Disclosures. Overall Goals. Objectives. What s worth the PA forms for Patients in the Safety Net? None relevant

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1 Disclosures What s worth the PA forms for Patients in the Safety Net? None relevant Janet Leung, MD ZSFG Clinical Assistant Professor of the Underserved CME Feb. 25, 2017 Objectives Consider your overall goals Consider starting A1c Consider patient factors to adherence, RF for side effects New agents GLP-1 agonists SGLT-2 inhibitors DPP-4 inhibitors CME question; Pearls Overall Goals Population goal is A1c <7% = Estimated average glucose of 154 mg/dl <8% for >80 years older limited life-expectancy Why? Limit long-term complications Limit short-term complications Infection risk, wound healing Limit symptoms For diabetics, glucosuria at glucose > 200 mg/dl 1

2 Limiting Complications Lower A1c, especially early in disease: microvascular disease and macrovascular disease many years later Limit hospitalizations, symptoms A1c increases risk of hypoglycemia A1c is not protective in insulin-dependent Hypoglycemia can be fatal: arrhythmia, neuroglycopenia, cognitive impairment Challenges of Underserved Populations Lack of insurance Lack of coverage for tes ng supplies = A1c 0.5% in per Language barriers Health literacy and numeracy Lack of refrigeration Insulin stable at room temperature x 1 month once opened May need 1 month x 11 refills rather than 3 months x 3 refills Convenience if working outside home, pen insulin (vs vial) for short-acting may improve adherence Food insecurity 1/7 Americans are food insecure Higher in ethnic and racial minority households ADA Standards of Medical Care in Diabetes p Limiting Complications: Effect of Intensive Control on Complications Study Microvasc CVD Mortality UKPDS DCCT / EDIC* ACCORD ADVANCE VADT Initial Trial Kendall DM, Bergenstal RM. International Diabetes Center 2009 Long Term Follow-up * in T1DM 2

3 Limiting Complications: Other RF: BP Limiting Complications: Other RF: Lipids Tight Glucose vs Tight Blood Pressure Control in the UKPDS AHA/ACC 2013 guidelines: Age with diabetes: statins (moderate-high) >75 with diabetes: moderate statin <40 with diabetes and not getting pregnant: discuss with patient UKPDS 33 vs 38 (Type 2 diabetes) Statins for almost all diabetics (atorvastatin now generic) Drug Options Metformin ALWAYS: keep until GFR <30 (½ dose if GFR45-60) Start low (500mg daily), at bedtime if needed, titrate up to 2g per day ~80% of patients who can t tolerate immediate release bc of GI SE are fine when switched to ER A1c > 10: start insulin with metformin Brings sugars down fastest, resolve hyper symptoms (polys) Then can titrate down/try other agents ADA Standards of Medical Care in Diabetes p Leong, Br J Diabetes Vasc Disease 2007 McGuire DK, JAMA

4 2 nd Drug after Meformin Classically, sulfonylurea (glipizide, glimepride) cheap, effective but hypoglycemia and weight gain Glimepride is daily but glipizide BID with meals (hold if not eating) TZDs: patients afraid of HF exacerbation (rosiglitazone, pioglitazone) and small risk of bladder CA, fractures (pio) A1c 1-1.5%; some risks are duration dependent Acarbose: flatulence limits use Insulin: Our Over-looked Ally Almost all forms of insurance covers some form. Walmart has vials for $24.88 If your patient can take daily medications, they are capable of taking insulin (or a family member can help them inject) If vision deficit, prescribe pen (count clicks) Ethnic minorities and women more reluctant than Caucasians and men Janson SL, Diabetes Care, 2010 Psychological Insulin Resistance My family member started insulin then was blind/had amputations/ needed dialysis/died! Answers for Patients I know it s scary that your family member has those. But it s usually caused by high sugars controlling yours now will decrease your risk of these problems. Answers for Healthcare Providers It really does! Look at the DCCT and DPP data!! Even a 1 point A1c change helps! Answers for Patients You didn t fail this is common with diabetes that overtime, your body stops producing enough insulin Hurts less than FSBG especially if reusing lancet. The fatty areas to inject have way less nerves than your fingertips! You didn t fail this is common with diabetes that over time, your body stops producing enough insulin Most patients at ~15 years will be on some insulin. Warn patients about this don t use insulin as a threat to increased medication adherence early in the disease. Answers for Healthcare Providers Use highest gauge and shortest needle - Pen: 4mm (5/32 ) x 31-32g - Syringe 6mm x 30 or 31g Most patients at ~15 years will be on some insulin. Warn patients about this don t use insulin as a threat to increase medication adherence 4

