NEW DIABETES CARE MEDICATIONS James Bonucchi DO, ECNU, FACE Adult Medicine and Endocrinology Specialists Disclosures Speakers bureau Sanofi AZ BI Diabetes Diabetes cost ADA 2017 data Ever increasing disorder. Prevalence continues to increase annually Related to obesity epidemic. $327 billion. Up 26% from 2012 which includes $90 billion in lost productivity. 30% hospital inpatient care costs 30% prescriptions to treat complications of diabetes 15% on anti diabetic medications and supplies 13% on office visits. Age Adjusted Prevalence of Obesity and Diagnosed Diabetes Among U.S. Adults Aged 18 Years or older Number and Percentage of U.S. Population with Diagnosed Diabetes, 1958 2010 Obesity (BMI 30 kg/m 2 ) 1994 2000 2010 8 7 Percentage with Diabetes 25 Diabetes No Data <14.0% 14.0 17.9% 18.0 21.9% 22.0 25.9% >26.0% 1994 2000 2010 Percentage with Diabetes 6 5 4 3 2 1 Number with Diabetes 20 15 10 5 Number with Diabetes (Millions) 0 1958 61 64 67 70 73 76 79 82 85 88 91 94 97 00 03 06 09 Year 0 No Data <4.5% 4.5 5.9% 6.0 7.4% 7.5 8.9% >9.0% CDC s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics CDC s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics 1
Prevalence of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, 2017 Prevalence estimates reflect BRFSS methodological changes started in 2011. These estimates should not be compared to prevalence estimates before 2011. GLP 1 Agents *Sample size <50 or the relative standard error (dividing the standard error by the prevalence) 30%. GLP 1 and DPP4 GLP 1 and DPP4 GLP 1 and DPP4 Ralph A. DeFronzo Diabetes 2009;58:773-795 The ominous octet. GLP 1 GLP 1 GLP 1 agents GLP 1 has incretin effect Oral glucose stimulates GLP 1 secretion Produced in small intestine L cells Receptors in beta cells, gastric mucosa, lung, heart, skin, immune cells and hypothalamus Glucose dependent insulin release from pancreatic beta cells Increases satiety Slows gastric emptying Promotes beta cell regeneration/prevents apoptosis 2009 by American Diabetes Association GLP 1 agents GLP 1 Exenatide twice daily, weekly Liraglutide daily Dulaglutide weekly Albiglutide off the market Semaglutide weekly Lixisenatide once daily or in combination with insulin glargine A1c reduction approx. 1% for the class, slightly higher in semaglutide compared to other agents. Liraglutide and semaglutide showed decrease CVD outcomes Liraglutide 3.8 year of f/u. ARR 1.3% 3 point MACE. A1c difference 0.4, weight difference 2.3 kg Semaglutide 2 years of f/u. ARR 2.3% 3 pt MACE mostly from stroke reduction. A1c difference 0.7 1%. Wt reduction 2.9 4.3 kg. 2
GLP 1 microvascular GLP 1 agonist No trials for microvascular primary outcomes to date Liraglutide: reduction in new onset persistent macroalbuminuria Semaglutide: increase in diabetic retinopathy (3 vs 1.8%), unexpected. Lixisensatide slight improve in urine albumin to creat ratio. Mortality: Meta analysis of 189 trials showed no difference in all cause mortality in incretin drugs, but sub analysis of GLP showed slight reduction in all cause mortality (7 vs 7.8%) Weight loss. Weight reduction of 1.5 2 kg for the class at 30 weeks. CV trials suggest a sustained effect GLP 1 agonists Short acting: Exenatide 5 mcg twice daily starting dose. Increase to 10 mcg twice daily. Lixisenatide 20 mg once daily. Liraglutide 0.6 mg once daily starting dose, titrate to 1.2 or 1.8 mg daily. Exenatide weekly 2 mg weekly Dulaglutide 0.75 1.5 mg once weekly Semaglutide 0.5 1 mg once weekly GLP 1 side effects Rare risk pancreatitis Exenatide and lixisenatide not for use GFR<30 Daily or weekly agents not for use with history of MTC or MEN 2A/2B Nausea/vomiting Diarrhea Injection site reaction Hypoglycemia DPP 4 inhibitors DPP4 inhibitors Dipeptidyl peptidase 4 inhibitors DPP4 enzyme is present on most cells Deactivates various enzymes including GLP 1 and GIP Increases GLP 1 levels endogenously Similar effects as GLP 1 agonists, but less robust reduction in A1c approx. 0.5% reduction in A1c added to metformin. No proven CV benefit to date based on trials. Oral agents 3
DPP4 inhibitors Sitagliptin. 100 mg oral daily. 50 GFR 30 45, 25 GFR <30 Saxagliptin 5 mg oral daily. 2.5 mg oral GFR<45 or strong CYP 4503A4/5 inhib Linagliptin 5 mg oral daily. No adjustment for GFR Alogliptine 25 mg oral daily. 12.5 mg GFR 30 60 and 6.25 mg GFR <30 DPP 4 inhibitor side effects No change in body weight. Low risk hypoglycemia Questionable immune risk, small risk of nasopharyngitis in metanalysis Acute pancreatitis reported Rare reports of hepatic dysfunction Skin reactions Possibly related to joint pain, rare. GLP 1 and DPP 4 Considered second line agents after metformin SGLT 2 Inhibitors Most endocrinologists prefer GLP 1 agents due to greater A1c reduction Weight loss weight GLP 1 agents, but injectable DPP4 inhibitors generally better tolerated from GI side effect profile DPP4 inhibitors generally cheaper 55 year old male presents with a 5 year history of diabetes. Treated with metformin, weekly exenetide With numbness/tingling in his feet that bothers him at night He tries to exercise, between a full time job and 1 kid in high school and in jr high, kids sports/activities fill up his free time. Diet, he reports this could be better but he is on the go. Last eye exam showed non proliferative stable retinopathy Labs: Cr 0.9 GFR >60 K 4.2 Na 139 A1c 8.3%, 6 months ago 7.8% (he did vow to exercise more and lose weight at last OV) Microalbumin 22 4
