DIABETES UPDATE 2018 Jerome V. Tolbert, M.D., Ph.D. Assistant Professor of Medicine Icahn School of Medicine at Mt. Sinai Division of Endocrinology and Bone Diseases 317 East 17 th Street New York, New York 10003
Purpose and Objectives PURPOSE Review and understand the ADA 2018 guidelines. OBJECTIVES Review New Diabetes Medications Review Recent cardiovascular Outcome Studies Understand the importance of Good Glycemic Control FINANCIAL DISCLOSURE Speakers Bureau for Astra Zeneca
Agenda Case study Glycemic targets Diabetic medications Guidelines
A Case: Mr. O.J. Naranja Mr. Naranja is a 43-year old cook. He is excited about his weight loss without even really trying, from 350 lbs down to 300 lbs (height 6 ft). When prompted, he admits that he drinks a lot ( only healthy stuff, like freshly squeezed orange juice! ) and has polyuria / nocturia 3x/night. Random blood sugar at 3pm is 327 mg/dl. 4
Diagnosing Diabetes A1c 5.7-6.4% = pre-diabetes 6.5% or greater = diabetes, never PoC 5 Fasting Postprandial or random
Mean glucose levels for specified HgbA1C levels Mean Plasma Glucose* Mean Fasting Glucose Mean Premeal Glucose Mean Post-meal Glucose Mean Bedtime Glucose A1C% mg/dl mg/dl mg/dl mg/dl mg/dl 6 126 <6.5 122 118 144 136 6.5-6.99 142 139 164 153 7 154 7.0-7.49 152 152 176 177 7.5-7.99 167 155 189 175 8 183 8-8.5 178 179 206 222 9 212 10 240 11 269 12 298 These estimates are based on ADAG data of ~2,700 glucose measurements over 3 months per A1C measurement in 507 adults with type 1, type 2, and no diabetes. The correlation between A1C and average glucose was 0.92. A calculator for converting A1C results into estimated average glucose (eag), in either mg/dl or mmol/l, is available at http://professional.diabetes.org/eag. ADA. 6. Glycemic Targets. Diabetes Care. 2015;38(suppl 1):S35; Table 6.1
New approach is Commensurate with Natural History of ALL DM Age 0-15 15-40+ 15-50+ 25-70+ Macrovascular Complications IR Phenotype Disability MI CVA Amp IGT ALL DM DEATH ETOH BP Smoking Eye Nerve Kidney Risk of Dev. Complications Blindness Amputation CRF Disability Microvascular Complications
A1c is 11% - You provide nutritional guidance (no more OJ!) What s your best initial medical treatment option? 1. No meds, see how he does on new diet, return to clinic in 3 months 2. Metformin 500mg twice a day 3. Glyburide 10mg twice a day 4. Sitagliptin 100mg daily 5. Insulin glargine 10 units daily 6. Insulin glargine 15 units daily, finger stick every morning, uptitrate dose 1 unit every day until fasting BG <130 mg/dl
Starting insulin - When the A1c is >10%, there is a high likelihood of glucose toxicity: Beta cells may (temporarily) stop making insulin. It is best to start insulin. Patients may regain their ability to make endogenous insulin and respond to non-insulin treatments after a few weeks. - Despite the low starting dose, it is safe to say that the patient will need more insulin. Write for testing supplies (BG meter, lancets, strips; write your insulin Rx for a larger amount (e.g. 50 units daily = 5 pens/mo); don t forget pen needles 31G 5/16 for pens or syringes 0.5 ml 31G short needles for vials.
Dipeptidyl Peptidase-4 (DPP-4) Inhibitors Sitagliptin Saxagliptin Linagliptin Alogliptin
Recognize CV benefits of some DM MEDS Bromo-QR Metformin/DPP-4 inh Neutral Adverse Modified from Abdul-Ghani, Diabetes Care July, 2017
A. β-cell-centric Construct: Egregious Eleven Basis for New Guideline for DM Care 4. Colon/Biome Probiotics DPP-4 Inh* GLP-1 RA ***WR 1. Liver Metformin INSULIN RESISTANCE 2. Adipose 3. Muscle TZDs** Metformin*** 5. Immune Dysregulation/ Inflammation DPP-4 Inh.* GLP-1 RA***WR (anti-inflammatories Immune Modulators 4. Stomach/ Small intestine GLP_1 RA***WR Pramlintide Alpha Glucosidase Inhibitors** Amylin 1. Pancreatic β-cells β-cell function β-cell mass 2. Incretin effect DPP-4 Inh* GLP-1 RA***WR Insulin FINAL COMMON DENOMINATOR 3. α-cell defect DPP-4 Inh* Glucagon HYPERGLYCEMIA GLP-1 RA***WR Pramlintide 5. Kidney SGLT-2 Inhibitors ***WR 6. Brain GLP-1 RA***WR Bromocriptine-QR** Appetite Suppressants *Logic for CV risk/outcome reduction exists **Supporting evidence exists ***Prospective Evidence-Based Data Exists WR- weight reduction
Logic for (early) Combination therapy- Use least number of Agents that treat most number of mechanisms of hyperglycemia
EMR- CDMP can take patient specific data and apply Therapeutic Principles Across Continuum of Care eg: Right Drug for Right Patient and vice versa
