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Primary Prevention Strategies: Aspirin, GLP-1 Agonists, Metformin Clinical Guidelines

Explore clinical pearls on aspirin, GLP-1 agonists, metformin, and psychotropic drug monitoring for primary prevention. Understand the latest guidelines and trial results to optimize patient care.

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Primary Prevention Strategies: Aspirin, GLP-1 Agonists, Metformin Clinical Guidelines

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  1. Primary Care Clinical Pearls: Aspirin in Primary Prevention, GLP-1 Agonists, Metformin, Psychotropic Drug Monitoring Nathan Bertsch, PharmD Mitchell Elting, MD

  2. Pearls of Wisdom • Most patients should not take aspirin for primary prevention of cardiovascular disease • We recommend standardized psychotropic drug monitoring to improve patient safety • Glucagon-like peptide-1 receptor agonists (GLP-1a) are becoming more realistic to use in practice • There are many strategies and compelling reasons to encourage patients to revisit the use of metformin

  3. Aspirin for Cardiovascular Primary Prevention • Current guidelines: • USPSTF (2016): • Ages 50-59 years with ≥10% 10-year-risk of CV disease • AND not at increased risk of bleeding • AND with a life expectancy of at least 10 years • AND willing to take low-dose ASA for at least 10 years • Also consider for age 60-69 years with >10% 10-year-risk of CV disease • Evidence is insufficient for different age groups U.S. Preventive Services Task Force. Final recommendation statement. Aspirin to prevent cardiovascular disease and colorectal cancer: preventive medication. April 2016

  4. Aspirin for Cardiovascular Primary Prevention • Current guidelines: • AHA/ASA (2014): • Adults with a 10-year CVD risk >10% • Potential benefit is high enough to outweigh potential aspirin risks • Women with stroke risk high enough that aspirin benefits outweigh risks (to prevent stroke) • Patients with chronic renal disease with eGFR 30 to 45 mL/min/1.73 m2 (to prevent stroke) Meschia JF, Bushnell C, Boden-Albala B, et al. Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association

  5. Aspirin for Cardiovascular Primary Prevention • Current guidelines: • ADA (2018): • Consider for patients with diabetes and increased CV risk • e.g., patients ≥50 years of age with at least one additional major risk factor: • Family history of premature atherosclerotic CV disease • Hypertension • Dyslipidemia • Smoking • Albuminuria • Are NOT at increased risk of bleeding American Diabetes Association. Standards of Medical Care in Diabetes-2018. Diabetes Care 2018;41(Suppl 1):S1-159

  6. Aspirin for Cardiovascular Primary Prevention New Studies in 2018

  7. Aspirin for Cardiovascular Primary Prevention • ARRIVE (n = 12,546): • Multinational trial • Enteric-coated aspirin 100 mg once daily vs placebo for primary prevention of CV events in men ≥55 with two to four risk factors and women ≥60 years of age with three or more risk factors • CV events: CV death, MI, unstable angina, stroke, or TIA • Risk Factors: estimated 10-year CV risk of about 10% to 20% per the 2013 ACC/AHA pooled cohort equations calculator • Patients with a history of GI bleed, frequent NSAID use, antiplatelet or anticoagulant use, or diabetes were excluded. Gaziano JM, Brotons C, Copolechhia R, et al. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomized, double-blind, placebo-controlled trial.

  8. Aspirin for Cardiovascular Primary Prevention • ARRIVE Trial Results: • Aspirin was not beneficial during 5 years of follow-up, but doubled the risk of GI bleeding • CV event rate: 4.29% vs 4.48%, HR 0.96, 95% CI 0.81 to 1.13, p=0.6038 • GI bleed rate: 0.97% vs 0.46%, HR 2.11, 95% CI 1.36 to 3.28, p=0.0007. • The actual 10-year CV event rate was lower than estimated (about 8% to 9%), perhaps due to optimization of modern medical therapies (e.g., statins, antihypertensives), making the study population essentially a low-risk population. • The GI bleed event rate was similar to the expected event rate.

