Faculty Disclosure. Type 2 Diabetes: Making Sense of New Therapies. Educational Need/ Practice Gap. Objectives. Current Diabetes Prevalence Data

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1 Faculty Disclosure Type 2 Diabetes: Making Sense of New Therapies Nothing to disclose Kristen Stakelin MD, CDE Associate Professor of Medicine Medical Director Adult Endocrinology UK Barnstable Brown Diabetes and Obesity Center Educational Need/ Practice Gap Gap: Many practitioners are not utilizing newer, antidiabetic therapies with high potential effectiveness in their own patient population Need: More information, education, and examples of when and how to use these medications Objectives Upon completion of this activity, participants will be able to: Discuss new and emerging therapies for the treatment of Type 2 Diabetes Be able to identify patient types that would be appropriate candidates for such therapies Expected Outcome What is the desired change/ result in practice resulting from this educational intervention? Improved awareness of newer antidiabetes medications and therapies, and greater comfort in prescribing those therapies for appropriate patients Current Diabetes Prevalence Data Total: 29.1 million- 9.3% of total population;11.3% adults 95% have type 2 diabetes Undiagnosed: 8.1 million Over age 65: 27% diabetes; 60% prediabetes Ethnic disparities: NA 17%, AA13%, W 7.6% Prediabetes: 35% of adults 1

2 Kentucky Diabetes Pike 14.4%,Fayette 9.8%,Boone 8.9% Type 2 DM More Lethal than T1DM Clinical and mortality outcomes were compared for ~400 type 1 and type 2 dm pts diagnosed age15 30 Median observation of 22 yrs Significant excess mortality for type 2: 11%vs 6.8% Death occurred with shorter disease duration Greater prevalence of microalbuminuria in type 2 Neuropathy scores and macrovascular complications increased in type 2 Constantino. Diabetes Care on line July 11, ADA-EASD Position Statement: Management of Hyperglycemia in T2DM ANTI HYPERGLYCEMIC THERAPY Therapeutic options: Lifestyle Weight optimization Increased activity level Healthy diet Diabetes Care, Diabetologia. 19 April 2012 Impact of Intensive Lifestyle on use and cost of medical services ILI resulted in: 11% fewer hospitalizations, 15 % shorter hospital stays 6% fewer medications Average cost savings per person of $5280 Diabetes Care 2014;37: Obesity Management to Treat T2DM Diet, PA, Behavioral therapy should be prescribed for overweight/obese ready to lose weight Such intervention should be high intensity ( 16 sessions over 6 mos) To achieve weight loss > 5% short term high intensity VLCD 800 kcal/d should be considered in selective pts by trained practitioners with close medical monitoring 2

3 Obesity Management to treat T2DM Minimize medications associated with weight gain Consider bariatric surgery for BMI >35 for those unable to control with lifestyle Bariatric surgery pts require lifelong lifestyle therapy support Weight loss drugs are adjunctive to intensive lifestyle support programs NWCR: Long Term Maintenance of Weight Loss Subjects in the National Weight Control Registry have lost at least 30 lbs and kept it off for at least 1 yr (avg=5.7 yrs) All eat a low calorie low fat (25%) diet All engage in high levels of physical activity: > 2800 kcal/week All self monitor weight at least weekly Most (80%) report eating breakfast daily Avg TV viewing < 150 minutes daily McGuire.1998.IntJObesity.22:572 Wyatt.2002.ObesRes.10:78 14 ADA Physical Activity Recommendations Physical Activity Regular PA glucose, CV risk factors, contributes to weight loss and well being Minimum of 150 min/wk moderate intensity aerobic activity (50 70 % maximum heart rate) If no contraindications, resistance training three times per week Breaking Up Prolonged Sitting Reduces Postprandial Glucose and Insulin Responses 24% 30% Diabetes drug costs on runaway pace as prices soar 300% (Health News Aug2015) In 2014 spending on diabetes drugs higher than any other class of traditional drugs(expr scrip) Less than half scripts were for generics Humalog increased 36% in 1 year Annual health care spending for people with diabetes $10,000 more than nondiabetics Diabetes Care 2012;35:976 Diabetes medication costs expected to increase 18% per year: 60 times greater than increases in family incomes 18 3

