In compliance with the accrediting board policies, the American Diabetes Association requires the following disclosure to the participants: Entity Activity Financial Consideration Comments Novo Nordisk Speaker/Consultant Speaker Fees/Honoraria Active Sanofi-Aventis Speaker/Consultant Speaker Fees/Honoraria Active Janssen Speaker/Consultant Speaker Fees/Honoraria Active Lilly Speaker/Consultant Speaker Fees/Honoraria Inactive Intarcia Consultant Honararia Active Astra-Zenica Consultant Honoraria Active Discuss the American Diabetes Association Antihyperglycemic therapy recommendations for T2DM Understand the importance of co-morbidities when choosing therapy Review the recent CV risk reduction findings in regard to anti-hyperglycemic therapies Discuss how to keep the patient centered in your choice of anti-hyperglycemic medication
Second Sentence: Ongoing patient self-management education and support are critical to preventing acute complications and reducing the risk of long-term complications. Standards of Medical Care in Diabetes -2018 Diabetes Care 2018;41(Suppl.1):S1-S2. Antihyperglycemic therapy in type 2 diabetes: general recommendations. *If patient does not tolerate or has contraindications to metformin, consider agents from another class in Table 8.1. #GLP-1 receptor agonists and DPP-4 inhibitors should not be prescribed in combination. American Diabetes Association Dia Care 2018;41:S73-S85 2018 by American Diabetes Association Combination injectable therapy for type 2 diabetes. American Diabetes Association Dia Care 2018;41:S73-S85 2018 by American Diabetes Association
Medication Centric Inattentive to Diabetes Life Cycle Less focused on Co-morbid conditions Promotes Polypharmacy What are Patients Thinking? Cost Side Effects Hassle Factors Future Implications What are Physicians Thinking? Efficacy Side Effect Profile Tolerability Coverage Co-Morbid Conditions Patient Safety Economics Efficacy
Co-Morbid Conditions Patient Cardiovascular Risk Underlying CVD, Stroke, MI, PVD Renal Risk Diabetic nephropathy, declining renal Fx GI Tolerability Underlying GI conditions Obesity - Endocrine Thyroid, PCOS, others Obesity: 1999-2004 (NHANES) Type 2 patients 27% overweight and 61% were obese Dyslipidemia: 99% eligible for lipid lowering therapy 1999-2004 (NHANES) 46% had elevated lipids (NHANES) 1999-2004 HTN: 67% of T2DM patients were being treated or 14% of had patients HTN with T2DM had no co- Chronic Kidney Disease: ~40% of patients with morbidity diabetes Cardiovascular Disease: Depression, Sleep Disorders, Cancers http://outpatient.aace.com/type-2-diabetes/management-of-common-comorbidities-of-diabetes Safety Patient Can I take this medication with the other medications that I am already taking? Will this medication affect other health problems that I am having? I see the ads on TV. They scare me.
Economics Patient Will my insurance cover this new medicine? Can I afford to take this with all of my other medications? If I get a coupon or co-pay card, how long will it last? Is the benefit that I will get be worth the money that I am spending? Efficacy Patient Will it work? Will it be worth it? HTN Hyperlipidemia Obesity Social elderly, frail, falls risk CVD stroke, MI, CAD, PVD, CHF CKD GI GERD, Gall Bladder, NASH, Pancreatitis, IBS, Crohn s, Ulcerative Colitis Endocrine obesity, PCOS, Thyroid, Adrenal
Choosing Medications While Giving Consideration to Co-Morbid Conditions HTN SGLT-2 Inhibitors Volume Contraction and possible hypotension need to be considered. Canagliflozin noted with SBP reductions of 3.3 and 5.0 mm/hg at 26 weeks 1 Empagliflozin: Mean Arterial Pressure reductions of 2.3 and 2.1 mm/hg at 24 weeks 2 Dapagliflozin: reduced mean seated SBP -10.4 vs -7.3 mm/hg and mean 24 hr ambulatory SBP -9.6 vs -6.7 mm/hg at 12 weeks 1. https://www.google.com/search?q=invokana+pi&oq=invokana+pi&aqs=chrome.0.69i59j0j69i60j0l3.2423j0j7&sourceid=chrome&ie=utf-8 (Accessed 1/13/2018) 2. Chilton R, et.al. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obesity Metabolism 2015;17(12):1180-1193. Weber, MA et.al Effects of dapagliflozin on blood pressure in hypertensive diabetic patients on renin-angiotensin system blockade. Blood Pressure 2016;25(2):93-103. Hyperlipidemia: SGLT-2 Class Medications: Can cause a slight elevation in LDL Cholesterol (canagliflozin 4.5 to 8%) 1 (dapagliflozin 2.9%) 2 (empagliflozin 4.6, 6.5%) 3 TZD Class Medications: Pioglitazone can cause a reduction in triglycerides (-9.9% to -12.3%), HDL Cholesterol (-18.1 to -20.3%), LDL Chol increased (+5.2% to +9.6%) 4 1. https://www.google.com/search?q=invokana+pi&oq=invokana+pi&aqs=chrome.0.69i59j0j69i60j0l3.2423j0j7&sourceid=chrome&ie=utf-8 (Accessed 1/13/2018) 2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202293s000lbl.pdf (Accessed 1/13/2018) 3. http://docs.boehringer-ingelheim.com/prescribing%20information/pis/jardiance/jardiance.pdf (Accessed 1/13/2018) 4. Spanheimer R et.al. Long-term lipid effects of pioglitazone by baseline anti-hyperglycemia medication therapy and statun use from the PROactive experience (PROactive 14). Am J Cardiol 2009;104(2): 234-239.
Obesity: Gain: SU Class can cause weight gain TZD Class can cause fluid retention and weight gain Glinide Class can cause weight gain Insulins Neutral: DPP-4i Class Biguanides metformin Lose: SGLT-2 Class GLP-1 Class Social elderly, frail, falls risk, isolated Anything that is a hypoglycemia risk SU s Insulins Glinides Volume Depletion SGLT-2 s Economics Everything past metformin and SU s tend to get expensive Try to simplify, limit or combine medications Insured: Follow formulary as much as possible Use Coupon programs when you can Sample Access: try to limit to extreme or emergency situations
Cardiovascular Risk Pre-2008 2008 The Present CVD TZD s Pioglitazone PROactive Trial 5238 Patients with evidence of macrovascular Dse. 34.5 month avg. time of observation Primary Endpoint: All-cause mortality, non-fatal MI, stroke, ACS, revascularization coronary or leg and amputation HR 0.90; CI 0.80-1.02, p=0.095 Secondary Endpoint: All-cause mortality, non-fatal MI and stroke HR 0.84; CI 0.72-0.98, p = 0.027 Dormandy, JA, et.al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitazone Clinical Trial In macrovascular Events): a randomized controlled trial. The Lancet 2005;366: 1279-1289. CVD TZD s Rosiglitazone RECORD Trial 1 4447 Patients HR for CV Death 0.84;CI 0.59-1.18, MI 1.14; CI 0.80-1.63, Stroke 0.72; CI 0.49-1.06 Heart Failure Admission or death HR 2.10; CI 1.35-3.27. Increased risk of long bone Fx, mainly women Nissen Meta-analysis 2 42 trials, avg. age 56 y Odds ratio for MI 1.43 Odds ratio of death 1.64 1. Home,PD, et.al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicenter, randomized, open-label trial. The Lancet 2009;373:2125-2135. 2. Nissen, SE, et al. Effect of Rositglitaone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. N Engl J Med 2007;356: 2457-2471.
CVD These events should include cardiovascular mortality, myocardial infarction, and stroke, and can include hospitalization for acute coronary syndrome, urgent revascularization procedures, and possibly other endpoints. https://www.fda.gov/downloads/drugs/guidances/ucm071627.pdf CVD What is 3 pt. : Cardivascular Death Non-fatal MI Non-fatal Stroke https://www.fda.gov/downloads/drugs/guidances/ucm071627.pdf Study EXAMINE 1 CARMELINA 2 SAVOR 3 TECOS 4 DPP-4i Alogliptin linagliptin saxagliptin sitagliptin N 5380 7003 16492 14671 Duration 40 months, median 18 months 2013-2018 2.1 years 3.0 Resulted 2013 Ant. 2018 2013 2015 Primary Endpoint HR 0.95; CI upper limit 1.16 TBD 1.00; CI 0.89-1.12 0.98; CI 0.88-1.09 Results p<0.001 TBD ity p<0.001 P<0.001 1. White,W, et al. Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes. N Engl J Med 2013; 369:327-335. 2. https://clinicaltrials.gov/ct2/show/nct01897532 (Accessed 2/2/2018) 3. Green, JB. et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2015; 373:232-242.