Smokes 1ppd x 30 years LDL 92 on Atorvastatin 20 mg a day. No history of CVD Has mild leg cramps with walking At this time, you wish to add additional therapy. Which agent would you consider adding? A. Glipizide B. Insulin glargine C. Empaglifozin D. Basal bolus insulin therapy E. Pioglitazone SGLT 2 Inhibitor FDA approved agents 2018 SGLT 2 reabsorbs approx. 90% filtered glucose load. Upregulated in Type 2 Diab SGLT 2 inhibitors block the SGLT 2 transporter. Canagliflozin Dapagliflozin Empagliflozin Ertugliflozin Results in increase glucose in the urine. Urinate out 75 125 grams of glucose a day. Reduces A1c approximately 0.8%. CV outcomes Empagliflozin 7028 patients CVD trial, mean A1c 8%, placebo controlled trial using both 10 and 25 mg dose Majority on antihypertensive including ACE/ARB Majority on statin therapy 48% taking insulin 3 year follow 3 pt MACE (death from CVD, nonfatal MI or nonfatal stroke) 1.6% ARR Death from CVD 2.2% ARR Rate of hospitalization lower for heart failure 2.7 vs 4.2% On label indication CV outcomes canagliflozin 10,142 patients across 2 CVD trials, placebo controlled Pts were taking antihypertensive and lipid lower agents including ACE/ARB and statins. 50% taking insulin 3.6 years 3 point MACE fewer in canagliflozin 26.9 vs 31.5 patients per 1000 patient years CV death reduction 1.2 ARR Rate of hospitalization from CHF 5.5 vs. 8.7 patients per 1000 pt years. Increased lower limb amputation risk Label at FDA for review 5
CV outcome Dapagliflozin (data pending later this year) and Ertugliflozin: on going trials Empagliflozin and progression of nephropathy Meier Analysis of Two Key Renal Outcomes. WannerC et al. N EnglJ Med 2016;375:323 334. Canagliflozin renal data CV trail with canagliflozin secondary outcome Progression of albuminuria lower 89.4 for treatment vs 128.7 for placebo per 1000 patient years Post hoc analysis composite outcome of sustained 40% reduction in GFR decline, need for dialysis, or death from renal disease 5.5 vs 9.0 (treatment vs placebo) per 1000 pt years. Further trials on going with these and other agents. SGLT 2 inhibitors Weight loss of 2 3 kg across the class Meta analysis shows sustained over 2 3 years. A1c reduction 0.8 1% for the class BP reduction of approx. 5 mmhg Side effects: dehydration, acute renal injury, UTI, genital mycotic infections DKA risk increased with use of the class Canagliflozin osteoporosis fractures seen in first 6 months therapy. Thought to be due falls with orthostatic hypotension. SGLT 2 intibitors Canagliflozin and empagliflozin can be used to GFR 45 Dapagliflozin and ertugliflozin can be used to GFR 60 Canagliflozin 100 mg before first meal of the day. Can increase to 300 mg a day Dapagliflozin 5 or 10 mg anytime with or without food. Empagliflozin 10 mg once daily in morning with or without food, may increase to 25 mg Ertugliflozin 5 mg once daily in AM with or without food. May increase to 15 mg daily. SGLT 2 inhibitors Monitoring renal function recommended. Not for use with ESRD or patients on dialysis Not for use in pregnancy or during lactation 6
SGLT 2 inhibitors amputation Canagliflozin CVD trial associated risk of lower limb amputation 5.9 vs 2.8 treatment vs placebo per 1000 pt years. History of prior amputation peripheral vascular disease and neuropathy higher risk Avoid use in these patient populations When to use SGLT 2 inhibitors Generally not considered first line treatment Personally consider this as 3 rd line after GLP 1 agent and metformin. Can consider after metformin in patient refusing injection therapy. Useful add on to insulin Not reported in dapagliflozin or empagliflozin Ertugliflozin across 7 phase 3 trials, lower limb amputation occurred in 1 (0/1%) placebo, 3 (0.2%) 5 mg group and 8 (0.5%) 15 mg group. Insulins At this time, you wish to add additional therapy. Which agent would you consider adding? A. Glipizide B. Insulin glargine C. Empagliflozin D. Basal bolus insulin therapy E. Pioglitazone New insulins Insulin glargine U300 Insulin degludec Insulin degludec New ultra long acting basal insulin Half life approx 36 hrs A1c reduction similar to U100 glargine and when titrated to BG low levels (70 90 range), May have less nocturnal hypoglycemia 7
Insulin glargine U300 Longer half life than U100 Glargine Lower volume Lasts approx 30 hrs Similar A1c control to glargine U100 Associated with less hypoglycemia than U100 glargine Inhaled insulin Regular insulin Powder form Inhaled just prior to meals Onset within minutes, effect gone in 90 minutes FEV1 at baseline, 6 months and annually Slight reduction in FEV1 while on med, back to baseline when off GLP 1 Insulin combinations Conclusion Great efficacy than either agent alone Associated with slight weight loss compared to weight gain with insulin monotherapy. No proven CV benefit Liraglutide insulin degludec Lixisenatide insulin U100 glargine Diabetes is an expensive disorder Life style changes and metformin are still first line New medications can help improve glycemic control and be weight neutral or weight loss Complications and hospitalizations by far are the large majority of the cost which are mostly preventable. 8