4 The Landscape of Glucose Altering Medications 9 Classes of Oral Meds: SU, metformin, glinides, TZDs, glucosidase inhibitors, DPP-4 inhibitors, colesevelan, bromocriptine, SGLT-2 inhibitors 3 Classes of injectables: insulin (including 19 products), GLP-1 agonists, amylin analog Hypoglycemia and weight gain are common side effects of the most frequently used drugs except metformin (which carries multiple precautions and has a significant GI side effect profile) 19 Diabetes Treatments Drug class Mechanism of action Expected HbA1c Cost Side effects/ contraindications Metformin Insulin sensitizer 1 1.5% $ GI upset; CI in CKD Sulfonylureas Insulin secretagogue 1 1.5% $ $$ Weight gain, hypoglycemia Glinides Insulin secretagogue 1% $$ Weight gain, hypoglycemia Alpha glucosidase inhibitors Block GI absorption of carbs 0.5% $$ Flatulence, GI upset TZDs Insulin sensitizer 0.5 1% $ Edema, weight gain, osteoporosis GLP 1 mimetics Incretin action 0.5 1% $$$ GI distress, pancreatitis DPP 4 inhibitors Augments incretins 0.5 1% $$$ URTIs SGLT2 inhibitors Increase renal clearance of glucose 0.5 1% $$$ UTIs, dehydration GLP 1 Mimetics Class itself is not new exenatide (Byetta) launched in 2005 Followed by liraglutide (Victoza /Saxenda ) in 2010, exenatide (Bydureon ) in 2012, albiglutide (Tanzeum ) and dulaglutide (Trulicity ) in 2014 GI tract Ingestion of food Role of Incretins in Glucose Homeostasis Release of gut hormones Incretins 1,2 Active GLP-1 & GIP Inactive GLP-1 DPP-4 enzyme Inactive GIP Beta cells Alpha cells DPP-4 = dipeptidyl-peptidase 4 1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20: Ahrén B. Curr Diab Rep. 2003;2: Drucker DJ. Diabetes Care. 2003;26: Holst JJ. Diabetes Metab Res Rev. 2002;18: Pancreas 2,3 Glucose-dependent Insulin from beta cells (GLP-1 and GIP) Glucose dependent Glucagon from alpha cells (GLP-1) Glucose uptake by muscles 2,4 Glucose production by liver Blood glucose Pros of GLP 1 Mimetics Good A1c lowering without hypoglycemia Potential for weight loss/ appetite supression Option of weekly dosing Decreased CV risk 4

5 Adverse Reactions Gastrointestinal: nausea, cramping, diarrhea Headache Injection site reaction Dizziness Hypoglycemia is rare Precautions/ Warnings Pancreatitis Renal impairment Hypoglycemia with concomitant sulfonylureas or insulin consider decreased doses Gastroparesis Hypersensitivity Increased INR with concomitant warfarin Contraindications Medullary thyroid carcinoma/ Thyroid C cell tumors Multiple Endocrine Neoplasia type 2 Personal history of pancreatitis Hypersensitivity Pediatric patients no studies Incretins and the Pancreas Studies by Singh 1 and Butler 2 suggested increased risk of pancreatitis and pancreatic neoplasia with incretin therapies Subsequent reviews by Endocrine Society, ADA, NIDDK and EMA found significant methologic problems with studies Data incomplete/inconclusive Calls for further release of unpublished data and independent analysis No change in current prescribing directions recommended Exenetide/ Bydureon Weekly GLP 1 injectables Not as easy as it sounds Apply needle Turn dial until green disappears and click is heard Tap against palm until reconstituted/ solution is clear, rotating pen every 10 taps Turn dial until orange disappears Inject hold until click is heard and count to 10 before removing 5

