in the US.2

 

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Care for diabetes patients is complicated by the presence of comorbid conditions. Approximately half of adults with diabetes have at least one comorbid chronic disease and 40% of elderly adults with diabetes have four or more comorbid conditions,3,4 exceeding all other major chronic conditions except ischemic heart disease in extent of comorbidities.3 Hyperlipidemia (77% comorbidity), hypertension (49% comorbidity), and coronary artery disease (11% comorbidity), are among the most common comorbid conditions due to their pathophysiological overlap with diabetes.5,6 Unsuccessful management of these conditions in diabetic patients can result in significantly greater cost burden and reductions in quality of life.7 Indeed, cardiovascular disease is the primary cause of mortality in diabetes.8 Conversely, effective management of cardiovascular conditions can enhance the management of diabetes.9 Other conditions such as depression (19% comorbidity)3,6 also worsen diabetes outcomes by causing poorer adherence to medications and self-management.10 Similar to cardiovascular conditions, effective management of these conditions can reduce economic burden and can improve glycemic outcomes and quality of life.10-14

 

Pharmacogenomics, the study of genetic mediators of medication response, has demonstrated success in improving pharmacotherapy outcomes across a range of medical conditions. Briefly, pharmacogenomic testing evaluates variants in genes known to affect the pharmacokinetics or mechanism of action of a medication. Specifically, much research has focused on the CYP450 genes, which encode enzymes involved in first pass metabolism of many medications. Variation in these genes can increase or reduce clearance of medications from the body, predisposing individuals to a decrease in medication efficacy and an increase in the prevalence of sometimes life-threatening adverse drug reactions. Pharmacogenomic implementation guidelines have been published for medications used to treat a number of common chronic conditions such as depression, cardiovascular disease, and chronic pain, among others.15-20

 

Surprisingly, genetic variation in pharmacogenomic genes is quite common; virtually every individual (90-99%)21-22 carries at least one clinically actionable variant. Pharmacogenomic variation does not typically pose health risks until one is exposed to a drug for which the variant is relevant. However, increased exposure to medications due to medical comorbidities will increase the occurrence of gene-drug interactions. The frequency of comorbidity and polypharmacy in the diabetic population makes this condition a prime target for pharmacogenetic intervention. In this white paper, we will review the evidence supporting the association of genetic variation with medication outcomes for medications used to treat diabetes and its common comorbidities: hypertension, hyperlipidemia, major adverse cardiovascular events, and depression. Given that type 1 diabetes accounts for only 5-10% of all diabetes cases,1 this review will primarily focus on management of type 2 diabetes (T2DM).

 

Pharmacogenomics of Diabetes Management

 

Pharmacotherapy for diabetes mellitus consists of a number of agents that differ in their pharmacokinetics, mechanism of action, efficacy, and side effect profile.

 

Metformin

Metformin is considered first-line monotherapy for type 2 diabetes by both the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE).8 Metformin is not metabolized, thus avoiding the polymorphic CYP450 family of enzymes. Some studies have focused on genetic variation in organic cation transporters responsible for metformin uptake into the bloodstream and hepatocytes or secretion into the renal tubular cells, with mixed results.23-28 Another gene, ATM, which encodes a serine/threonine kinase, initially showed promise for predicting metformin effects on HbA1C values,29,30 but failed to replicate in a later large study.31 More research is needed to conclusively demonstrate an effect of these polymorphisms on metformin response.

 

Sulfonylureas

Sulfonylurea medications are generally divided into first-generation medications (including chlorpropamide, tolazamide, and tolbutamide) and second-generation medications (including glipizide, glyburide, and glimepiride). While they remain the second most commonly prescribed oral medications for the treatment of T2DM, their place in treatment algorithms has become more controversial with the approval of newer medications that are less prone to cause hypoglycemia. The ADA recommends sulfonylurea use equally to other second-line agents, while the AACE recommends their use only after lower-risk medications have been tried.8

 

All of the second-generation sulfonylureas (as well as tolbutamide) are metabolized by CYP2C9, and several studies have demonstrated an impact of CYP2C9 genetic variation on serum levels of these medications. For example, in 2010, Zhou et al found that carriers of the CYP2C9*2 and *3 alleles were 3-4 times more likely to achieve target HbA1c after 18 months of initiation of a combination of sulfonylurea and metformin, compared with patients with the normal function genotype.32 Variant allele carriers were also less likely to experience treatment failure with sulfonylurea monotherapy compared to functional allele carriers. Similarly, Becker et al found that CYP2C9*2 and *3 carriers needed a lower tolbutamide dose to achieve optimal outcome.33 Furthermore, a study of Indian patients with T2DM showed that CYP2C9*2 and *3 allele carriers had a better response to glyburide without an increase in risk of hypoglycemia.34 Finally, a small study of glimepiride in Asian patients showed a greater mean change in HbA1c levels at 6 months among CYP2C9*3 carriers.35

 

Thiazolidinediones

Pioglitazone and rosiglitazone are the two thiazolidinedione medications that are FDA-approved for T2DM. While the ADA considers these medications second-line agents, the AACE lists them as fifth line agents due to their risk of causing edema, heart failure, and fractures.8 Both medications are metabolized primarily by CYP2C8 and to a lesser extent by CYP2C9 and CYP3A4.36 These medications are distributed into the hepatocytes by an organic anion transporter encoded by the SLCO1B1 gene, which has genetic polymorphisms known to impact response to statin medications.18 Only one study has examined the impact of these genes on thiazolidinedione outcomes. Dawed et al found that the CYP2C8*3 variant was associated with reduced glycemic response to rosiglitazone, while the SLCO1B1 rs4149056 variant was associated with improved glycemic response.37

 

Newer Classes

Newer classes of oral glucose lowering agents that have come to market in the last 10 years include DPP- 4 inhibitors, SGLT2 inhibitors, and GLP1 agonists. Because of their recent entry to the market, most of these medications have not yet been extensively studied for pharmacogenomic associations.

 

DPP-4 inhibitors include sitagliptin, saxagliptin, linagliptin and alogliptin. They are considered second- line agents by the ADA, but fourth line agents by the AACE.8 Like metformin, most are renally excreted and avoid metabolism by CYP450 enzymes.36 One exception, saxagliptin, is metabolized by CYP3A4/5 but has not yet been evaluated for an association with any of the known polymorphisms in CYP3A4 and CYP3A5. One recent study implicated a single polymorphism near the CTRB1 and CTRB2 genes in response to DPP-4 inhibitors38 but this finding has not yet been replicated.

 

SGLT2 inhibitors include dapagliflozin, empagliflozin and canagliflozin. They are considered second line agents by the ADA and third line medications by the AACE.8 Dapagliflozin and canagliflozin are metabolized by UGT enzymes,39-40 while empagliflozin is primarily excreted unchanged with only minor metabolism by UGT enzymes.41 Only one study has evaluated pharmacogenetic associations with SGLT2 inhibitors, but found no effect of polymorphisms in the SLC5A2 gene on empagliflozin treatment response.42 GLP1 agonists are some of the newest oral glucose lowering agents and include exenatide, liraglutide, lixisenatide, dulaglutide, and semaglutide. They are considered second line agents by the ADA and second or third line medications by the AACE.8/sup> They are metabolized by ubiquitous proteolytic enzymes that are unlikely to be affected by genetic variation. No studies have yet evaluated these medications for pharmacogenetic associations.

 

Summary

The pharmacogenomics of oral glucose lowering agents continues to be an emerging field of inquiry. Research into predictors of metformin response continues to expand, and it is likely that research efforts will begin focusing on some of the newer classes of medications. While more research is needed to support the use of pharmacogenomics to predict patient outcomes with other classes of diabetes medications, there are sufficient data to support the use of pharmacogenomics with sulfonylureas and, to a less extent, thiazolidinediones.

