Diabetes. Jens Juel Christiansen, endokrinolog

Diabetes Jens Juel Christiansen, endokrinolog

Diagnostiske kriterier for diabetes og prædiabetes 1 Ref 1: NBV 2015 Diabetes og hjertesygdom, Dansk Cardiologisk Selskab www.cardio.dk 26.2 Diagnostik af diabeteshjertepatienten

10 % 10 % 80 % 320.545 danskere har diabetes 200.000 danskere ved endnu ikke, at de har type 2- diabetes 750.000 danskere skønnes at have forstadie til diabetes (prædiabetes) 1 ud af 18 danskere har diabetes Antallet af diabetikere er fordoblet på 10 år Diabetes koster det danske samfund omkring 86 mio. kr. om dagen Antal diabetikere I Danmark var 320.545 personer diagnosticeret med diabetes pr. 31. december 2012. Det svarer til godt 5,7% af befolkningen og en fordobling af antallet af diabetikere på 10 år 1. I 2025 vil over 600.000 danskere have en diabetesdiagnose. Fordeling ift. diabetestype Diabetes 1 udgør ca. 10 % Diabetes 1 ½ udgør ca. 10 % (tælles ofte med under diabetes 2) Type 2- diabetes udgør ca. 80 % Kønsfordeling - totale antal med diabetes 1 Kvinder udgør 49 % Mænd 51 %

Diabetes type I

Actrapid Humulin Insuman Apidra Humalog Novorapid Fiasp Humulin NPH Insulatard Abasaglar Lantus Levemir Toujeo Tresiba Humant insulin Humant insulin Humant insulin Insulin glulisin Insulin lispro Insulin aspart Humant protamininsulin Humant protamininsulin Insulin glargin Insulin glargin Insulin detemir Insulin glargin Insulin degludec

Insulinpumpe

Insulinpumpe Programmering: Ens hele døgnet eller variabel i definerede døgnintervaller Bolusinsulin: Måltidsinsulin: Kulhydratratio (g/ie) antal g spist kulhydrat der dækkes af 1 IE tilført insulin Korrektionsinsulin: Insulinsensitivitet (mmol/ie) antal mmol blodsukkersænkning af 1 IE tilført insulin Basalrate-insulin: Kontinuerlig infusion: Basalrate (IE/time)

Insulinpumpe Programmering: Ens hele døgnet eller udspecificeret i definerede døgnintervaller Bolusinsulin: Måltidsinsulin: Kulhydratratio (g/ie) antal g spist kulhydrat der dækkes af 1 IE tilført insulin Korrektionsinsulin: Insulinsensitivitet (mmol/ie) antal mmol blodsukkersænkning af 1 IE tilført insulin Basalrate-insulin: Kontinuerlig infusion: Basalrate (IE/time)

Diabetes type II

Glukosemetabolisme og kardiovaskulær sygdom 1 18 Ref 1: Laakso M et al, Eur Heart J Suppl 2003;; 5 (suppl_b):b5-13 (fig. 4)

The clinical impact of type 2- diabetes is seen in a wide variety of organs 1-5 Diabetic retinopathy Leading cause of blindness in working-age adults 1 Diabetic nephropathy Leading cause of end-stage renal disease 2 Stroke 1.2- to 1.8-fold increase in stroke 3 Cardiovascular disease 75% diabetic patients die from CV events 4 Diabetic neuropathy Leading cause of non-traumatic lower extremity amputations 5 1. Fong et al. Diabetes Care 2003, vol26 suppl.1;; 2. Molitch et al. Diabetes Care 2003 vol26 suppl.1;; 3. Kannel et al. Am Heart J 1990, vol120. No3;; 4. Hogan et al Diabetes Care 2003 vol26 suppl.1;; 5. Mayfield et al. diabetes Care 2003 vol26 suppl.1 www.connectinhealth.dk

In this case, CV disease is represented by MI or stroke. *Male, 60 years of age with history of MI or stroke CVD, cardiovascular disease; MI, myocardial infarction; T2D, type 2 diabetes The Emerging Risk Factors Collaboration. JAMA 2015;314:52 Life expectancy is significantly decreased in patients with T2D and established CVD* 60 years End of life No diabetes Diabetes 6 years Diabetes + CVD 12 years