5 Uninsured in Medication USD/month DPP-4 inhibitor SGLT-2 inhibitor GLP-1 agonist Lantus & Lispro/Aspart 385 & 505 Glipizide/glimepride 9-15 TZDs 12 Acarbose 28 Walmart Walgreens Rx Savings Club* NPH & Regular (VIAL) 147 & & NPH 70/30 (VIAL) Metformin 9 $4 for IR 1g BID or $5 for IR TID; $5 for 1g 1g ER ER or $15 for 1.5g ER $4 Glip: 5mg x 30 $5 Glipizide: 5mg x 30 or or 10mg x 60 10mg x 60 DPP-4 Dipeptidyl peptidase-4 inhibitor A1c <0.7% Inhibits degradation of endogenous incretins So more insulin gets secreted and less glucagon Prices from GoodRx as of 2/2017 Walmart $4/$10 formulary without insurance *Walgreens "Prescription Savings Club" after $20/year + $5-15/mo enrollment GLP-1 Glucagon-like peptide 1 receptor agonist A1c 1-1.5% on average as add-on Stimulates GLP-1 receptors In pancreas, incretin effect: more insulin, less glucagon In brain: suppresses appetite In gut: slows emptying, increases satiety SGLT-2 Sodium Glucose Co-transporter-2 inhibitor A1c 0.5-1% Blocks glucose resorption in proximal tubule of kidney by SGLT-2 5

6 Renal Handling of Glucose (GFR L/day) x (glucose conc 90 mg/dl) = g/day filtered glucose Glucose 90% S1 10% SGLT2 SGLT1 S3 The new agents: Class Summary I rarely use DPP-4i s unless patient has predominantly prandial excursions uncontrolled by an SU + risk for dehydration or falls, and refused injectables of any sort SGLT-2 vs GLP gm No Glucose/day ( kcal) NEJM 2015: EMPA-REG trial found empagliflozin (SGLT2) decreased cardiac mortality 2016: LEADER trial found liraglutide (GLP1) decreased cardiac mortality Inzucchi SE, NEJM

7 Benefits beyond A1c and Weight SGLT-1 CV benefit thought to be class-related Study in empagliflozin (FDA labeled for CV protection) Likely applies to canagliflozin, dapagliflozin Renal protection (HR 0.61, CI vs placebo) Concern for dehydration, vulvovaginal candidasis But decreased incident/worsening nephropathy No increased risk of AKI GLP-1 agonist CV benefit in liraglutide (?unclear class effect) Renal protection (HR 0.78, CI vs placebo) Buse JB, NEJM 2016 Wanner 2016, NEJM GLP-1 agonists Liraglutide: most GI side effects, daily start with 0.6 mg, to 1.2 in 1 week, then mg daily = Saxenda (weight loss drug) Exenatide: IR (Byetta) is BID, with more GI SE Exenatide ER = Bydureon: weekly Fewer SE, but subcutaneous nodules Dulaglutide (Trulicity) Albiglutide (Tanzeum) Actually Prescribing GLP-1 Agonists Victoza (3 pens/month (18mg in 3mL/pen), pen needles x 30 days) Pen is 0.6, 1.2, or 1.8 mg dose. Max out if you can Prescribe pen needles, dial in as with insulin. Prime on first use of each pen Bydureon (4 pens/kit/month) 2mg dose only Kit (reconstitute by shaking like salad dressing) Pen (rotate and tap up to 80x against hand until clear) Both need to be shaken vigorously Trulicity (4 pens/month) 0.75 mg, and 1.5 mg dose No wait, remove stand, no need to reconstitute, needle is already on Audible 2 nd click lets you know it s done Tanzeum (4 pens/month) 30mg, and 50 mg dose 30mg dose needs to mix twist and rock x 5x, rest x 15 min, rock x 5x 50mg x 30 min Yellow liquid with air bubble, click-on included needle 7

8 Ellis SL. Ther Adv Endocrinol Metab 2015 A1c for add-on GLP-1 tx Ellis SL. Ther ADv Endocrinol Metab 2015 Weight Loss for add-on GLP-1 tx NS NS -3.8% NS NS So for A1c, liraglutide ~ dulaglutide > exenatide QW (abligutide?) > exenatide BID >~ lixisenatide Weight loss: Liraglutide > dulaglutide ~ Exenatide BID ~ exenatide weekly (?abiglutide) > lixisenatide Nausea: GLP-1 agonist: Side-Effects exenatide BID (~30%)> liraglude (18-30%) and dulaglutide (16-30%) > exenatide weekly (14-26%) > lixisenatide > albiglutide (10%) Injection site reaction: exenatide weekly (~20%) > albiglutide (~12%) > exenatide BID (~9-12%) > liraglutide (<6%) and dulaglutide (<1%) Diarrhea, abdominal pain, HR 3-5 BPM Contraindications to GLP-1 Agonists History of pancreatitis History of family history of medullary thyroid cancer or MEN2A or 2B Gastroparesis (Cholelithiasis/sludging) For exenatide, if GFR <30 Sometimes used off-label in T1DM (NOT FDAapproved!) 8