 

Pharmacogenomics of Cardiovascular Medications

 

Hyperlipidemia and hypertension are two of the most common diabetes comorbidities. Together with hyperglycemia, these conditions constitute the “three H’s” of metabolic syndrome. These two conditions are significant predictors of overall cardiovascular health in diabetics and ADA guidelines emphasize both hyperlipidemia and hypertension management as a key component of effective diabetes treatment.43

 

Hyperlipidemia is the most common diabetes comorbidity and is a more important risk factor for cardiovascular disease than hyperglycemia.44 While the prevalence of LDL-C levels is similar in diabetics and non-diabetics, diabetic patients have a 2-3 fold increased risk of elevated triglycerides and low HDL-C compared to the general population.44 Moreover, for the same serum lipid levels, individuals with diabetes have a greater risk of cardiovascular disease than non-diabetic individuals.45 Similarly, the risk of coronary artery disease in patients with comorbid diabetes and hypertension is three-fold higher than in patients with either diabetes or hypertension alone46 and the risk of stroke, nephropathy, and retinopathy is also increased.47

 

Treatment of these underlying risk factors reduces the risk of cardiovascular disease in diabetic individuals. Statin treatment reduced the risk of CVD-related mortality by 19-25% in two studies.45 Likewise, the UKPDS 36 study showed that for each 10 mm Hg decrease in systolic blood pressure (SBP), there was a corresponding decrease in deaths related to diabetes (15% decrease), myocardial infarction (11% decrease), microvascular complications (13% decrease), and any complication (12% decrease).48 Improving efficacy and adherence to statin and antihypertensive therapy via pharmacogenetic-guided treatment would be expected to result in further decreases in major adverse cardiovascular events.

 

Statins

Statins are the preferred treatment for hyperlipidemia and are effective at lowering lipid levels and consequent risk of cardiovascular disease in individuals with diabetes.44 Medications in the statin class include atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin. Like many medication classes, statins are not uniformly metabolized in the same fashion. Fluvastatin is primarily metabolized by CYP2C9, while atorvastatin, lovastatin, and simvastatin are metabolized by CYP3A4/5. Pravastatin and rosuvastatin do not undergo CYP-mediated metabolism.49

Cytochrome P450 variation has been shown to have an impact on statin efficacy and safety profiles. Carriers of the CYP3A4*22 variant, which reduces activity of the CYP3A4/5 enzyme system, have higher plasma concentrations of simvastatin and was associated with reduced dose requirement and greater reductions in total cholesterol and LDL-c levels.49 Carriers of the CYP3A5*1 allele, which increases activity of the CYP3A4/5 enzyme system, had reduced response to simvastatin, lovastatin, and atorvastatin.50 Genetic variation in CYP2C9 has been shown to increase serum levels of fluvastatin,51,52 and has been shown to increase adverse event rates by over 6-fold.53

 

Another well-known example of hyperlipidemia pharmacogenomics is the SLCO1B1 gene, which encodes a protein that transports statins into the hepatocyte. As the hepatocyte is both the site of action and the site of metabolism for most statin medications, this protein plays a critical role in their clinical effect.49 Individuals who carry two copies of the SLCO1B1 rs4149056 variant, which reduces transport of statin into the hepatocyte, have shown a 120-221% increase in simvastatin AUC compared with wild-type patients.54 Moreover, these individuals have a nearly 17-fold increase in likelihood of statin-induced myopathy compared to individuals with the normal genotype.55 This increase in myopathy risk may explain the two-fold increase in discontinuation rates among variant carriers.56 These data have led the Clinical Pharmacogenetic Implementation Consortium (CPIC) to establish clinical guidelines for the use of SLCO1B1 genotyping to inform simvastatin prescribing.18

 

SLCO1B1 variation has also been found to impact efficacy of some statins. Carriers of the rs4149056 allele have shown reduced total cholesterol and LDL-c response with pravastatin and atorvastatin, while SLCO1B1*14 carriers showed improved response to fluvastatin.49 Pharmacokinetic variability, though not necessarily clinical outcomes, has been observed as a function of SLCO1B1 genotype with all of the statins except lovastatin.49

 

Angiotensin Converting Enzyme Inhibitors

Angiotensin converting enzyme (ACE) inhibitors, along with angiotensin II receptor blockers (ARBs), are considered first line therapy for hypertension in diabetes due to their nephroprotective effects.8 ACE facilitates the conversion of angiotensin I to angiotensin II, which limits the production of aldosterone, thereby reducing sodium and water reabsorption in the kidney. While some studies have evaluated associations between ACE inhibitor efficacy and genetic variants in the ACE gene (in particular, rs1799572), the results have been conflicting.57,58 As a class, ACE inhibitors largely avoid CYP-mediated metabolism, reducing the impact of metabolism-related pharmacogenomic variants. However, studies have found that SLCO1B1 variation can increase enalapril serum levels59 and may increase risk of enalapril-induced cough by as much as 7-fold.60 Though more research is needed, SLCO1B1 is an intriguing target as a pharmacogenetic predictor of enalapril tolerability.

 

Angiotensin II Receptor Blockers

Angiotensin II receptor blockers (ARBs) target the angiotensin II receptor. However, studies have failed to show a consistent association between genetic variation in angiotensin receptor genes and ARB response577 Unlike ACE inhibitors, many ARBs are metabolized by the CYP450 enzyme system. In particular, losartan, azilsartan, candesartan, valsartan, and irbesartan are all metabolized to greater or lesser degrees by CYP2C9 and CYP3A4/5.61 Pharmacogenomic variation in these genes has been shown to impact the clinical profile of these medications. For example, data shows that variants in CYP2C9 can impact losartan pharmacokinetics, reducing its conversion to its pharmacologically active form.57 Corresponding reductions in losartan efficacy have also been observed.62-64 In particular, one study looked at the impact of CYP2C9 variation on losartan response in type I diabetic patients with nephropathy, finding that individuals carrying the CYP2C9*3 variant showed less improvement after 4 months of losartan therapy. CYP2C9 variation has also been shown to impact irbesartan response65-66 and changes in pharmacokinetic parameters as a function of CYP2C9 genotype have been reported with candesartan67,68 and valsartan.69 Thus, CYP2C9 genotype may be an important predictor of response to ARBs in hypertensive diabetics.

 

β-Blockers

β-blockers are extensively prescribed for heart failure and continue to be prescribed as an effective therapy for the treatment of hypertension in diabetes, especially as an adjunctive medication.8 β-blockers that have been evaluated for pharmacogenomic associations include carvedilol, metoprolol, and propranolol. A considerable amount of data has shown significant impacts of CYP450 variation on β-blocker pharmacokinetics and outcomes. The FDA-approved drug label for metoprolol notes the impact of CYP2D6 poor metabolism on pharmacokinetics and cardioselectivity of metoprolol, while the Dutch Pharmacogenetics Working Group has published metoprolol dosing guidelines as a function of CYP2D6 metabolizer status.70 The impact of CYP2D6 genotype on carvedilol pharmacokinetics and clinical response has also been extensively demonstrated.57,71 While CYP2D6 variation has been shown to impact propranolol pharmacokinetics, its effect on response is still somewhat controversial.72-74 Several well- studied pharmacogenomic variants have been shown to impact β-blocker pharmacodynamics, including variants in genes encoding the β-adrenergic receptors themselves (ADRB1 and ADRB2).57,75,76

 

Anticoagulant/Antiplatelet Medications

When diabetes-related cardiovascular disease progresses to the point where intervention is required, anticoagulant and antiplatelet medications are often prescribed to manage risk of thrombosis and stroke, particularly after procedures such as heart valve replacement and stent placement. Clopidogrel and warfarin are some of the most commonly prescribed medications in these situations and both are among the best-known examples of pharmacogenomics.

 

Clopidogrel is one of several medications to have a black box warning in the FDA-approved drug label that explicitly calls out differential risk as a function of patient genotype, noting that “effectiveness of Plavix depends on conversion to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19.” The black box warning further notes that clinical tests are available to identify CYP2C19 poor metabolizers and recommends that practitioners “consider use of another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers.”77 CYP2C19 genotype may also interact with diabetes status to further reduce antiplatelet response to clopidogrel.78

 

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In late 2017, a landmark study was published by Cavallari et al that assessed clinical outcomes following clinical implementation of CYP2C19 testing in 1,815 patients who underwent percutaneous coronary intervention (PCI).79 Those with a normal genotype received standard therapy (approximately 85% received clopidogrel, with the rest receiving an alternative antiplatelet medication). However, if a patient carried a loss-of-function (LOF) allele, their provider was alerted and alternative anti-platelet therapy was suggested (approximately 61% received alternative antiplatelet therapy, with the rest receiving clopidogrel). After 12 months, patients with a LOF allele who received clopidogrel were 2.3 times more likely to experience a major adverse cardiovascular event than patients with a LOF allele who received alternative therapy (p = 0.013). Patients with an LOF allele who received alternative therapy had similar outcomes to those without an LOF allele.