  9. Aspirin for Cardiovascular Primary Prevention • ASCEND (n = 15,480): • Compared enteric-coated aspirin 100 mg once daily to placebo in patients ≥40 years of age with diabetes (but no evidence of cardiovascular disease) for prevention of CV events • CV events: vascular death, MI, stroke, or TIA ASCEND Study Collaborative Group. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med 2018 Aug 26. doi: 10.1056/NEJMoa1804988.

  10. Aspirin for Cardiovascular Primary Prevention • ASCEND Trial Results: • Aspirin provided some benefit for prevention of serious vascular event • 8.5% vs 9.6%, rate ratio 0.88, 95% CI 0.79 to 0.97, p= 0.01 • NNT = 91 over 7.4 years to prevent one CV event • No benefit was seen for any specific event (e.g., MI), and benefit was mainly seen in the first five years of use • Benefit was largely offset by bleeding events • NNH = 112 over 7.4 years to cause one major bleeding event

  11. Aspirin for Cardiovascular Primary Prevention • ASPREE (n = 19,114): • Multinational trial • Enteric-coated aspirin 100 mg once daily vs placebo in patients ≥70 years of age (African Americans or U.S. Hispanics ≥65 years of age). • Patients taking antiplatelets or anticoagulants were excluded, as were patients with BP ≥180/105 mmHg. • Patients were allowed short-term use of NSAIDs at the lowest dose. • 11% of enrollees had diabetes. McNeil JJ, Nelson MR, Woods RL, et al. Effect of aspirin on all-cause mortality in the healthy elderly. N Engl J Med 2018 Sep 16. doi: 10.1056/NEJMoa1805819

  12. Aspirin for Cardiovascular Primary Prevention • ASPREE (n = 19,114): • Aspirin did not reduce CV events • Increased the risk of major bleeding • 8.6 vs 6.2 events per 1,000 person-years, p<0.001 • There was no evidence that any subgroup responded differently, including patients with diabetes.

  13. Aspirin for Cardiovascular Primary Prevention • Bottom Line: • Aspirin DOES NOT likely provide net benefit for primary prevention in… • Patients ≥70 years of age • Nondiabetics with an estimated 10-year event rate <20%, especially those with increased bleeding risks • Essentially, most patients should not take Aspirin for CV primary prevention: • This is a BIG change, and it may take the guidelines time to catch up • Bleeding risks offset benefits • Aspirin for primary prevention doesn't seem to decrease CV events in other patients, even those with multiple CV risks

  14. Aspirin for Cardiovascular Primary Prevention • What about diabetics? • Aspirin's benefits are nearly a "wash" in patients with diabetes • Using aspirin for about 7 years may avoid a CV event in one in 90 patients...at the cost of major bleeding event in one in 110 (ASCEND trial)

  15. Aspirin for Cardiovascular Primary Prevention • Who can benefit from Aspirin use? • Aspirin 81 mg/day for SECONDARY prevention • Patients with a prior heart attack or stroke, peripheral artery disease, or angina • In these cases, CV benefits clearly outweigh bleeding risks. • What can I recommend instead for CV primary prevention? • Lifestyle recommendations: • DASH or Mediterranean diet • Adherence to HTN and statin meds • Smoking cessation • Talking points with patients about Aspirin as CV primary prevention: • Benefits and risks are usually a toss-up, bleeding risk higher in at risk populations • Bleeding risk increases with age • Aspirin is one more pill to take.

  16. Aspirin for Cardiovascular Primary Prevention • What about “rebound” CV events? • Is a major concern in secondaryprevention, especially with a coronary stent • However, bleeding risk with aspirin for primary prevention likely outweighs any possible CV risk of stopping it Clinical Resource, Aspirin for CV Primary Prevention and More. Pharmacist’s Letter/Prescriber’s Letter. November 2018.