Glycemic targets Glycemic goals in adults <7% in general, pre-prandial 80-130 mg/dl, peak postprandial < 180 mg/dl <6.5% if no hypoglycemia and if safely achievable <7.5% in T1DM <8% in elderly patients or short life expectancy, frequent hypoglycemia, high CV risk, cannot achieve despite major effort Hypoglycemia (low BG): Screen for unawareness, frequency, severity, symptoms, BG <70 mg/dl Severe or repeated hypoglycemia: warrants change in management
General Goals for glycemia Ismail-Beigi, NEJM 4/2012
Insulin Secretagogues: Sulfonylureas Glipizide Glyburide Glimepiride
Dipeptidyl Peptidase-4 (DPP-4) Inhibitors Sitagliptin Saxagliptin Linagliptin Alogliptin
Incretin Effect Increased release of insulin in response to oral glucose administration as compared to intravenous administered glucose The effect is due to the release of gastrointestinal peptide hormones (Incretins) from GI endocrine cells, which increase insulin release in response to the ingestion of food The main incretins are glucagon-like polypeptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) Patients with type 2 diabetes have a decreased incretin effect, which is due to a decrease in the secretion of GLP-1 decreased insulin secretion GLP-1 is rapidly metabolized by dipeptidyl peptidase IV (DPP- IV) 2 therapeutic strategies to help overcome the decreased incretin effect: More stable GLP-1 Inhibit DPP-IV
Sitagliptin (Januvia ), Saxagliptan (Onglyza ), Alogliptin (Nesina ), Linagliptan (Tradjenta ) Pharmacokinetics (Sitagliptin) Mechanism of Action Inhibitors of Dipeptidyl Peptidase-4 Increase circulating levels of native GLP-1 and GIP (glucose- dependent insulinotropic polypeptide) reduction post-meal glucose excursions by: Increasing insulin release Decreasing glucagon level Cost: Expensive! Typical dosing: Sitagliptin 100mg po daily; or in a patient with CKD: Linagliptin 5mg po daily Oral bioavailability of over 85% Half-life of ~12 hours Primarily excreted in the urine (87%), minimal liver metabolism Adverse Effects and Associated Contraindications/Precautions Upper respiratory infections Stuffy/runny nose Headache Rare allergic reactions small excess risk for hospitalization for acute pancreatitis: only 2 additional cases per 100 patients over a 3-year period Reduce dose in patients with renal impairment (except for Linagliptin)
SGLT2 Inhibitors Canagliflozin Dapagliflozin Empagliflozin
Canagliflozin (Invokana ), Dapagliflozin (Farxiga ), Empagliflozin (Jardiance ) Mechanism of Action Pharmacokinetics Sodium-glucose transporter inhibition Prevents glucose reabsorption in the proximal tubule glucosuria Oral, once daily Adverse Effects and Associated Contraindications/Precautions Cost: Expensive! Typical dosing: Empagliflozin 10mg daily, Canagliflozin 100mg daily. You do not get that much greater effect w higher doses Urinary tract infections Genital mycotic infection Increased urination Elevated creatinine Elevated fracture risk DKA Expert Rev. Clin Pharmacol. 6)5), 519-539 (2013)
Empagliflozin improves CV risk and slows CKD Progression Empagliflozin 10mg, 25mg, Placebo RCT w 7020 subjects over 3.1 yrs Composite outcome: death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke Empagliflozin: HR 0.86 for primary CV outcome Empagliflozin: HR 0.61 for CKD progression No difference in heart attacks or stroke, but substantially reduced all-cause mortality (rr - 0.32) and CHF hospitalization (rr -0.35) Zinman et al, NEJM 9/2015 Wanner et al., NEJM 6/2016 24
O.J. Naranja returns for follow-up after 6 months. He did not come back because his sugar has been great, now on insulin glargine 84 units daily and metformin ER 1500mg daily Fasting BG always <130 mg/dl, often under 80 mg/dl. He is upset about his weight gain of 20 lbs, to now 320 lbs (BMI 43). A1c is 8.4%. What s going on? Mount Sinai 25
Any of the following steps will be helpful except: 1. Add a GLP-1 agonist 2. Add acarbose with meals 3. Add short-acting insulin with meals 4. Referral for weight loss surgery 5. Increase insulin glargine further, to 100 units daily 26
Glucagon-Like Polypeptide-1 (GLP-1) Receptor Agonists Exenatide / Exenatide QW Liraglutide, Dulaglutide, Albiglutide
Holst JJ, et al. Trends Molec Med. 2008;14:161-168.
Summary Summary Take a patient centric approach when selecting diabetic medications. Combination therapy should be used in most patients with uncontrolled diabetes. Consider a GLP-1 receptor agonist or SGLT 2 inhibitor medication which may have cardiovascular benefits. 29
Contact Information Jerome V. Tolbert, M.D., Ph.D. Assistant Professor of Medicine Icahn School of Medicine at Mt. Sinai. Division of Endocrinology, Diabetes and Bone Diseases jerome.tolbert @mountsinai.org 212-844-1273