Type 2 diabetes is increasingly prevalent New Therapies for Diabetes Lynn Mack, M.D. Associate Professor Diabetes, Endocrinology, & Metabolism The Nebraska Medical Center lmack@unmc.edu No Conflicts of Interest Globally, 387 million people are living with diabetes 1 This will rise to 592 million by 2035 1 At least 68% of people >65 years with diabetes die of heart disease 2 Hazard ratio (95% CI) (diabetes vs no diabetes) 3 2 1 0 CV death 1. IDF Diabetes Atlas 6th Edition 2014 http://www.idf.org/diabetesatlas; 2. Centers for Disease Control and Prevention 2011; 3. Seshasai et al. N Engl J Med 2011;364:829-41 Mortality risk associated with diabetes (n=820,900) 3 All-cause mortality Number of Medication Classes 12 SGLT-2 inhibitors 11 10 9 8 7 6 5 4 3 2 Diabetes Drug Classes Increasing Rapidly Sulfonylureas Biguanides GLP-1 Receptor Agonists TZDs α-glucosidase inhibitors Biguanides DPP-4 inhibitors Amylinomimetics Glinides Dopamine agonists Bile acid sequestrants 1 Insulin (1922) 1950 1960 1970 1980 1990 2000 2010 Matching Pharmacology to Pathophysiology Hepatic Glucose Output DeFronzo 1988; White, 1998 -Glucosidase Inhibitors Metformin (Thiazolidinediones) Glucose Influx Hyperglycemia Peripheral Glucose Uptake Insulin Secretagogues Thiazolidinediones (Metformin) Insulin Secretion 5 Oral Antihyperglycemic Monotherapy Maximum Therapeutic Effect on A1C Nateglinide Acarbose Repaglinide Rosiglitazone Pioglitazone Glimepiride Glipizide GITS Metformin Starlix Miglitol, Glycet Prandin Avandia Actos 0-0.5-1.0-1.5-2.0 Reduction in A1C (%) Diabetes Care. 2000;23:202-207; Precose (acarbose) package insert; Drugs. 1995;50:263-288; J Clin Endocrinol Metab. 2001;86:280-288; Diabetes Care. 2000;23:1605-1611; Diabetes Care. 1996; 6 19:849-856; Diabetes Care. 1997;20:597-606; Am J Med. 1997;102:491-497 Amaryl Glucotrol XL
The Incretin Effect GILA MONSTER 7 8 Actions of GLP-1 Exenatide (Byetta, Bydureon) Subcutaneous injection Given within 1 hour before the morning & evening meals (bid) Average A1c reduction 0.8-1.0 Side effects: nausea, vomiting Weight loss average 5-6 lbs 9 10 Liraglutide ( Victoza) Once a day GLP-1 agonist Dosed at 0.6, 1.2 and 1.8mg doses Contraindications- not to be used in patients with family History of Medullary thyroid cancer or MEN syndrome. Common side effects Nausea, headache diarrhea, hypoglycemia Less common Pancreatitis, urticaria (Byetta ) (Victoza ) (Bydureon ) (Tanzeum ) (Trulicity ) (Lyxumia )
Trulicity Victoza GLP-1 Receptor Agonists Byetta (exenatide) 2 times per day Victoza (liraglutide) Once a day Bydureon (exenatide ER) Once a week Trulicity (dulaglutide) Once a week Januvia* Onglyza* Tradjenta-no renal dose adjustment Nesina* FDA Alert 8/15: Class may cause severe & Disabling joint pain (*reduce dose for renal function)
SGLT-2 Inhibitors Filtered glucose load ~180 g/day Urinary glucose <0.5 g/day Glucose reabsorption occurs in the proximal tubule through the action of SGLT1 and SGLT2 X SGLT-2 Inhibitors Side effects/contraindications: Moderate to severe renal impairment (less efficacy when GFR <45 60, current agents have variable label restrictions) Hypotension Genital mycotic infx UTI Don t use with loop diruretic SGLT2 Inhibitors Change in HbA1c in 12-16 Week Monotherapy Studies of SGLT2 Inhibitors Compounds in development Canagliflozin (Invokana ) Dapagliflozin (Farxiga ) Empagliflozin (Jardiance ) Ipragliflozin (Suglat ) Development status Approved by FDA (March 2013) Approved by FDA (January 2014) Approved by FDA (August 2014); Approved in Japan (January 2014) Ipragliflozin Jaridance 16 wk study in Canagliflozin Empagliflozin Japanese patients 12 wk study in Japanese patients (N=383) 12 wk study (N=408) (N=129) 100 mg qd 200 mg qd 300 mg qd Placebo 5 mg qd 10 mg qd 25 mg qd Placebo 50 mg Placebo 0.6 Mean 0.4 change in HbA1c (%) 0.2 from baseline 0-0.2-0.4-0.6-0.8-1 Mean Baseline HbA1c, % 8.09Statistical significance not reported 7.9 8.32 Inagaki N, et al. Presented at ADA, 2011 (abstract #0999-P); Ferrannini E et al. Diabetologia. 2010;53(suppl 1):S351; Kashiwagi A, et al. Presented at EASD Annual Meeting, Empagliflozin & Ipraglifloxin not FDA Lisbon, 12-16 September 2011 (abstract #149). approved