 

These data indicate that CYP2C19 testing is an effective predictor of post-PCI clopidogrel outcomes. Prospective use of CYP2C19 genotyping can reduce risk of major adverse cardiovascular risk post-PCI and can also be used to triage individuals to the most appropriate and cost-effective therapy. For example, CYP2C19 normal metabolizers taking alternative therapies may be able to be triaged to the less expensive clopidogrel, reserving the more expensive alternative medications for individuals carrying LOF alleles.

 

The case of warfarin has been somewhat more controversial. FDA labeling has included CYP2C9 genotype-guided dosing information since 2007.80 CPIC guidelines were published in 2011 and updated in 2017.20 However, trials examining clinical utility of warfarin have produced mixed results. Early studies failed to meet the primary endpoint of time in therapeutic range,81-82 although these studies have also been criticized for failing to mirror standard clinical practice.83 The COAG trial did show a trend toward fewer adverse events in the genotype-guided arm81 and the GIFT trial was launched to further explore these clinical outcomes.84 This study, which enrolled 1,650 patients randomized to either CYP2C9-guided dosing or standard clinical dosing, demonstrated a 27% reduction in the composite endpoint of venous thromboembolism, major bleeding, INR ≥ 4, or death in the genotype-guided arm compared to the clinical dosing arm. These data argue powerfully for the clinical implementation of warfarin despite earlier failures with less clinically relevant endpoints.

 

Economic Outcomes

To date, cost-effectiveness analyses for cardiovascular medications have been limited to clopidogrel and warfarin only. These analyses generally follow a similar pattern of comparing pharmacogenomic-guided therapy with one or more alternative approaches that do not require pharmacogenomic testing.

 

In the case of clopidogrel, one cost-effectiveness analysis compared pharmacogenomic-guided therapy antiplatelet selection (with normal allele carriers receiving clopidogrel and LOF allele carriers receiving alternative antiplatelet therapy) with universal clopidogrel therapy, universal alternative antiplatelet therapy, and platelet-reactivity guided therapy.85 The analysis evaluated costs over the lifetime of a 60-year-old patient undergoing a PCI and found that pharmacogenomic-
guided testing resulted in the lowest overall cost over a lifetime and with the highest number of quality-adjusted life years gained. Another study evaluated the cost-effectiveness of genotype-guided antiplatelet therapy over a 30-day and 1-year window, finding that genotype-guided treatment was cost effective over 30 days and 1 year in 62 and 70% of simulations, respectively.86 A 2015 review of CYP2C19-guided antiplatelet therapy found that genotype-guided therapy was cost-effective in all seven studies that were reviewed, not including the two studies described previously.87

 

Analyses of warfarin cost-effectiveness have produced largely, though not universally, positive results. Seven cost-effectiveness analyses have demonstrated genotype-guided anticoagulant therapy to be cost- effective relative to standard warfarin treatment and/or universal use of direct oral anticoagulant therapy,88-94 with two analyses finding standard warfarin dosing to be superior95-96 and one analysis finding standard warfarin dosing and genotype-guided dosing to be essentially equivalent.97

 

Summary

Pharmacogenomics has a significant role to play in the management of cardiovascular risk factors in diabetes. Pharmacogenomic testing for clopidogrel and warfarin is now well established, with recent trials providing definitive evidence for clinical utility of genotyping prior to prescription of these medications. Pharmacogenomic testing for CYP3A4, CYP3A5 and SLCO1B1 can also be used to optimize the selection and dosing of statin medications for hyperlipidemia. In particular, SLCO1B1 already has published guidelines on its clinical implementation and routine testing is occurring at many major medical centers. Similarly, testing for SLCO1B1, CYP2D6, and CYP2C9 for the individualization of ACE inhibitors, beta-blockers, and ARBs, respectively, may reduce the time to effective dose (thus improving efficacy), while decreasing the risk of side effects (thus increasing adherence), resulting in better hypertension outcomes. Thus, adoption of pharmacogenomics is likely to result in significant improvements in cardiovascular health and quality of life among individuals with type 2 diabetes, with a reduced overall cost to the healthcare system. Moreover, by targeting a high-cardiovascular-risk population such as patients with type 2 diabetes, cost-effectiveness of pharmacogenomic testing is likely to exceed universal testing of the general population.

 

Pharmacogenomics of Antidepressant Medications

 

Few conditions have a greater impact on global functioning and quality of life than depression. In diabetes, comorbid depression is associated with poorer cognitive functioning, worsened glycemic outcomes, decreased adherence to behavioral and pharmacotherapeutic interventions, greater frequency and severity of diabetes complications (such as lower extremity amputation), and decreased quality of life.10,98-100 The prevalence of depression in type 2 diabetes is nearly twice as high (19.1%) compared to those without diabetes (10.7%).101 The relationship between depression and diabetes is likely bidirectional, with depression as both a risk factor for and a consequence of diabetes102 and the two conditions share neurobiological pathways.98

 

Depression is primarily treated through pharmacotherapy and/or psychotherapy. Overall efficacy of antidepressants in both diabetics and the general population is poor, with only 50% of individuals responding to their first trial of an antidepressant, while intolerability and nonadherence to medications are quite common.103-104 Antidepressant use has been shown to be effective in reducing depressive symptoms, improving glycemic control, and improving quality of life for diabetic patients.14,105,106

 

Clinical Outcomes

Pharmacogenomic testing in psychiatry is supported by an abundance of data. CPIC guidelines exist for tricyclic antidepressants (TCAs)15 and selective serotonin reuptake inhibitors (SSRIs)16 and over 30 neuropsychiatric medications contain pharmacogenomic information in their FDA-approved package inserts.107 Psychiatric pharmacogenomic testing has been evaluated in multiple published double-blind randomized controlled trials, with all showing statistically significant108-110 or trending111 improvements in depressive symptomatology in the genotype-guided arm relative to the treatment-as-usual arm. Naturalistic studies have likewise shown that genotype-guided treatment can improve antidepressant response by as much as 56% over treatment-as-usual.112-115 Studies have also demonstrated improved antidepressant adherence with genotype-guided treatment relative to standard treatment.108,116,117 Outside of depression, evidence also exists for the use of pharmacogenomics to predict antidepressant outcomes in diabetic neuropathy.118

 

Economic Outcomes

Psychiatric pharmacogenomic testing has been demonstrated to reduce healthcare medication costs. One large study that compared 2,168 genotype-guided patients to 10,880 matched controls demonstrated savings of over $1,000 USD per person in medication expenditures over a one year timeframe.116 Interestingly, diabetes and cardiovascular medications made up ~28% and ~16% of these savings, respectively. This is likely due to the aforementioned effect of improved mental wellbeing on physical health.14,105,106

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Pharmacogenomic testing has also been demonstrated to positively impact and lower healthcare utilization costs. One study found that patients taking genetically inappropriate medications accrued an additional ~$5,200 in healthcare utilization costs relative to patients on genetically appropriate medications,119 while another study found that CYP2D6 abnormal metabolizers had longer hospitalization stays and more adverse events, resulting in increased healthcare costs.120 Additionally, prospective use of psychiatric pharmacogenomic testing reduced healthcare utilization in two studies.117,121

 

Summary

Psychiatric pharmacogenomic testing can improve patient outcomes in depression, leading to increased medication adherence and reduced healthcare costs. Psychiatric pharmacogenomic testing has shown a direct impact on medication costs associated with diabetes and cardiovascular disease and is likely to produce similar benefits in healthcare utilization and patient quality of life. The evidence supporting the clinical utility of pharmacogenomic testing for psychiatric medications may be the most extensive of any disease state.