Study CANVAS 1 DECLARE 2 EMPA-Reg 3 SGLT-2 Canagliflozin Dapagliflozin Empagliflozin N 10142 17276 7020 Duration 188.2 weeks 3.1 years Resulted 2017 Mid-2018 (anticipated) 2015 Primary Endpoint HR 0.86;CI 0.75-0.97 TBD 0.86; CI 0.74-.099 Results p<0.001 Superior p=0.02 TBD Superiority p=0.04 1. Neal,B et.al. Canagliflozin and Cardiovasculary and Renal Events in Type 2 Diabetes. N Engl J Med 2017; 377:644-657. 2. https://clinicaltrials.gov/ct2/show/nct01730534 (Accessed 2/1/2018) 3. Zinman, B et.al. Empagliflozin, Cardiovascular Outcomesn and Mortality in Type 2 Diabetes. N Engl J Med 2015; 373:2117-2128. Study CANVAS 1 DECLARE 2 EMPA-Reg 3 SGLT-2 Canagliflozin Dapagliflozin Empagliflozin N 10142 17276 7020 Duration 188.2 weeks 3.1 years Resulted 2017 Mid-2018 (anticipated) 2015 Primary Endpoint HR 0.86;CI 0.75-0.97 TBD 0.86; CI 0.74-.099 Results p<0.001 Superior p=0.02 TBD Superiority p=0.04 1. Neal,B et.al. Canagliflozin and Cardiovasculary and Renal Events in Type 2 Diabetes. N Engl J Med 2017; 377:644-657. 2. https://clinicaltrials.gov/ct2/show/nct01730534 (Accessed 2/1/2018) 3. Zinman, B et.al. Empagliflozin, Cardiovascular Outcomesn and Mortality in Type 2 Diabetes. N Engl J Med 2015; 373:2117-2128. Study ELIXA 1 EXSCEL 2 LEADER 3 REWIND 4 SUSTAIN-6 5 GLP-1RA Lixisenatide Exenatide LR Liraglutide Dulaglutide semaglutide N 6068 5400 9340 8300 2735 Duration 25 month median 3.2 years 3.8 years Up to 6.5 years Resulted 2015 2017 2016 2019 2016 Primary Endpoint + hosp for unstable angina HR 1.02; CI 0.89-1.17 Results P<0.001 0.91;CI 0.83-1.00 P<0.001 Time to event 0.87; CI 0.78-0.97 P<0.001 Superior P<0.01 Time to event TBD TBD 104 weeks Time to event 0.74; CI 0.58-0.95 p<0.001 1. Pfeffer,MA et.al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med 2015;373:2247-2257. 2. Holman,RR et al. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2017;377:1228-1239. 3. Marso, SP et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016;375:311-322. 4. ClinicalTrial.gov: https://clinicaltrials.gov/ct2/show/nct01394952 (Accessed Jan 31st, 2018) 5. Marso SP et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2016;375:1834-1844.
Study ELIXA 1 EXSCEL 2 LEADER 3 REWIND 4 SUSTAIN-6 5 GLP-1RA Lixisenatide Exenatide LR Liraglutide Dulaglutide semaglutide N 6068 5400 9340 8300 2735 Duration 25 month median 3.2 years 3.8 years Up to 6.5 years Resulted 2015 2017 2016 2019 2016 Primary Endpoint + hosp for unstable angina HR 1.02; CI 0.89-1.17 Results P<0.001 0.91;CI 0.83-1.00 P<0.001 Time to event 0.87; CI 0.78-0.97 P<0.001 Superior P<0.01 Time to event TBD TBD 104 weeks Time to event 0.74; CI 0.58-0.95 p<0.001 1. Pfeffer,MA et.al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med 2015;373:2247-2257. 2. Holman,RR et al. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2017;377:1228-1239. 3. Marso, SP et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016;375:311-322. 4. ClinicalTrial.gov: https://clinicaltrials.gov/ct2/show/nct01394952 (Accessed Jan 31st, 2018) 5. Marso SP et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2016;375:1834-1844. CVD CV Risk Reduction Canagliflozin Empagliflozin Liraglutide CV Risk: PVD and SGLT-2i Lower Extremity Amputation 1 CANVAS Trial higher risk of amputations at toes, feet or legs with canagliflozin (6.3 vs. 3.4 participants with amputations/ 1000 pt. yrs.) (HR 1.97) Highest absolute risk was with patients who had a previous amputation or PVD. 1. Neal,B et.al. Canagliflozin and Cardiovasculary and Renal Events in Type 2 Diabetes. N Engl J Med 2017; 377:644-657.