Change in Body Weight in 12-Week Add-on to Metformin Studies of SGLT2 Inhibitors Perspectives on SGLT2 Inhibition Canagliflozin (placebo adjusted values) Empagliflozin 12 wk study (N=451) 12 wk study (N=495) 100 mg 200 mg 300 mg 300 mg 50 mg qd qd qd qd bid Sitagliptin 1 mg qd 5 mg qd 10 mg qd 25 mg qd 50 mg qd Placebo Sitagliptin Placebo 1 0.5 0 Mean change in -0.5 body weight (kg) -1 from baseline -1.5-2 -2.5-3 -3.5 Baseline body weight, kg 87 Statistical significance not reported Potential Advantages Once daily administration Decreases FPG, PPG, A1c Weight loss (60g urine glucose = 240 kcal/day= ½ lb/week) No/ Low risk of hypoglycemia Modest blood pressure lowering Effect independent of insulin secretion or insulin resistance Use complementary with other T2D Rx-?T1D,? Pre-diabetes Potential for use in Type 1 Diabetes Concerns Bacterial urinary tract infections Fungal genital infections May not be as effective in patients with renal impairment Transient initial period of dehydration, polyuria, thirst No known long-term effects on kidney and on CV outcomes Added cost to diabetes therapy FDA alert 5/15: all 3 drugs may cause ketoacidosis Rosenstock J, et al. Diabetes Care 2012;35:1232-38; Seman L, et al. Presented at EASD Annual Meeting, Lisbon, 12-16 September 2011 (abstract #147) Empagliflozin not FDA approved EMPA-REG Trial- CV death Empagliflozen prevented 1 in 3 CV deaths, 38% RR reduction in cv mortality, 32% RR reduction in all cause mortality Zinman, B et al NEJM 2015 SGLT-2 & CV risk: Class effect to lower risk? Lower glucose with low risk of hypoglycemia Lower BP Lower weight Silvio Inzucchi, MD: Possible explanation is that people with T2DM often have diastolic dysfunction which may progress to mild heart failure-maybe SGLT-2 preventing heart failure, which in turn reduces sudden death Tend to increase HDL & LDL but mild impact
Newer insulins: Glargine (Lantus) U-300 (Toujeo) Get more insulin with smaller volume A1c reduction: 1.5 2.0% Lower risk of hypoglycemia Extended duration of action Less weight gain Consider in those who take large doses of insulin for better absorption Newer Insulins U500 insulin (500 u/ml) -Concentrated regular insulin; pharmacologic profile similar to NPH; use in severe insulin resistance, example patient needing over 200 u/d of insulin -total insulin requirement 0.5 to 1 u/kg/d, dose bid to qid, most commonly tid Afrezza- inhaled insulin Mealtime ( short-acting) insulin Use with long-acting insulin Not for use in those with asthma, COPD, or smokers Need to check FEV1 before and after starting treatment (and also 6 mo, 12 mo after) Side effects- cough, headache, hypoglycemia FDA approved insulin coming soon: Degludec Degludec (Tresiba) A1c reduction: 1.5 2.0% reduction Extended duration of action: ½ life 25 hours; duration 42 hours More flexibility with dosing Multiple concentrations Lower risk of night-time hypoglycemia What else is coming? GLP-1 agonist/basal insulin combination: Novo Nordisk: Xultophy (degludec/liraglutide) Phase 3 trial: a1c lowered 1.8% at 1 yr, wt loss 0.4 kg vs degludec arm where a1c lowered 1.4% with 2 kg wt gain, more hypoglycemia Sanofi: LixiLan (lixisenatide/glargine) Phase 2 trial: a1c lowered 1.8% vs 1.6% with Lantus alone Case 1 41 y/o female with diagnosis of diabetes & breast cancer in pregnancy at about 20 weeks, treated with NPH 8-0-0-8 & Humalog 1-2 units at meals during pregnancy (and given chemotherapy for breast cancer) Delivered elsewhere, stopped testing sugars once home 8 weeks post partum admitted with glucose over 500 to outside hospital, + urine/serum ketones, but GAD negative, detectable c- peptide Discharged on Toujeo 40 units daily + Humalog pens 8 units per meal Afraid to take the above doses of insulin so didn t take it, since discharge from hospital on diet alone fingerstick BS 196, 142, 89, 250 She still has the Toujeo pen at home, she weighs 50 kg, she eats a low CHO diet, insurance is Medicaid, she will be undergoing resection of left breast soon. What now?
Case 2 51 y/o female with T2DM diagnosed 4 yr ago with worsening control when put on prednisone for sciatica & prednisone now stopped. PCP referred her for consideration of an insulin pump. Taking Levemir 53 u q HS with Novolog sliding scale at meals, metformin 2000 mg per day (Actos in past caused significant LE swelling). BMI 33 & gained 20# since starting insulin, works with PT 2x per week for sciatica. She wants help with meal plan & is planning to start a swim program. A1c 8.3%. Fingerstick blood sugars tested 2x per day: fasting 113 to 144, 2 hours after supper 124 to 200 (no hypoglycemia) Should she be started on an insulin pump? Inzucchi S, Diabetes Care 2015 Case 2 (con t) Main indication for insulin pump: hypoglycemia & not a problem for her This patient interested in improved glucose control & weight loss Suggestion: Bydureon weekly, reduce Levemir to 40 units, continue metformin 3 week f/u by e-mail with her reducing Levemir to 30 units since clinic visit: fastings 85 to 150 and day sugars 107 to 167 Summary Many options now to manage diabetes Preference for treatments that are either weight neutral or promote weight loss, have low risk of hypoglycemia, low side effect profile, not cost prohibitive, & lower CV risk Balance the above with what patient/insurance will pay