 

Future Directions: Genetic Predictors of Diabetes Risk

 

While not directly related to pharmacogenomics, a brief discussion of genetic predictors of diabetes diagnosis is warranted. Monogenic forms of diabetes (i.e. inherited forms of diabetes caused by single genes) may represent one underutilized area of genetic testing in diabetes. The most well characterized form of monogenic diabetes is maturity-onset-diabetes of the young (MODY), a term encompassing 13 subtypes of the condition, each characterized by a single gene causing the illness presentation. As the clinical presentation of MODY is similar to both type 1 and type 2 diabetes, it is often misdiagnosed and may make up 1-2% of all diabetes cases.122 Neonatal diabetes mellitus, which usually presents in the first six months of life, is also caused by known, detectable mutations.122

 

Type 2 diabetes mellitus, on the other hand, is multifactorial and is the result of a complex interplay between environment and numerous, largely uncharacterized genetic variants. Indeed, the NHGRI-EBI Catalog of published genome-wide association studies lists well over 1500 statistically significant associations, including variants in TCF7L2, KCNJ11, PPAR-γ, and FTO. However, each of these variants confers a very small increase in absolute risk for type 2 diabetes, making them presently useless as diagnostic markers. However, as the field advances, polygenic risk scores may be developed that, when validated, can assist in the prediction and early detection of type 2 diabetes so that interventions can occur before the disease progresses.

 

Conclusion

The treatment of type 2 diabetes mellitus, with its myriad of risk factors, treatment options, complications, and comorbidities is incredibly complex, resulting in significant social and economic burden in the United States. Pharmacogenomic testing has been demonstrated to significantly improve the treatment of cardiovascular and psychiatric conditions associated with diabetes, and data on the pharmacogenomics of glycemic agents themselves continue to accumulate. As clinicians adopt the use of pharmacogenomic testing for the management of pharmacotherapy in diabetic patients, it is likely that significant gains will be seen in medication efficacy, tolerability, and adherence, resulting in overall improved outcomes and reduced healthcare costs for the patient and healthcare system.

 

References

 

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Overview of the Dangers and Side Effects of Psychotropic Medications

By | ADHD Medications, Antianxiety Medications, Antidepressants, Antipsychotics, Pharmacogenetic Testing, Precision Medicine, Psychiatric Medications | No Comments

Get the Rxight® Genetic Test to Know Your Risks

Psychiatric medications (often called “psychotropics”) are routinely used to treat a variety of psychiatric disorders – ranging from ADHD (attention deficit hyperactive disorder) and depression to bipolar disorder and anxiety to schizophrenia – Psychiatric medications are generally jused as an adjunct to psychotherapy.

 
It is estimated that 17 percent (some 80 million people) in the United States are taking some form of psychiatric medication (Scientific American, “1 in 6 Americans Takes a Psychiatric Drug,”  Dec 13 2016) According to the article, an earlier government report, from 2011, found that just over 10% of adults are taking prescription drugs for “problems with emotions, nerves or mental health,” published in the journal JAMA Internal Medicine.

 
While the potential benefits of psychotropic medications have been demonstrated in research and clinical practice for decades, patients are cautioned to remain vigilant of the many side effects of psychiatric medications.

 
This article presents a detailed summary of the major types of mental health medications and their associated risks for side effects as reported by the U.S. Food and Drug Administration (FDA) and the National Institute of Mental Health (NIMH) and an overview of the benefits of the Rxight® genetic test for psychiatric medications in identifying your unique genetically determined risk for developing side effects or non-response to dozens of these psychiatric medications along with hundreds of other medications across 50 pharmacological classes.

Antidepressant Side Effects

What are antidepressants?
Antidepressants are commonly used to treat depressive disorders. They also are used for other conditions, such as pain, anxiety and insomnia. Although antidepressants are not FDA-approved specifically to treat ADHD, they are sometimes used “off-label” for ADHD treatment.

The most commonly prescribed types of antidepressants today are called . Examples of SSRIs include:

Other types of antidepressants are serotonin and norepinephrine reuptake inhibitors (SNRIs) .These are chemically similar to SSRIs and include and duloxetine (Cymbalta)  and venlafaxine (Effexor).

 
Another antidepressant that is commonly used is bupropion – a third sub-class of antidepressant which acts differently than either SSRIs or SNRIs.  Bupropion is also used to treat seasonal affective disorder (SAD) and for smoking cessation treatment.

SSRIs, SNRIs, and bupropion are commonly used today because they do not cause as many side effects as the older (“first generation”) classes of antidepressants, and moreover are effective in treating a broader range of depressive and anxiety disorders.

 
Older antidepressant medications include tricyclic antidepressants, tetracyclic antidepressants, and monoamine oxidase inhibitors (MAOIs).  These are less commonly prescribed since the development of the newer generation antidepressants.
 
What are the possible side effects of antidepressants?
Some antidepressants may cause more side effects than others. The most common side effects listed by the FDA include:

  • Sexual problems (impotence or inability to orgasm)
  • Nausea and vomiting
  • Weight gain
  • Sleepiness or fatigue
  • Diarrhea

In 2004, the FDA ordered a “black box” label – the most serious warning it issues – on all antidepressants to caution of psychiatric drugs’ increasing suicide risk in children and adolescents. In 2006, the FDA increased the age to include young adults up to age of 25. (FDA, Revision to Product Labeling, 2004)

 
Call your doctor immediately if you have any of the following symptoms, especially if they are new, worsening, or worry you (U.S. Food and Drug Administration, 2011):

  • Suicidal thoughts or actions
  • New or worsening depression
  • New or worsening anxiety
  • Feeling restless or agitated or
  • Panic attacks
  • Insomnia
  • New or worsening irritability
  • Acting aggressively, being angry, or violent
  • Acting on dangerous impulses
  • An increase in activity and talking (mania)

Additionally, drug interactions can occur.  Specifically, combining the newer SSRI or SNRI antidepressants with one of the commonly-used “triptan” medications for treating migraines can cause a life-threatening condition called “serotonin syndrome.” Serotonin syndrome is marked by agitation, hallucinations, high temperature, or unusual blood pressure changes. Serotonin syndrome is usually associated with the older antidepressants called MAOIs, but it can happen with the newer antidepressants as well.

 
Antidepressants may cause other side effects that were not included in this list, as determined by individual genetics and ability to metabolize the drug in the liver.

 
How do patients respond to antidepressants?
Some people respond better to some antidepressant medications than to others.  It is critical to know that some people may not feel better with the first medicine they try. Additionally, sometimes people taking antidepressants feel better and stop taking the medication too soon, and the depression may return.

 
These inter-individual differences are based in genetics, and the Rxight® genetic test will indicate which antidepressants may not work for you right from the start instead of having to go through trial and error with your doctor  With Rxight results, you your doctor can work together to find the best and most effective antidepressant treatment tailored to your unique genetics.

 

Antipsychotic Side Effects

What are antipsychotics?
Antipsychotic medicines are primarily used to manage psychosis, a condition that affects the mind. Psychosis is characterized by some loss of contact with reality, often including or hallucinations (hearing or seeing things that are not really there), or delusions (false, fixed beliefs). It can also be a symptom of a physical condition such as drug abuse or a mental disorder such as schizophrenia, very severe depression (also known as “psychotic depression”), or bipolar disorder.

 
Antipsychotic medications are frequently used in combination with other drugs to treat delirium, dementia, and mental health conditions, including:

The older antipsychotic medications are conventionally referred to as “typical” antipsychotics or “neuroleptics”. Some of the common typical antipsychotics include:

Second generation antipsychotic medications are also called “atypical” antipsychotics. Some of the most common atypical antipsychotics are:

According to a 2013 research review by the Agency for Healthcare Research and Quality , typical and atypical antipsychotics both work to treat of bipolar disorder (preventing mania) and symptoms of schizophrenia Additionally, some atypical antipsychotics have wider applications and are used for treating bipolar depression or general depression.

 
What are the possible side effects of antipsychotics?

Antipsychotics are known to have a large number of side effects (also called adverse events) and risks, including potentially fatal complications.