  17. Psychotropic Drug Monitoring

  18. Follow-Up Intervals for Behavioral Health

  19. Psychotropic Drug Monitoring • Antidepressants • Baseline: TSH and CBC. EKG if pt > 40 yo or starting tricyclic antidepressant (TCA). • Routine: Yearly CBC, CMP, and PHQ-9. • Antipsychotics • Baseline: CMP, lipids, AIMS, and EKG. • Routine: CMP, lipids, and AIMS test q6-12 months. EKG yearly. • AIMS tests exists as a template in some EHRs. Others may need to scan results in.

  20. Psychotropic Drug Monitoring • Lithium • Baseline (within last 3 months): TSH, CBC, and CMP. EKG if has CV risk factors or if > 40 years’ old, pregnancy test • Initiation: BMP q3months during first 6 months. TSH once within first 6 months • Routine: BMP, CBC, EKG, TSH, and Lithium level every 6-12 months. • Drug Level Frequency: Lithium level in 5-7 days after initiation and after each dose change. Repeat x 1 in 2 weeks once therapeutic. Recheck at 3 months and then q6-12 months thereafter. • Therapeutic Levels (drawn at least 8-12 hours after last dose): 0.6-1.2 mEq/L

  21. Psychotropic Drug Monitoring • Divalproex (Depakote) • Baseline (within last 3 months): CBC and CMP, pregnancy test • Initiation: Repeat CMP within 1 month of initiation. • Routine: CBC and CMP every 6 months. Valproic acid level q6-12 months. • Drug Level Frequency: Check in 3-5 days after initiation and after each dose change. Repeat x 1 in 2 weeks once therapeutic. • Valproic Acid Levels (drawn 8-12 hours after last dose): 50-125 mcg/mL • Other drugs: Carbamazepine/oxcarbazepine and stimulants (included in handouts)

  22. GLP-1 Receptor Agonists

  23. Consensus Statement by AACE and ACE on the Comprehensive Type 2 Diabetes Management Algorithm – 2018 Executive Summary: Vol 24 No. 1.

  24. Consensus Statement by AACE and ACE on the Comprehensive Type 2 Diabetes Management Algorithm – 2018 Executive Summary: Vol 24 No. 1.

  25. How Do GLP-1 Receptor Agonists Work? • Affect glucose control through several mechanisms: • Enhancement of glucose-dependent insulin secretion • Slowed gastric emptying • Reduction of postprandial glucagon and food intake • GLP-1 receptor agonists DO NOT usually cause hypoglycemia in the absence of therapies that otherwise cause hypoglycemia

  26. How Effective Are GLP-1 Receptor Agonists? • When compared to placebo, all GLP-1 agonists reduced HbA1c levels by 0.8-1.5% depending on the agent • Short acting GLP-1 RAs mainly target postprandial sugars • Long acting GLP-1 RAs target both postprandial and basal • More effect on basal than postprandial Clinical Resource, Comparison of GLP-1 Agonists. Pharmacist’s Letter/Prescriber’s Letter. January 2017.

  27. Examples of GLP-1 Receptor Agonists

  28. GLP-1 Receptor Agonist Precautions • History of pancreatitis avoid use • Case reports of both hemorrhagic and necrotizing pancreatitis • Not approved for Type 1 diabetics • Renal precautions/considerations exist for all agents • Dosing and cut-offs vary • Use with caution in patients with history of gastroparesis • Do not use in patients with a personal or family history of medullary thyroid cancer or MEN 2A or 2B • Use with caution in patients with history of hypersensitivity reactions

  29. GLP-1 Receptor Agonist Adverse Effects • GI related side effects (10-50%) • Nausea, vomiting, diarrhea • Hypoglycemia (rare) • Mainly seen when used with other diabetes medications • Insulin, sulfonylureas, meglitinides • Injection site reactions (0.2-4%) • Abscess, cellulitis, necrosis • Exenatide has higher rates (17-24%) • Immunogenicity (6.4-50%) • Antibodies to GLP-1 agonists can develop in patients – unknown implications… • Highest with exenatide • Rodent studies: benign and malignant thyroid C-cell tumors and calcitonin release • There is a major difference in rats vs humans, however. Long term data unknown