Inkretineffekten

Figure made by AstraZeneca from data in : 1. Drucker et al. Lancet 2006;;368(9548):1696-1705;; 2. Nauck et al. Eur J Intern Med. 2009;;20 Suppl 2:S303-308;; 3. Kendall et al. Am J Med. 2009;;122(6 Suppl):S37-50. The metabolic effects of Incretins 1-3 Fat Oral Intake of Glucose Satiety Pancreas Muscle Glucose uptake Glucose Insulin Incretins Glucagon Small Intestine DPP-4 enzymatic inactivation Rapid incretin inactivation Hepatic glucose production Glucose GLP-1 GIP DPP-4 Liver

Dose- response relation for effects of GLP- 1 1 Figur fra referance 1 25 Ref 1: Madsbad S Lancet 2009;373:438-9,

Ref 1: Scirica BM et al. NEJM 2013;; 369:1317-1326;; Ref 2: White et al N Engl J Med 2013;; 369:1327-1335;; Ref 3: Green et al N Engl J Med 2015;; 373:232-242 CV end points with DPP4 inhibitors 1-3 SAVOR 1 EXAMINE 2 TECOS 3 Scirica BM et al. NEJM N 2013; 369:1317-1326 fig. 1A White et al N Engl J Med 2013; 369:1327-1335 fig 2A Green et al N Engl J Med 2015; 373:232-242 fig 3A Primary endpoint: CV death, non-fatal MI, non-fatal stroke Primary endpoint: CV death, non-fatal MI, non-fatal stroke Primary endpoint: CV death, non-fatal MI, non-fatal stroke or hospitalization for unstable angina

A=B+C+D LEADER N Engl J Med 2016; 375:311-322

Alogliptin Linagliptin Saxagliptin Sitagliptin Vildagliptin Vipidia Trajenta Onglyza Januvia Galvus Dulaglutid Exanatid Exenatid Liraglutid Lixisenatid Trulicity Bydureon Byetta Victoza Lyxumia

SGLT2- hæmning

Target of SGLT2 Inhibitors 1-3 Ref 1: Forxiga SmPC Jan 2015. Ref 2: Lee YJ et al: Kidney Int suppl 2007 106; 27-35 Ref 3: Bays H; Diabetes Ther 2013; 4: 195-220

Dapagliflozin as add- on to metformin versus SU: HbA1c over 4 years 1 Head- to- head studiebeskrivelse kan ses til sidst i denne præsentation Ref 1: Del Prato S et al. Diabetes Obes Metab. 2015 doi: 10.1111/dom.12459 fig. 1 B

Dapagliflozin as add- on to metformin versus SU: weight loss sustained over 4 years 2 Head- to- head studiebeskrivelse kan ses til sidst i denne præsentation Ref 2: Del Prato S et al. Diabetes Obes Metab. 2015 doi: 10.1111/dom.12459

Empagliflozin also reduces body weight and systolic blood pressure* Adjusted mean change from baseline body weight, kg 0,0-0,5-1,0-1,5-2,0-2,5-3,0 Monotherapy 1 Add- on to MET 2-1.93 Body weight - 2.15-1.63-2.01 Patients, n 224 224 217 213 BL weight, kg 78.4 77.8 81.6 82.2 Adjusted mean change from baseline SBP, mmhg 0,0-1,0-2,0-3,0-4,0-5,0-6,0-7,0 Systolic blood pressure Monotherapy 1 Add- on to MET 2-2.6-4.1-3.4-4.8 Patients, n 224 224 217 213 BL SBP, mmhg 133.0 129.9 129.6 130.0 Empagliflozin 10 mg Empagliflozin 25 mg *Empagliflozin is not indicated for weight loss or blood pressure reduction (secondary endpoints) All data are placebo corrected at Week 24. p<0.0001; p<0.001; p=0.0231; p=0.0028. BL, baseline; MET, metformin; SBP, systolic blood pressure 1. Roden M et al. Lancet Diabetes Endocrinol 2013;1:208; 2. Häring H- U et al. Diabetes Care 2014;37:1650