 
The FDA lists the following side effects of antipsychotic medicines:

  • Constipation
  • Nausea
  • Vomiting
  • Uncontrollable movements, such as tics and tremors (the risk is higher with typical antipsychotic medicines)
  • Seizures Drowsiness
  • Blurred vision
  • Low blood pressure
  • Dizziness
  • Restlessness
  • Weight gain (the risk is higher with some atypical antipsychotic medicines)
  • Dry mouth
  • A low number of white blood cells, which fight infections

Typical antipsychotic medications can also cause additional side effects related to physical movement, such as:

  • Tremors
  • Restlessness
  • Rigidity
  • Muscle spasms

Long-term use of antipsychotic medications may lead to a condition called tardive dyskinesia (TD). Tardive dyskinesia causes uncontrolled muscle movements, commonly around the mouth. TD can range from mild to very severe, and in some people, the problem cannot be cured and becomes disfiguring.

 
Avoid the Risk of Antipsychotic Side Effects with Rxight®

The Rxight® medication panel includes 18 popular antipsychotics on the market. Because the potential side effects of both typical and atypical antipsychotics can be very serious and potentially fatal, knowing your risks ahead of time with Rxight® can be an invaluable test for you and your prescriber.

 

Mood Stabilizer Side Effects

What are mood stabilizers?
Mood stabilizers work by decreasing abnormal brain activity. They are used mainly to treat bipolar disorder and the mood swings associated with other mental conditions including:

  • Depression (usually in conjunction with an antidepressant)
  • Disorders of impulse control
  • Schizoaffective Disorder

Anticonvulsant (anti-seizure) medications are most frequently used as mood stabilizers. They were originally developed for treatment of seizures, but they were found to help control mood swings as well. One anticonvulsant commonly used as a mood stabilizer especially in patients with symptoms of both mania and depression, or those with rapid-cycling bipolar disorder, is valproic acid (sold as Depakote). Anticonvulsants used as mood stabilizers include:

Lithium is a non-anticonvulsant mood stabilizer approved for the treatment of mania and the maintenance treatment of bipolar disorder.

 
What are the potential side effects of mood stabilizers?

Mood stabilizers can cause several side effects, some of which may be serious, especially at high dosages. These side effects include:

  • Potentially fatal rash (Stevens-Johnson Syndrome)
  • Itching
  • Extreme thirst
  • Tremor
  • Nausea and vomiting
  • Fast, slow, or irregular heartbeat
  • Slurred speech
  • Blackouts
  • Changes in vision
  • Hallucinations
  • Loss of coordination
  • Swelling

Mood stabilizers may cause other side effects that are not included in this list. Your unique reaction to anticonvulsants is based in genetics, and the Rxight® genetic test will indicate which mood stabilizer not work for you may right from the start instead of having to go through trial and error with your doctor – a process which can be expensive, lengthy and dangerous.  With Rxight® results, you your doctor can work together to find the best and most effective antidepressant treatment tailored to your genotype, preferably before treatment begins.

 

Anti-Anxiety Medication Side Effects

What are anti-anxiety medications?
Anti-anxiety medications (also called “anxiolytics”) work by reducing the symptoms of anxiety, such as that seen in panic attacks, or extreme worry and fear. The most commonly prescribed anti-anxiety medications are called “benzodiazepines.” Benzodiazepines are most frequently used to treat a condition called generalized anxiety disorder, while in cases of social phobia (social anxiety disorder) or panic disorder (panic attacks). Benzodiazepines are usually second-line treatments, behind antidepressants such as SSRIS.

Benzodiazepines used to treat anxiety disorders – all of which are tested in the Rxight® panel – include:

Short-acting benzodiazepines such as Lorazepam and another class of medication known as beta-blockers are used to treat non-persistent symptoms of anxiety. Beta-blockers are used primarily to manage physical symptoms of anxiety (e.g., shaking, rapid heartrate, and sweating).

 
Buspirone  (which is chemically unrelated to the benzodiazepine family) is sometimes indicated for the long-term treatment of chronic anxiety. It is not effective to use on an “as-needed” basis like the benzodiazepines.

 
How common is addiction to benzodiazepines?
One of the serious risks of anti-anxiety medications is that you can build up a tolerance to benzodiazepines if they are taken over a long period of time and may need increasingly higher doses to get the same effect. There is a serious risk of addiction and dependence. To avoid these problems, doctors usually prescribe benzodiazepines for short periods, particularly in the elderly (NIMH, “Despite Risks, Benzodiazepine Use Highest in Older People”), and people with addiction tendencies. If people suddenly stop taking benzodiazepines, they may have withdrawal symptoms or their anxiety may return.

 
What are the possible side effects of anti-anxiety medications?
Like other medications, anti-anxiety medications may cause side effects, many of which are serious. The most common side effects of benzodiazepines are sleepiness and dizziness. Other possible side effects include:

  • Headache
  • Confusion
  • Tiredness
  • Nausea
  • Blurred vision
  • Nightmares

Tell your doctor immediately if any of these symptoms are severe or do not go away:

  • Drowsiness
  • Difficulty thinking or remembering
  • Increased saliva
  • Dizziness
  • Unsteadiness
  • Problems with coordination
  • Blurred vision

If you experience any of the symptoms below, call your doctor immediately:

  • Swelling of the eyes, face, lips, tongue, or throat
  • Difficulty breathing or swallowing
  • Rash
  • Hives
  • Hoarseness
  • Seizures
  • Yellowing of the skin or eyes (jaundice)
  • Depression
  • Difficulty speaking
  • Difficulty breathing

Common side effects of beta-blockers include:

  • Fatigue
  • Dizziness
  • Weakness
  • Cold hands

 

Stimulant Side Effects

What are Stimulants?
Stimulants increase alertness, attention, and energy, as well as elevate blood pressure, heart rate, and respiration. Stimulant medications are generally prescribed to treat individuals diagnosed with ADHD (attention-deficit hyperactivity disorder). People with ADHD who take prescription stimulants describe a calming and “focusing” effect from the medication.  This is due to its effects on the brain chemical dopamine.

Stimulants used to treat ADHD – all of which are analyzed in the Rxight® DNA test – include:

In 2002, the FDA approved non-stimulant medication atomoxetine (Strattera) for use as a treatment for ADHD. Additional non-stimulant antihypertensive medications, clonidine  and guanfacine, are also approved for treatment of ADHD.

In addition to treating ADHD, stimulants are prescribed to treat other health conditions, including narcolepsy, and occasionally depression.

 
What are the possible side effects of stimulants?
Stimulants may cause side effects, most of which are relatively minor and disappear when dosage levels are lowered. The most common side effects include:

  • Loss of appetite
  • Insomnia
  • Stomach pain
  • Headache

Less common side effects include:

  • Motor tics or verbal tics
  • Personality changes

What are serious side effects of stimulant medications?
While side effects of stimulant medications tend to be minimal, patients and parents of patients are cautioned that serious adverse effects may occur, as reported by the FDA Drug Safety Communication in 2013. Also see
FDA Warns of Psychiatric Adverse Events from ADHD Medications
.

 
Heart-related problems:

  • Sudden death in patients who have heart problems or heart defects
  • Stroke
  • Myocardial infarction (heart attack)
  • Increased blood pressure and heart rate

Mental (Psychiatric) problems:

  • Behavior and thought problems
  • New or worse aggressive behavior or hostility
  • New or worse bipolar illness
  • New psychotic symptoms (or new manic symptoms)
  • Physical or psychological dependence

For additional details on the FDA warnings and manufacturer labeling for medications covered in the Rxight® panel, please refer to our list of medications covered.

 

About Rxight® Pharmacogenetic Testing

The Rxight® genetic test analyzes your risks based on your unique genetic makeup through a process called “SNP genotyping.” The report which will be shared with you in a personal consultation with a pharmacist. The report “red-flags” medications which may cause you to have issues, or conversely highlight medications which may not be effective for you.

 
Rxight® is based on pharmacogenetics — the study of how genes affect a person’s response to medicines. Our panel of over 200 clinically significant medications includes dozens of commonly prescribed psychiatric medications, including antidepressants across five sub-classes, mood stabilizers used in bipolar disorder and schizoaffective disorder, antipsychotics, ADHD medications (stimulant and non-stimulant), and anti-anxiety medications.