6 Albiglutide/Tanz eum When 2 shows in window, rock back and forth 5 times. Place in cup for 15 or 30 minutes, then rock 5 times again Turn dial to 3 (hear click) and it is ready to inject Hear click and count to 10 before withdrawing needle Dulaglutide/ Trulicity Does not need reconstitution Pull base cap straight down Place pen against skin Turn to unlock Inject and hold until second click Consider Use 2 nd or 3 rd line agent especially in high CV risk patients Add on to insulin therapy break the cycle of weight gain and increasing insulin doses In type 2 diabetics needing to lose weight (5 6 lb) As a bridge to insulin therapy GLP 1 agonist and basal insulin combination: a meta analysis 15 studies, 4300 subjects Greater reductions in A1c than other combinations No increased risk of hypoglycemia Mean weight reduction of 3.2kg Compared to basal bolus insulin: greater A1c reduction, less hypoglycemia and mean weight reduction of 5.6 kg Lancet Sept 2014; epub 34 LEADER Trial Liraglitude Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results A Long Term Evaluation Multicenter international study presented 6/13/16 at ADA Scientific Sessions and published in NEJM online simultaneously Began in 2010; studied 9340 high risk adults with T2DM for years. Subjects received either 1.8 mg once daily liraglutide or placebo and primary endpoint was the first of 3 major CV events: CV death, nonfatal MI, or nonfatal stroke Coming Soon 1 St Basal insulin GLP 1 combo launching soon Oral GLP 1 mimetics Results showed decreased risk of all 3 events compared to placebo, including a 22% lower rate of CV death 6

7 SGLT-1 and SGLT-2 SGLT2 Inhibitors Two sodium glucose transporters, cause glucose reabsorption, have been identified: SGLT-1 and SGLT-2 SGLT-2 is found only in the proximal tubule of the kidney, accounts for 90% of the reabsorption of glucose SGLT-1 is found in the gut and other tissues, account for approximately 10% of glucose reabsorption SGLT2 inhibitors SGLT2-I Canagliflozin (Invokana ) 1 st in class March 2013 Dapagliflozin (Farxiga ) 2014 Empagliflozin (Jardiance ) 2014 SGLT2 Potential Benefits A1C lowering 50% of patients achieved A1c <7% (baseline 8%) Superior to sitagliptin as add on to metformin/su: A1c reduction 1% v. 0.66% Superior to glimeperide in combo with metformin: A1c reduction 0.93% v 0.81% Weight loss: 3% of body weight Lower BP Consider Use 2 nd or 3 rd line agent Desire weight loss HTN Edema Lancet 2013;382:941 7

8 SGLT2 Adverse Effects Genital mycotic infections Urinary tract infections Dehydration Hypotension Polyuria SGLT2 Warnings and Precautions Hypotension particularly in renal impairment, the elderly, patients on diuretics, ACE, or ARB Ketoacidosis regardless of blood glucose level AKI consider temporarily discontinuing in settings of decreased oral intake or fluid loss Hypoglycemia consider decreasing insulin or sulfonylureas SGLT2 Warnings and Precautions cont. Hypokalemia Bone fracture Increased LDL levels Drug interaction with digoxin SGLT2 Contraindications Severe renal impairment (GFR <45), ESRD, dialysis Hypersensitivity Not recommended in pregnancy, lactation, or severe hepatic impairment Euglycemic DKA and SGLT2 inhibitors (Diabetes Care. Sept 2015;38:1687) 13 cases of euglycemic DKA in 9 pts. Factors included concomitant infection, reduced insulin doses, increased activity, alcohol ingestion Normal glucose levels led to delayed recognition by pt and providers All responded to fluids and insulin Pts need to be counseled extensively 47 Empaglifozin (Jardiance ): a game changer? Evidence that lowering glucose convincingly reduces CV events is tenuous EMPA REG trial 7000 pts with type 2 DM and high CV risk were assigned to standard care plus placebo or empagliflozin and observed over 3 years Empag treated pts had a 38% risk reduction of death from CV disease, 35% risk reduction of hospitalization for CHF, 32% risk reduction of death from any cause A1c difference: Empag 7.8% vs placebo 8.1%.. Zinman. NEJM.2015;373:

9 Exciting New Era in Diabetes Management? For the first time, there are now not one, but two trials that are showing cardiovascular benefit, with an antidiabetic drug rather than just lack of harm In EMPA REG, separation between the curves came early, whereas in LEADER separation starts early and diverges over time Likely 2 different mechanisms for CV benefit Does the combo of the two provide even more benefit? Insulin Regimens Basal add-on to orals Premixed add-on to orals (human vs analog) Basal plus (one bolus with largest meal) Basal-bolus (MDI) with fixed bolus or carb counting +plus correction Insulin plus GLP1 or pramlintide Insulin pump 50 New Concentrated Insulins U300 insulin glargine (Toujeo ) offers a smaller depot surface area leading to a reduced rate of absorption Degludec (Tresiba ) available as U100 or U200: FDA approval 9/15 U200 Lispro (Humalog ): unchanged pharmacokinetics Garber AJ. Diabetes Obesity Metab; [Epub ahead of print; published online 31 Oct 2013]. Owens DR, et al. Diabetes Metab Res Rev. 2014;30(2): Steinstraesser A, et al. Diabetes Obes Metab Feb 26. [Epub ahead of print]. Accessed March 11, High Concentration Glargine U300: Toujeo U300 insulin glargine offers a smaller depot surface area leading to a reduced rate of absorption Provides a flatter and prolonged pharmacokinetic and pharmacodynamic profiles and more consistency Half-life is ~23 hours Steady state in 4 days Duration of action 36 hours Garber AJ. Diabetes Obesity Metab; [Epub ahead of print; published online 31 Oct 2013]. Owens DR, et al. Diabetes Metab Res Rev. 2014;30(2): Steinstraesser A, et al. Diabetes Obes Metab Feb 26. [Epub ahead of print]. Accessed March 11, U300 Glargine Dispensed only in pens 300 units per ml/ 1.5 ml per pen= 450 units per pen 3 or 5 pens per pack 1:1 conversion Can dial up to 80 units in one dose in increments of 1 unit of insulin Degludec/ Tresiba Longest duration of action may be dosed any time of day/ may change the time of day for schedule changes or missed doses 25 hour half life 42 hour duration Steady state 3 4 days Available as u100 and u200 1:1 conversion 9

10 Degludec Pens U units per ml 300 ml/ 300 units per pen 5 pens per pack Max dose per injection 80 units (1 unit increments) U units per ml 300 ml/ 600 units per pen 3 pens per pack Max dose per injection 160 units (2 unit increments) Use of concentrated insulins Overnight hypoglycemia High dose/ high volume Basal insulin wearing off < 24 hours Schedule changes Contraindications concentrated insulins Hypoglycemia Hypersensitivity Not for use in DKA Adverse Reactions concentrated insulins Hypoglycemia Allergic reactions Injection site reactions Lipodystrophy Weight gain Edema Rash Itching U-500 Insulin Used in patients with severe insulin resistance, requiring > 200 units /day Available only as Regular insulin Pharmacokinetic peak similar to NPH (8-12 hrs) and duration up to 24 hrs Typically used BID : breakfast and supper (60:40) but pts requiring higher doses can inject TID with meals (40:30:30) Not combined with other insulins Cochran. Diabetes Care.2005; 28:

11 U 500 insulin Dose with extreme caution inadvertent overdose may result in life threatening hypoglycemia Dose in milliliters: example pt on 200 units total dose U100, will be on 40 total units U 500. Divide BID (60:40) for 24 units QAM and 16 units QPM. Rx will read: Humulin Regular U 500, 0.24 ml (24 syringe units) QAM with food and 0.16 ml (16 syringe units) QPM with food U 500 KwikPen 1:1 conversion from U100 dose if A1c >8%; use 80% of u100 dose if A1c <8% 3 ml pen holds 1500 units 2 pens per pack Max dose in 1 injection is 300 units (5 unit increments) Make sure pt understands that dose from U 500 bottle/ vial is very different from pen as taking a pen dose from the vial would result in significant overdose Afrezza Rapid Acting inhaled insulin only inhaled insulin currently available To be used in combination with long acting insulin in type 1 or type 2 diabetics Not recommended for DKA Not recommended in patients who smoke or who quit smoking < 6 months Afrezza Product of MannKind Corporation FDA approval June 2014; Launch February 2015 Marketed initially by Sanofi with MannKind, but Sanofi ended its bid to market the drug in early 2016 due to low prescribing volume and revenue Mannkind is re launching with better pricing and more appealing with convenient titration packs and hand held in office spirometer devices Healthline online 6/20/2016 Afrezza Peak serum concentration in minutes and declines to baseline in approximately 180 minutes Comes with the inhalation device and 4, 8, or 12 unit cartridges 11

12 Afrezza contraindications Hypoglycemia Chronic lung disease Hypersensitivity Afrezza Adverse Effects Hypoglycemia Cough Throat pain Headache Afrezza Warnings/Precautions Acute bronchospasm Decrease in FEV1: baseline spirometry, 6 months, then annually 2 cases lung cancer in clinical trials Hypokalemia Hypersensitivity Edema Case 1 51 yr old woman diagnosed with diabetes 2 years ago, currently on Metformin 2g/d She now presents with vaginal itching, nocturia and a 15 lb weight loss She had 2 pregnancies resulting in 9-10lb infants Her BMI is 32 kg/m 2 BP 140/90; smoker FBS is 225 mg/dl, HbA1c is 8.5 % Case 1. What would you recommend? A. Add DPP-4 inhibitor B. Add Insulin C. Add a GLP-1 agonist D. Add a sulfonylurea E. Add a SGLT2 inhibitor Case 2 56 yo male with T2DM for 5 years PMH: HTN, GERD Smokes 1 ppd Takes metformin, and a sulfonylureacompliant with meds A1C 8.7% BMI 39 GFR 60 Referred by PCP to start insulin, but pt is very anxious due to requirement of CDL for his job 12

13 Case 2. What would you recommend? A. Add DPP-4 inhibitor B. Add Insulin C. Add a GLP-1 agonist D. Add a sulfonylurea E. Add a SGLT2 inhibitor Case 3 60 yo male with 20 year h/o T2DM Has CKD, HTN, HL, and peripheral neuropathy and chronic low back pain that keep him sedentary Quit smoking 10 y ago Takes 100 units glargine BID, and also takes aspart several times per day, but has trouble quantifying it. He thinks it s probably units depending on what he eats or how I feel. Tests FSBG in the mornings and maybe 1 other time per day Diet is high fat/ high CHO country cooking A1C is 10.1% Case 3. What would you recommend? Insulin Pump Therapy A. Set a base meal dose plus correction to add to his current glargine dose B. Change his glargine to U300 C. Add a GLP-1 agonist D. Change his insulin to humulin regular U 500 E. Refer for insulin pump therapy 76 Insulin Pump Therapy Pumps are a delivery device for SQ rapid analog insulin Patients must be competent in basal bolus therapy including carb counting Self glucose monitoring is required at least 4 6 times per day Pump therapy requires more decision making by the patient.. Smart pumps do not exist! DKA can occur if insulin delivery is stopped for a few hours Out of pocket expenses are significant This requires graduate school level of competence Insulin Pump Therapy is NOT For people who are tired of their diabetes A bionic pancreas A fix it for uncontrolled diabetes Required for type 1 diabetes 78 13

14 Continuous Glucose Monitoring Measures glucose in the interstitial fluid on a continuous basis/ 24 hours per day All studies to date done on T1 diabeticsshows improved glycemic control ADA endorses for diabetics on intensive insulin/mdi regimens Very useful in frequent hypoglycemia and hypoglycemia unawarenes Medicare does not cover Continuous Glucose Monitoring Continuous Glucose Monitor: Dexcom 14