The CV effects of Empagliflozin were studied in a dedicated CV outcomes trial published in the New England Journal of Medicine EMPA- REG OUTCOME was a randomised, double- blind, placebo- controlled CV outcomes trial 1 7020 42 Patients Countries 3.1 Years Median observation time Results were achieved on top of standard of care 1 Patients CV risk factors, including glucose, were actively managed in placebo and Empagliflozin treatment arms 95%* 81%* 89%* 98%* therapy 1 therapy 1 medications 2 Antihypertensive Lipid- lowering Anticoagulants 1 Glucose- lowering *Patients receiving therapy at baseline 1. Zinman B et al. N Engl J Med 2015;373:2117; 2. Zinman B et al. Cardiovasc Diabetol 2014;13:102

Empagliflozin is an SGLT2 inhibitor that was studied in a dedicated CV outcomes trial published in the New England Journal of Medicine EMPA- REG OUTCOME was a randomised, double- blind, placebo- controlled CV outcomes trial With 7020 patients in 42 countries 3.1 years median observation time ü ü ü ü Key inclusion criteria Established CV disease History of MI, stroke or unstable angina >2 months prior to study Coronary artery disease Peripheral occlusive arterial disease Adults ( 18 years of age) with T2D BMI 45 kg/m 2 HbA1c 7% and 10%* û û Key exclusion criteria egfr <30 ml/min/1.73 m 2 (MDRD) Acute coronary syndrome, stroke or transient ischaemic attack within 2 months prior to informed consent *Stable background therapy for 12 weeks before randomisation: for insulin, dose was to remain unchanged by >10% from the dose received 12 weeks before randomisation); for drug- naïve: HbA1c 7% and 9%. BMI, body mass index; CV, cardiovascular; egfr, estimated glomerular filtration rate; HbA1c, glycated haemoglobin; MDRD, Modification of Diet in Renal Disease; MI, myocardial infarction; SGLT2, sodium- glucose co- transporter- 2; T2D, type 2 diabetes

Pooled data from 10 mg and 25 mg doses of Empagliflozin. *SOC included CV medications (e.g. antihypertensive agents, lipid- lowering therapies and anticoagulants) and glucose- lowering agents given at the discretion of the physician; Nominal p- value; Calculated at 3.1 years (median); CVD, cardiovascular disease; HR, hazard ratio; MACE, major adverse cardiovascular events; MI, myocardial infarction; RRR, relative risk reduction; SOC, standard of care. Zinman B et al. N Engl J Med 2015;373:2117 Empagliflozin significantly reduced the risk of CV events on top of standard of care in patients with T2D and established CVD* 14% RRR in CV events Early and sustained reduction in CV events Absolute risk for CV events : 12.1% Placebo 10.5% Empagliflozin Primary endpoint: CV- events defined as CV death, non- fatal MI and non- fatal stroke (3P- MACE).

Empagliflozin reduced CV death by 38% on top of Standard of care* in patients with T2D and established CVD Absolute risk for CV death: 5.9% Placebo 3.7% Empagliflozin Early and sustained reduction in CV death Pooled data from 10 mg and 25 mg doses of Empagliflozin. The primary endpoint of the EMPA- REG OUTCOME study was a composite of CV death, non- fatal MI and non- fatal stroke (i.e. 3- point MACE). *SOC included CV medications (e.g. antihypertensive agents, lipid- lowering therapies and anticoagulants) and glucose- lowering agents given at the discretion of the physician; Including coronary artery disease, peripheral artery disease, or a history of MI or stroke; Nominal p- value. CV, cardiovascular; CVD, cardiovascular disease; HR, hazard ratio; MACE, major adverse CV events; MI, myocardial infarction; RRR, relative risk reduction; SOC, standard of care; T2D, type 2 diabetes. Zinman B et al. N Engl J Med 2015;373:2117

Empagliflozin reduced hospitalisation for heart failure by 35% on top of standard of care* in patients with T2D and established CVD Early and sustained reduction in HHF Absolute risk for HHF: 4.1% Placebo 2.7% Empagliflozin Empagliflozin is not indicated for heart failure. Hospitalisation for heart failure was a secondary endpoint. Pooled data from 10 mg and 25 mg doses of Empagliflozin used in the EMPA- REG OUTCOME trial. *SOC included CV medications (e.g. antihypertensive agents, lipid- lowering therapies and anticoagulants) and glucose- lowering agents given at the discretion of the physician; Including coronary artery disease, peripheral artery disease, or a history of MI or stroke; Nominal p- value. CVD, cardiovascular disease; HHF, hospitalisation for heart failure; HR, hazard ratio; MI, myocardial infarction; RRR, relative risk reduction; SOC, standard of care; T2D, type 2 diabetes. Zinman B et al. N Engl J Med 2015;373:2117