 
Based on how well you metabolize those particular medications, which is determined by your genes that encode liver enzymes that break down drugs, you will be at risk for developing side effects or the medication not working well or at all. With the results of the Rxight® test you and your prescriber can find the right medication for you, preferably before treatment begins.

 
Contact us today by phone 1 (888) 888-1932 or email to learn more about how Rxight® pharmacogenetic testing can help you find the right medication, right from the start.

Co-Occuring Autism and Depression: A Clinical Challenge

By | Antidepressants, Antipsychotics | No Comments

Is depression more common in patients with autism spectrum disorder (ASD) than in the general population? Yes, according to research on the co-morbidity of mood disorders and ASD – which according to the CDC affects an estimated 1 in 45 children in the U.S.
 
An article published in Dialogues in Clinical Neuroscience, “Challenges in the diagnosis and treatment of depression in autism spectrum disorders across the lifespan” (2015), found that some research points to rates of depression as high as 57 percent in ASD patients. One study of adult patients found the rate of suicide of ASD adults was almost 2 percent, compared to less than.5 percent of adults without autism.
 

Clinicians Face Difficulties Differentiating between Depression and ASD

 
It can be difficult to differentiate between symptoms of autism and those of depression. In fact, diagnosing depression in those with autism represents a clinical challenge that dates back to Leo Kanner’s original description of the condition in his 1943 paper where he identified that individuals with autism spectrum disorders show little facial emotion – called a “flat affect.” However, in autism, affect doesn’t necessarily correspond to the individuals’ mood, which is an internal state not always congruent with emotion.
 
Another challenge that clinicians face in diagnosing depression in patients with autism is the overlap in symptoms. Those of depression typically include a flat facial expression as with autism, reduced appetite, sleep disturbance, low energy, reduced motivation, social withdrawal and reduced desire to communicate with others. Many of these same symptoms can stem from autism rather than depression.
 

Find the Right Medications with Rxight® Pharmacogenetic Testing

 
Two drugs for treating the irritability and aggression that is commonly associated with the autism – risperidone (Risperdal) and aripiprazole (Abilify) – have been approved by the Food and Drug Administration. Additionally, so-called “off-label” medications include naltrexone, which is FDA-approved for the treatment of alcohol and opioid addictions. It can ease disabling repetitive and self-injurious behaviors. (Autism Speaks, “Medicines for Treating Autism’s Core Symptoms”).
 
MD Labs’ CLIA-certified Rxight® genetic testing panel – which among the most comprehensive available – includes risperidone and aripiprazole, along with 26 antidepressant medications across clinically significant antidepressant classes. Over 200 other medication are also covered in the Rxight® panel.
 

Your Insurance May Cover Testing with Rxight®

 
Many insurance companies now cover tetrabenazine (Xenazine), nortriptyline (branded as Pamelor and Aventyl Hydrochloride) and amitriptyline (branded as Elavil, Endep and Vanatrip), antidepressants within the Rxight® panel.
 
If you or a loved one suffers from depression and has been diagnosed with ASD as well, ask your doctor about authorizing the Rxight® Pharmacogenetic Test. Genetic testing with Rxight® enables you and your prescribers to know – preferably ahead of time – which medications may causes potentially dangerous adverse reactions and conversely which may be ineffective.
 
To get started, we invite you to email us today or call 1-888-888-1932 to discover how you may benefit from our pharmacogenetic testing program.

Pharmacogenetic Testing Could Help Reduce Side Effects Caused by Commonly Prescribed Diabetes Medication

By | Antidepressants, Diabetes | No Comments

Diabetes is a serious public health issue, and is projected to be the seventh leading cause of death worldwide by 2030. In the sub-Saharan African region, it is estimated that nearly 1 in 10 people suffer from diabetes, according to the World Health Organization Global Report on Diabetes (WHO, 2016). In the United States, we see similar statistics. The CDC reported in 2014 that nearly 1 in every 11 people in the U.S. are diagnosed with diabetes, accounting for nearly 29.1 million people (Centers for Disease Control and Prevention, 2014 National Diabetes Statistics Report).
 
Complications can arise in those with diabetes and therefore, proper medication therapy is crucial.
Diabetic Peripheral Neuropathy (DPN) is the most common complication of diabetes and occurs in up to half of diabetic patients, according to a recent study in Pharmacogenomics (Chaudhry et al., April 2017).

 
The most common symptoms of diabetic neuropathy are increased pain sensitivity, numbness and spontaneous pain in the limbs. Patients frequently describe the pain as burning and shooting.
 

Amitriptyline: The Drug of Choice for DPN in Developing Countries

 
Since there are currently no treatments available to completely restore nerve function, drug therapy is often aimed at managing the pain. Antidepressants in particular, specifically amitriptyline, are often used to treat DPN.
 
This Pharmacogenomics study investigated the use of amitriptyline for DPN in a South African population. Amitriptyline is used to treat the DPN pain due to its numbing effect on the nerves. It is regarded as the drug of choice to for painful peripheral neuropathy in this population given its cost effectiveness.
 

Genetics Influence How You’ll React to Medications

 
Common side effects of amitriptyline include blurred vision, drowsiness, constipation, urinary retention and dryness of mouth/eyes. More serious side effects include build-up of metabolic toxins in the heart or the nervous system.
 
Genetics play a major role in how the body metabolizes medications. Amitriptyline is mainly metabolized in the liver and cleared by the kidneys. How one’s body metabolizes this medication in encoded by two specific genes and one of these genes is responsible for adverse drug reactions (ADRs).
 
In the case of amitriptyline, patients who are “slow metabolizers” will experience adverse reactions. Patients who are “fast metabolizers” do not experience these adverse reactions. However, since these fast metabolizers clear the drug from their bodies so quickly, they are at risk for not benefiting from treatment.
 

Study Calls for Pharmacogenetic Screening in Amitriptyline Therapy

 
The study concluded that pharmacogenetic testing might be useful for tailoring treatment and thereby improving amitriptyline effectiveness. Chaudhry et al. noted that if a patient is a non-responder to amitriptyline, or experiences severe side effects, pre-emptive genetic screening can be performed so an alternative medication may be considered, or the dose adjusted appropriately.
 
“Our findings…support the use of pharmacogenetic testing in the context of amitriptyline therapy for the management of diabetic pain,” the authors stated, adding that PGx testing can be “valuable to guide drug choice and dosage and thereby improve treatment outcomes in patients with DPN.”

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The U.S. Opioid Epidemic and How Your Genetics Factor into Your Risk for Addiction

By | Opioids, Pain Medications | No Comments

Find Out Your Medication Risks with the Rxight® Genetic Test
 
The United States is amidst an opioid epidemic and the numbers are sobering. According to the U.S. Department of Health and Human Services, the rate of overdose deaths involving opioids, including prescription opioid pain relievers, has nearly quadrupled since 1999, and over 165,000 people have died from prescription opioid overdoses. The Rxight® Pharmacogenetics Program can help you understand how your genetics play a role in your likelihood for addiction.
 
On a typical day, more than 650,000 opioid prescriptions are dispensed, 3,900 people use prescription opioids, which include hydrocodone (Vicodin), codeine and tramadol (Ultram), for recreational purpose, and about 80 people die from an opioid-related overdose, according to the HHS. https://www.hhs.gov/opioids/about-the-epidemic/#us-epidemic
 

Tragic Reports of Opioid Overdose, Death Commonplace

 
Accounts of overdose and death from prescription or illicit opioids have been seen in the media with alarming frequency. For example, on Mar 17 2017, three Ohio children discovered their parents dead in bed of an apparent opioid medication overdose. In another gut-wrenching story, a panicked two-year-old from Massachusetts is seen on video attempting to revive her mother, who is unconscious on the floor in a store from an opioid overdose. The opioid epidemic has reached staggering proportions to the point where “[i]t is no longer a shock to see drug users collapse in public,” a September 2016 article in the New York Times stated.
 