9 GLP-1 Summary In my experience, much easier to start injectable GLP-1 agonists than basal insulin Patients have less preconceived notions Low risk of lows when used alone WEIGHT LOSS! Appetite suppression Even daily is tenable for patients If you had a choice: liraglutide ~ dulaglutide > exenatide (nodules, but least GI SE) > abiglutide (less effective, laborious) Always keep on the metformin! SGLT-2 inhibitors Works by wasting glucose in the urine So the higher the glucose, the higher the polyuria and glucose loss In A1c 8, decreases A1c 0.5-1% If A1c 11, decreases A1c 2.6% Start low (dehydra on risk, hypoglycemia), then Consider pre-emptive decrease in insulin dose Be certain your patients are not Type 1 diabetics Or, if lantus dose <10 units daily, risk DKA as doesn t last 24 hr Actually Prescribing SGLT-2 inhibitors Canagliflozin (Invokana): mg before breakfast Dapagliflozin (Farxiga): 10 mg daily Empagliflozin (Jardiance): mg daily Now FDA approved for CVD Contraindications to SGLT-2 inhibitor EGFR <45 for canagliflozin and empa; <60 for dapagliflozin Relative: Ketosis prone T2DM People with recurrent UTI, GU fungal infections People at risk of AKI HyperK People with osteoporosis at risk of fracturing Meininger G et al, JCEM

10 New DM Agents Summary (1/3) Food insecurity Cheap option: Tolbutamide or glipizide with meal Oral DPP-4s as a weak precursor for prandial insulin Injectable GLP-1s are great for weight loss + glucose control Oral SGLT-2s have polyuria/access to bathroom/yeast infection/need to hydrate may be limiting SE. They work better at higher A1c (as more glucosuria, as long as can keep hydrated) New DM Agents Summary (2/3) Remember, insulin always works. Consistent basal insulin -> A1c ~8-9 Walmart s Relion $25 per vial: NPH, regular, NPH/regular 70/30 Humalog/novolog ~$200+; levemir, glargine, basaglar ~$250+ FYI: Basaglar not bioidentical to lantus Higher risk of a hypoglycemia and weight gain Your formulary and patient s co-pay will likely drive your choices New DM Agents Summary (3/3) Obesity: beyond intensive lifestyle intervention and before bariatric surgery GLP-1 agonist (esp liraglutide, dulaglutide) > SGLT-2 Cardiac disease: either SGLT-2 or liraglutide (SGLT-2 for mild HF, can likely lasix) Renal disease: slight preference for GLP-1 given risk of dehydration of SGLT2i Osteoporosis: GLP-1 > SGLT-2 (canagaflozin) Higher A1c and refuse to start insulin: SGLT-2 (can decrease A1c of 11 to 8) None of these agents are approved for T1DM Question 65 year old woman with osteoporosis, obesity (BMI 35), HTN, type 2 diabetic complicated by microalbuminuria with A1c 8 on metformin 1g BID and glipizide 5 BID, presents for evaluation. She lives alone and is scared of having hypoglycemia but will only check her sugars once a day at most. What is your best option? a) Increase glipizide to 10mg BID b) Add liraglutide daily c) Stop glipizide and add canagliflozin d) Stop glipizide and add dulaglutide once a week e) Add lantus once a day 10

11 Buzz Words 65 year old woman with osteoporosis, obesity (BMI 35), HTN, type 2 diabetic complicated by microalbuminuria with A1c 8 on metformin 1g BID and glipizide 5 BID, presents for evaluation. She lives alone and is scared of having hypoglycemia but will only check her sugars once a day at most. What is your best option? Answer a) Increase glipizide to 10mg BID Unlikely to get to A1c goal of <7 b) Add liraglutide 1.8 mg daily Liraglutide has significant side effects, so start low at 0.6 mg, and increase weekly to 1.8 mg per day as tolerated. c) Stop glipizide and add canagliflozin Unlikely to get to goal, and canagliflozin has higher risk of fracture d) Stop glipizide and add dulaglutide 0.75mg weekly Will improved glucose control and help with some weight loss. Dulaglutide + metformin is unlikely to cause hypoglycemia e) Add lantus 10 units once a day Will control his sugars but likely will increase weight gain. Higher risk of lows with concurrent glipizide. Will need titration up, Pearls for Diabetes A diet history is key in DM: not just *what* they eat but when and if: Many of our patients have high carb diets: changing it to include fiber/protein can help significantly for both glucoses, satiety, and obesity Food insecure patients: hold glipizide or short-acting insulin if not eating. Consider GLP-1, SGLT-2 End of vs Beginning of month/paycheck effect If obese, GLP-1 agonists are great If A1c >10, refuses insulin, and can keep hydrated, consider SGLT-2 If hyperglycemic + sx, start insulin early. Can always decrease/add other agents later. 11