  30. The Newest GLP-1 Receptor Agonist: Ozempic (semaglutide) • Ozempic in clinical trials showed a 1.4-1.6% A1c reduction • Superior to Trulicity in head-to-head trial • Ozempic showed 2x the weight reduction when compared to Trulicity • 9-13 pound weight reduction at 40 weeks • Unique warning: 1.2% higher risk of diabetic retinopathy complications in a 2 year trial • Most risky in patients with history of pre-existing diabetic retinopathy • It is thought that rapid improvements in glucose control are a contributor to temporary worsening of diabetic retinopathy • Why the focus on Ozempic? • Ozempic will be the preferred GLP-1 agonist for many insurance companies this year (2019, Tier 3) Pratley, Richard E, Aroda, Vanita R. Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomized, open-label, phase 3b trial. Diabetes & Endocrinology. The LANCET. Vol 6, Issue 4, P275-286. April 01, 2018

  31. GLP-1 Receptor Agonist: Take Home Points • Lower risk of hypoglycemia compared to insulin and sulfonylureas • GI symptoms are the most common complaint • Weight loss is a selling point for some patients • 1.5-2.5 kg over 30 weeks • Expensive • Injection site reactions seem to be more common/bothersome than with insulin glargine

  32. Metformin

  33. Metformin – The Good • Mechanism of Action: • Decrease hepatic glucose production • Decrease intestinal absorption of glucose • Improve insulin sensitivity by increasing peripheral glucose uptake and utilization* • Grade A LOE in ADA 2019 • Preferred initial pharmacologic agent for treatment of type 2 diabetes • Prevention of type 2 diabetes in prediabetes (BMI > 35, Age <60, women with prior GDM) American Diabetes Association. 8. Pharmacologic Approaches to Glycemic Treatments:Standards of Medicare Care in Diabetes-2018. Diabetes Care 2018; 41:S73

  34. Metformin – The Good • Low risk of hypoglycemia • Modest weight loss • Great antihyperglycemic efficacy • Durable effects • Robust cardiovascular safety data • Also improves plasma lipids (TG and LDL-chol) • Recent changes by FDA expand use in CKD • Oral administration • Available in many formulations • CHEAP ($) American Diabetes Association. 8. Pharmacologic Approaches to Glycemic Treatments:Standards of Medicare Care in Diabetes-2018. Diabetes Care 2018; 41:S73

  35. Metformin – The Bad • Gastrointestinal intolerance • D, N, V, dyspepsia, abdominal pain • Vitamin B12 malabsorption/deficiency in 16% of users can lead to anemia and peripheral neuropathy • Contraindicated with eGFR< 30 mL/min/1.73 m2 • Lactic acidosis concerns Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm – 2018 Executive Summary: Vol 24 No. 1.

  36. Metformin – Practical Solutions to the Bad • Monitor B12 levels periodically or if patient develops neuropathy or anemia • Supplement • Lactic Acidosis • Discontinue in setting of acute dehydration, hypoperfusion, sepsis, or hypoxemia • Surgery, trauma, infection, fever, CHF exacerbations, iodinated contrast Singh AK, Kumar A, Karmakar D, Jha RK. Association of B12 deficiency and clinical neuropathy with metformin use in type 2 diabetes patients. J Postgrad Med. 2013;59:253-257. DAILYMED. Metformin- metformin ER 500 mg tablet. https://dailymed.nlm.nih.gov/

  37. Metformin – Practical Solutions to the Bad • Gastrointestinal Intolerance • Slow down dose escalations (every 1-2 weeks usually, up to 6 weeks) • Consider allowing patient self-titration • Take WITH FOOD! (large meal) PL Detail-Document, Improving Tolerability to Metformin. Pharmacist’s Letter/Prescriber’s Letter. December 2015.