Research Shows Certain Gene Variants May Be Linked to Addiction to Opioids

 
Both the ability to metabolize opioids and your susceptibility to becoming dependent on them are grounded in your genetic makeup, according to research published in Addiction Science and Clinical Practice “Pharmacogenetics: A Tool for Identifying Genetic Factors in Drug Dependence and Response to Treatment” (Dec 2010). 
Specifically, the impact of genetic variation on responses to several drugs of abuse including opioid pain medications and several variations have been implicated in likelihood for addiction and dependence. The article states that drugs including opioids activate the pathways that play an essential role in drug reward and reinforcement as well as a general sense of calm and well-being.
 

Your Genetics Can Indicate Your Risk for Overdose

 
Additionally, this study reveals how several oral opioids, such as codeine, oxycodone, and hydrocodone, are metabolized by another enzyme, which gives the users a feeling of a “high.” Some genes are highly variable, with some of these variations leading to a completely inactive enzyme. Individuals who inherit such “defective” alleles from both parents are referred to as “poor metabolizers” and thus less likely to become dependent.
Individuals proven to be poor metabolizers of these drugs are also more susceptible to toxicity and overdose at standard doses. Conversely, individuals who are “fast metabolizers” are more prone to addiction.
 

Pharamcogenetic Testing for Opioids with Rxight®

 
MD Labs’ Rxight® is the most comprehensive pharmacogenetics program available on the market, grounded in the analysis of 18 genes and their alleles. The Rxight® genotyping technology tells you how you might respond to over 200 clinically relevant prescription and over-the-counter medications, including 15 common opioid pain medications. This genetic guidance can help you determine if you could have an adverse reaction at standard doses, or conversely not respond to the medication. Rxight® specifically identifies whether you are a slow, normal or rapid metabolizer of the medications on the panel. It also flags the medications that could be of concern to you and your prescribers. Since your DNA does not change, your Rxight® test results are good for life.
 
Contact Rxight® by phone (888) 888-1932 or email us at info@rxight.com to get started today.

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Utility of PGx Testing in Hospitals Bolstered by Research on the Pharmacogenetics (PGx) of Antiplatelet Response

By | CMS Cardiac Bundle, Provider | No Comments

MD Labs Has Turnkey PGx Program for Hospital Implementation

Target Audience: Hospital Executives; Hospital-based Cardiologists, Quality Directors and Pharmacists
 
There is mounting evidence on the cost saving opportunities of applying Pharmacogenetic (PGx) testing following percutaneous coronary intervention (PCI) and coronary stent procedures. In concert with an interventional cardiologist, MD Labs has developed a PGx protocol for Catheter Labs that U.S. hospitals are in the process of adopting. This is of particular importance given the new CMS Cardiac Bundle being introduced into hospitals.
 
The benefits of this protocol are bolstered by studies such as the one in Expert Opinion on Drug Metabolism & Toxicology “The pharmacogenetic control of antiplatelet response: candidate genes and CYP2C19” (July 2015) which surveyed clinical outcomes of using pharmacogenetics to guide antiplatelet therapy used for preventing ischemic events in patients with acute coronary syndromes (ACS), percutaneous coronary intervention (PCI) and other indications. The pharmacogenetics of available antiplatelet agents – aspirin, clopidogrel, prasugrel and ticagrelor – were analyzed.
 

CYP2C19 Implicated in Clopidogrel Response Variability

 
The authors found abundant data in its literature meta-analysis supporting the clinical validity of CYP2C19 and clopidogrel response variability among ACS/PCI patients, stating “[t]he increased risks for reduced clopidogrel efficacy among ACS/PCI patients that carry CYP2C19 loss-of-function alleles should be considered when genotype results are available.” It was also found that “insufficient candidate genes” have thus far been implicated for prasugrel or ticagrelor.
 

The Clinical Utility of Pre-emptive PGx Testing for Plavix

 
The authors concluded by citing the need for pre-emptive PGx testing for clopidogrel (Plavix), for which they found a “clear association” with CYP2C19, explaining that pre-emptive pharmacogenetics testing would circumvent the issue of the need for rapid turnaround which is one of the frequently cited barriers to implementing CYP2C19 genetic testing for antiplatelet therapy.
 
A  pre-emptive approach – as offered by genotyping platforms such as MD Labs’ Rxight® – would integrate CYP2C19 genotype data into cath labs and the patient EMRs to alerts prescribers through clinical decision support at the point-of-care if and when clopidogrel is ordered and the patient carries an at-risk CYP2C19 genotype.
 
“Although this model has inherent challenges … pre-emptive CYP2C19 genetic testing has recently been deployed at several academic medical centers,” the authors stated. The authors called for “an ongoing effort towards the application of clinical pharmacogenetics by increasing clinician education and acceptance.”
 

CMS Cardiac Bundle Paves Way for PGx Testing for ACS Patients

 
With the coming of the CMS Cardiac Bundle program for hospitals (effective Oct 1, 2017) there is now added financial incentive to implement PGx testing as part of the standard of care for cardiac patients about to undergo antiplatelet pharmacotherapy.
 
1,200 participating hospitals in 98 metropolitan areas in the U.S. are mandated to be held financially accountable for the costs of heart attacks and bypass surgery under the CMS protocol for cardiac care.  There is therefore significant incentive to reduce costs through various measures such as integrating PGx testing into standing orders for coronary stent procedures and percutaneous coronary interventions (PCIs). For these treatments, anti-platelet pharmacotherapy is an established standard of care to reduce thrombotic risk, with Plavix (clopidogrel) as a first-line agent tested.
 

Implementing PGx in Your Hospital

 
A crucial part of MD Labs’ Rxight® turnkey program is the incorporation of PGx trained and certified pharmacists as part of the protocol to serve as expert resources for physicians and to provide consultations with the patients; pharmacist involvement in patient care has been shown to reduce hospital readmission rates.  DNA test kits are provided by MD Labs, and results are accessible via online provider and patient portals. Contact MD Labs (1-888-888-1932 or info@rxight.com) for details on the PGx protocol as applied to PCI and stent procedures, and how to integrate the Rxight® pharmacogenetics program into your cath lab.

Another Study Confirms Financial Benefit of Pharmacogenetic Testing for Patients Receiving a Stent

By | CMS Cardiac Bundle, Provider | No Comments

Contact MD Labs to Learn How You Can Implement PGx in Your Cath Lab

 
Target Audience: Hospital Executives, Hospital-based Cardiologists, Quality Directors and Pharmacists
 
Evidence continues to grow demonstrating the financial utility and cost-saving opportunity of applying Pharmacogenetic (PGx) testing following coronary stent procedures and percutaneous coronary intervention (PCI). MD Labs, working with an interventional cardiologist, has developed a PGx protocol for Catheter Labs that is being adopted by hospitals around the country. This is especially important given the new CMS Cardiac Bundle being introduced into hospitals.
 
The benefits of this protocol are reinforced by the article “Financial Analysis of CYP2C19 Genotyping in Patients Receiving Dual Antiplatelet Therapy Following Acute Coronary Syndrome and Percutaneous Coronary Intervention” published in the Journal of Managed Care and Specialty Pharmacy (Jul 2015). This study, discussed in the article, analyzed the financial impact of CYP2C19 genotyping for a set of patients with ACS who received percutaneous coronary intervention and coronary stent implantation and were treated with clopidogrel, prasugrel, or ticagrelor in a managed care setting.
 

CYP2C19 Metabolism Determines Clinical Response and Adverse Events in Plavix Users

 
Diminished CYP2C19 activity impairs clopidogrel metabolism and thereby increases risk of adverse clinical outcomes. Specifically, slow and intermediate CYP2C19 metabolizers treated with clopidogrel suffer higher cardiovascular event rates – including myocardial infarction, stent thrombosis, and stroke – than patients with normal CYP2C19 genotypes, and conversely rapid metabolizers are found to be hypo-responsive. It was concluded from the study that clopidogrel should be used as a first-line agent for all but this subset of patients.
 

Pharmacogenetics Reduces Costs by an Estimated $444K Annually, per One Thousand Patients

 
A budget impact analysis based on market share rates was conducted using overall and average cost per patient modelling based on the rate of CYP2C19 genotyping in a theoretical patient cohort. The magnitude of the financial impact from CYP2C19 genotype-guided antiplatelet therapy was emphasized, and it was expected that use of CYP2C19 genotyping would displace market share from clopidogrel to either prasugrel or ticagrelor. Total estimated annual costs of adverse clinical outcomes (e.g., MI, bleeding, stroke) and antiplatelet treatment were measured. The analysis showed an estimated annual savings of roughly $444,852 when PGx was employed in all patients in the theoretical 1,000 person cohort versus none.
 