CV Risk: PVD and SGLT-2i Reasonable Recommendations: Diabetes Foot Exam Check Pulses and document Hx of PVD if questions, check Art. Duplex Hx of Amputations Interval Changes in Foot Health CKD Improve: ACE/ARB medication to improve renal function HTN Control BGM/A1c Control Cautions: Metformin DPP-4 s (linagliptin ok here as it is gut cleared) SGLT-2i GLP-1RA CKD Stage Process 1-5 based on GFR Stage 1: 120-90 ml/min/1.73m 2 Stage 2: 89-60 ml/min/1.73m 2 Stage 3a: 59-45 ml/min/1.73m 2 Stage 3b: 44-30 ml/min/1.73m 2 Stage 4: 29-15 ml/min/1.73m 2 Stage 5: <15 ml/min/1.73m 2 Cautions: Metformin
Cautions: Metformin CKD Safe Dosing for Metformin Stage 3a: 59-45 ml/min/1.73m 2 Stage 3b: 44-30 ml/min/1.73m 2 CKD Safe Dosing for Metformin Stage 2: per package Stage 3a: 500 mg am and 1 gm pm Stage 3b: 500 mg BID Stage 4: Withdraw medication/contraindicated Stage 5: Contraindicated. Metformin should be withdrawn in patients like to experience acute kidney injury in the context of severe pathologies Lalau,JD, et.al. Metformin Treatment in Patients With Type 2 Diabetes and Chronic Kidney Disease Stages 3A, 3B, or 4. Diabetes Care 2018; https://doi.org/10.2337/dc17-2231. GI GERD, Gall Bladder, NASH, Pancreatitis, IBS, Crohn s, Ulcerative Colitis, gastroparesis
GI GERD, Gall Bladder, NASH, Pancreatitis, IBS, Crohn s, Ulcerative Colitis, gastroparesis Metformin: GI Upset both upper and lower TZD s, GLP-1RA: Can be beneficial with NASH DPP-4i: Small pancreatitis risk GI GERD, Gall Bladder, NASH, Pancreatitis, IBS, Crohn s, Ulcerative Colitis, gastroparesis GLP-1RA: Pancreatitis contraindication Hx of pancreatitis Consider high triglycerides Active alcoholism Do not use with gastroparesis Endocrine obesity, PCOS Obesity: Cautions: Insulins, SU s, glinides, TZD s Beneficial: SGLT-2i, GLP-1RA PCOS: TZD s may be of benefit here
HTN Hyperlipidemia Obesity Social elderly, frail, falls risk CVD stroke, MI, CAD, PVD, CHF CKD GI GERD, Gall Bladder, NASH, Pancreatitis, IBS, Crohn s, Ulcerative Colitis Endocrine obesity, PCOS Patient Cases: A B C SU s Met TZD Glin DPP-4i -GI Insulins SGLT- 2i GLP- 1RA Case #1: 41 year old female patient with a Dx of T2DM for the past 7 years.
SU s Met TZD Glin DPP-4i -GI Insulins SGLT- 2i GLP- 1RA Case #2: 68 year old female patient with a Dx of T2DM for the past 19 years. SU s Met TZD Glin DPP-4i -GI Insulins SGLT- 2i GLP- 1RA Case #3: 39 year old male patient with a Dx of T2DM for the past 4 years. HTN Hyperlipidemia Obesity Social elderly, frail, falls risk CVD stroke, MI, CAD, PVD, CHF CKD GI GERD, Gall Bladder, NASH, Pancreatitis, IBS, Crohn s, Ulcerative Colitis Endocrine obesity, PCOS
The Standards of Medical Care in Diabetes can serve as a guide for us as we choose therapy for patients with diabetes Co-Morbid Conditions play a critical role in the health of our patients with diabetes and their choice of medications/therapy Specifically, consideration of CV risk for patients with diabetes is important in deciding therapy with your patient