  38. Metformin Dose-Response Curve

  39. Metformin Formulations Each EHR has a different string for ER/XR formulations and may link to a specific formulation when sent to pharmacies. Add something along the lines of “MAY SUBSTITUTE ANY GENERIC ER OR XR FORMULATION FOR THIS PRESCRIPTION” to get around this. “MAY USE 500MG OR 1000MG TABLETS FOR THIS PRESCRIPTION”

  40. A Brief Word on Formulations… • Metformin has 3 different extended-release formulations that are unique in their drug delivery • Substitution is state AND insurance dependent • Bioequivalence, AB rating, etc. • This same concept applies to MANY other medicines, and may be the source of much frustration… • Venlafaxine, bupropion, inhalers, colchicine, diltiazem, potassium chloride, PPIs, and more.. • Tablets versus capsules

  41. Metformin – Practical Solutions to the Bad • A worthy challenge…

  42. Insulin in the Community • Recent studies have come out to suggest that NPH is still a reasonable option for patients • Cost continues to be a huge concern with insulin • Humulin R, Humulin N, Humulin 70/30 (Reli-On Brands) • Walmart only… • 10mL vial (100 units/mL) = $25 • Syringes cost $13 per box of 100 • Needles cost $9 per box of 50 Lipska KJ, Parker MM, Moffet HH, Huang ES, Karter AJ. Association of initiation of basal insulin analogs vs neutral protamine Hagedorn insulin with hypoglycemia-related emergency department visits or hospital admissions and with glycemic control in patients with type 2 diabetes. JAMA 2018;320(1):53-62.

  43. Pearls of Wisdom • Most patients should not take aspirin for primary prevention of cardiovascular disease • We recommend standardized psychotropic drug monitoring to improve patient safety • Glucagon-like peptide-1 receptor agonists (GLP-1a) are becoming more realistic to use in practice • There are many strategies and compelling reasons to encourage patients to revisit the use of metformin

  44. Thank you!

  45. References • U.S. Preventive Services Task Force. Final recommendation statement. Aspirin to prevent cardiovascular disease and colorectal cancer: preventive medication. April 2016 • American Diabetes Association. Standards of Medical Care in Diabetes-2018. Diabetes Care 2018;41(Suppl 1):S1-159 • Gaziano JM, Brotons C, Copolechhia R, et al. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomized, double-blind, placebo-controlled trial. Lancet 2018;392:1036-46. • ASCEND Study Collaborative Group. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med 2018 Aug 26. doi: 10.1056/NEJMoa1804988. • McNeil JJ, Nelson MR, Woods RL, et al. Effect of aspirin on all-cause mortality in the healthy elderly. N Engl J Med 2018 Sep 16. doi: 10.1056/NEJMoa1805819 • Consensus Statement by AACE and ACE on the Comprehensive Type 2 Diabetes Management Algorithm – 2018 Executive Summary: Vol 24 No.1 • Clinical Resource, Comparison of GLP-1 Agonists. Pharmacist’s Letter/Prescriber’s Letter. January 2017. • American Diabetes Association. 8. Pharmacologic Approaches to Glycemic Treatments:Standards of Medicare Care in Diabetes-2018. Diabetes Care 2018; 41:S73 • Consensus Statement by AACE and ACE on the Comprehensive Type 2 Diabetes Management Algorithm – 2018 Executive Summary: Vol 24 No.1 • DAILYMED. Metformin- metformin ER 500 mg tablet. https://dailymed.nlm.nih.gov/ • PL Detail-Document, Improving Tolerability to Metformin. Pharmacist’s Letter/Prescriber’s Letter. December 2015. • Pratley, Richard E, Aroda, Vanita R. Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomized, open-label, phase 3b trial. Diabetes & Endocrinology. The LANCET. Vol 6, Issue 4, P275-286. April 01, 2018

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