Contact MD Labs to learn more. 1-888-888-1932 or info@Rxight.com

More Time To Prepare for the CMS Cardiac Bundle Program – Start Date Pushed to Oct 1 2017

By | CMS Cardiac Bundle, Provider | No Comments

Contact MD Labs to Learn How You Can Implement PGx in Your Cath Lab

 
Target Audience: Hospital Executives, Hospital-based Cardiologists, Quality Directors and Pharmacists
 
The CMS (Centers for Medicare & Medicaid Services) has pushed the implementation of its bundled payment initiatives for cardiac care from July 1 to Oct. 1, 2017, according to an interim final rule posted to the Federal Register “Medicare Program; Advancing Care Coordination Through Episode Payment Models (EPMs); Cardiac Rehabilitation Incentive Payment Model; and Changes to the Comprehensive Care for Joint Replacement Model; Delay of Effective Date.”
 

New Start Date Gives Hospitals Additional Preparation Time

 
The three-month delay “allow[s] time for additional review, to ensure that the agency has adequate time to undertake notice and comment rulemaking to modify the policy if modifications are warranted, and to ensure that in such a case participants have a clear understanding of the governing rules and are not required to take needless compliance steps,” the interim rule stated.
 

The Utility of PGx Testing for Hospital Cost Reduction

 
Under the CMS bundled payment initiative, participating hospitals in 98 metropolitan areas in the U.S. are mandated to be held financially accountable for the costs of heart attacks and bypass surgery, and thus have incentive to reduce costs through various measures such as integrating PGx testing into standing orders for coronary stent procedures and percutaneous coronary interventions (PCIs). For these treatments, anti-platelet pharmacotherapy is an established standard of care to reduce thrombotic risk, with Plavix (clopidogrel) as a first-line agent tested.
 
Pharmacogenetic testing is shown to reduce drug-related complications and readmission rates, thus sparing added costs to hospitals and providers, as discussed in a recent report out of the University of Illinois Hospital & Health Sciences System, which demonstrated that pharmacogenetic testing reduced 90-Day ER and Hospital Readmission Rates by 68 percent.
 

Contact MD Labs for Information on the CMS Initiative and its Turnkey PGx Testing Program

 
Contact MD Labs (1-888-888-1932) or info@Rxight.com) for details on the PGx protocol as applied to PCI and stent procedures, and how to integrate its Rxight® PGx program into your hospital lab.
 
A cornerstone of MD Labs’ Rxight® program is incorporating PGx trained and certified pharmacist as part of the protocol, as pharmacist involvement in patient care is also proven to help reduce readmission rates. The Rxight® Program provides turnkey implementation and includes pharmacist training in PGx and certification to conduct PGx consultations. DNA test kits are provided by MD Labs, and results are accessible via online provider and patient portals.

FDA Warns of Psychiatric Adverse Events from ADHD Medications

By | ADHD Medications, Adverse Drug Reactions | No Comments

Medications commonly used for ADHD (attention deficit/hyperactivity disorder) may carry an increased risk of triggering some of the same psychiatric symptoms as those seen in schizophrenia and mood disorders, even in patients who did not have previous psychiatric problems. These psychiatric symptoms include psychotic episodes marked by auditory or visual hallucinations, paranoia, delusions, and mania.
 
ADHD is a condition that affects approximately 10 percent of the pediatric population in the U.S., according to estimates by the Centers for Disease Control and Prevention (CDC). The primary symptoms of ADHD are inattention, hyperactivity, and impulsivity. Individuals with ADHD may have difficulty functioning in work or school, and suffer with issues of low self-esteem or depression.

 
On February 21, 2007, the Food and Drug Administration issued a requirement that ADHD drug manufacturers inform patients about the associated adverse psychiatric symptoms (FDA Asks Attention-Deficit Hyperactivity Disorder (ADHD) Drug Manufacturers to Develop Patient Medication Guides). The FDA warned about psychotic events from the use of ADHD medications in its 2006 briefing “Adverse Events Associated with Drug Treatment of ADHD: Review of Post marketing Safety Data,” presented to the Pediatric Advisory Committee: “The most important finding of this review is that signs and symptoms of psychosis or mania, particularly hallucinations, can occur in some patients with no identifiable risk factors, at usual doses of any of the drugs currently used to treat ADHD.”

 
Stimulant medications prescribed for ADHD include Focalin (dexmethylphenidate hydrochloride), Adderall (amphetamine), Dexedrine (dextroamphetamine), Vyvanse (lisdexamfetamine) and Ritalin (methylphenidate hydrochloride). All these ADHD medications are tested as part of the Rxight® genetic testing panel, which is designed to analyze your body’s ability to metabolize these and over 200 other common prescription and over-the-counter medications.

 
The Rxight® pharmacogenetic test is grounded in the analysis of a set of genes and their alleles to determine how you will metabolize different medications and assimilate them into the body based on your unique genotype. If you are a so-called “fast metabolizer” of a particular medication, you process the drug and therefore may require a higher than normal dose to achieve therapeutic benefit. Conversely, if you are a “slow metabolizer” you are prone to toxic effects from the medication and its metabolites building up in your system and causing potentially serious adverse reactions, such as a stimulant intoxication in the case of ADHD medications.

Amphetamines for ADHD: Side Effects, Dangers and Addiction

By | ADHD Medications, Adverse Drug Reactions | No Comments

Amphetamines are a distinct class of drugs that stimulate the central nervous system producing an increase in awareness, alertness and wakefulness. This class of stimulant drugs is sometimes used in the treatment of ADHD (attention-deficit/hyperactivity disorder) as well as obesity and narcolepsy, but they are not widely accepted for use due largely to the risks of addiction and the resulting withdrawal symptoms that ensue when amphetamines are abruptly stopped.  Some of the common amphetamines that are prescribed include Ritalin (methylphenidate) and Adderall (a mixture of amphetamine and dextroamphetamine) used for ADHD, and Ephedrine (ephedrine sulfate) for use as a bronchodilator. Other amphetamines on the market include: Dextrostat, Concerta, Levoamphetamine, Ritalin, Dexedrine, Focalin and Vyvanse.

 

Amphetamine Side Effects

 
Amphetamines have many adverse side effects on the brain, the central nervous system, and the user’s body.  The neurotransmitters norepinephrine and dopamine are released from nerve endings within the brain when amphetamines are used and the ability of the neurotransmitters to reuptake is inhibited.  This causes an influx of the neurotransmitters at the synapses or the nerve endings of the brain which can lead to various side effects.  When the nerve cells within the brain and the spinal cord are activated by the use of amphetamines, there is an increase in mental alertness and the ability for the user to stay awake. Increased focus and the ability to concentrate are also present.  That is why amphetamines are sometimes used in the treatment of ADHD, to help those with focus disorders and in the treatment of sleep disorders such as narcolepsy.

 

Addiction and Serious Adverse Reactions to Amphetamines

 
The FDA has reported that amphetamines have a high potential for abuse. Untoward effects of amphetamines include the risk of hypertension, particularly with a higher than recommended oral dose.  Insomnia is a common side effect.  Unrecognized underlying cardiovascular disease may cause serious results.  Excessive or prolonged use of amphetamines can have several negative side effects including ulcers, psychosis, and damage to the central nervous system.  Long term use of amphetamines can lead to an increased physical dependence on and tolerance to the drugs.

 
Immediate side effects of ADHD medications can be dangerous, even life-threatening. Amphetamines can also lead to heart attack, stroke or death caused by increased strain on the heart.  Blood pressure increases with increased doses of amphetamines put the user at even greater risk for heart attack or stroke. Amphetamines are highly addictive drugs and should never be used recreationally. If you want to more know more information about how the drug will react to your body before taking the drug, genetic testing will provide you with information about how it will react to your genome. Talk to your provider about any prescription for these medications, and carefully monitor the patient while taking these medications.

 

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