Empagliflozin reduced all- cause mortality by 32% on top of standard of care* in patients with established CVD HR 0.68 (95% CI 0.57, 0.82) p<0.0001 32% RRR in all-cause mortality # Absolute risk for All- cause mortality: 8.3% Placebo 5.7% Empagliflozin Early and sustained reduction in all- cause mortality All- cause mortality was a secondary endpoint. #Pooled data from 10 mg and 25 mg doses of Empagliflozin. All- casuse mortality was a secondary endpoint. *SOC included CV medications (e.g. antihypertensive agents, lipid- lowering therapies and anticoagulants) and glucose- lowering agents given at the discretion of the physician; Nominal p- value. CV, cardiovascular; HR, hazard ratio; RRR, relative risk reduction; SOC, standard of care; Zinman B et al. N Engl J Med 2015;373:2117

The mechanisms that explain the CV benefits of Empagliflozin are likely to be multifactorial Empagliflozin modulates several factors related to CV risk 1 SGLT2 inhibition in the kidney Haematocrit Intravascular volume Systolic BP Empagliflozin is a reversible, highly potent and selective inhibitor of SGLT2 2 Na+ & glucose excretion Glomerular hypertension Diuresis Renal oxygenation Cardiac stress Myocardial contractility Renal blood flow BP, blood pressure; CV, cardiovascular; SGLT2, sodium- glucose co- transporter- 2 1. Sattar N et al. Diabetologia 2016;59:1333; 2. Boehringer Ingelheim. Jardiance (empagliflozin) summary of product characteristics. Jan 2017

Empagliflozin has a confirmed risk and tolerability profile in patients with T2D Common AEs in phase III trials 1 10 8,8 Overall incidence of AEs was similar to placebo Adverse events (%) 8 6 4 2 0 7,2 7,0 Urinary tract infections 4,0 3,9 1,0 1,4 Genital mycotic infections 3,5 3,3 Increased urination Common AEs included hypoglycaemia (combined with SU and insulin) genital infections urinary tract infections increased urination and thirst pruritus In patients taking SGLT2 inhibitors, rare cases of diabetic ketoacidosis have been reported Placebo Empagliflozin 10 mg Empagliflozin 25 mg SGLT2, sodium- glucose co- transporter- 2; T2D, type 2 diabetes For a complete list of contraindications, warnings and precautions, please refer to the summary of product characteristics 1. Boehringer Ingelheim. Jardiance (empagliflozin) summary of product characteristics. Jan 2017

Number needed to treat to prevent one death in landmark trials in patients with high CV risk 1994 2000 Pre- ACEi/ARB era Pre- statin era Simvastatin 1 for 5.4 years <29% statin Ramipril 2 for 5 years High CV risk* 5% diabetes, 26% hypertension High CV risk 38% diabetes, 46% hypertension *defined as patients with coronary heart disease (history of angina pectoris or acute myocardial infarction); defined as patients with history of coronary artery disease, stroke, peripheral vascular disease, or diabetes plus at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low high- density lipoprotein cholesterol levels, cigarette smoking, or documented microalbuminuria) and no heart failure. Absolute risk reduction cannot be directly compared across different outcome trials. ACEi, angiotensin- converting enzyme inhibitor; ARB, angiotensin receptor blocker; CVD, cardiovascular disease. 1. 4S investigators. Lancet 1994;344:1383; 2. HOPE investigators. N Engl J Med 2000;342:145

Number needed to treat to prevent one death with Empagliflozin added to standard of care in patients with established CVD 2015 >80% ACEi/ARB >75% statin Empagliflozin for 3 years T2D with established CV disease 92% hypertension ACEi, angiotensin- converting enzyme inhibitor; ARB, angiotensin receptor blocker; CVD, cardiovascular disease; T2D, type 2 diabetes Zinman B et al. N Engl J Med 2015;373:2117

Start behandling tidligt

Duckworth W et al. N Engl J Med 2009;360:129-139. Enrollment and Outcomes.

Duckworth W et al. N Engl J Med 2009;;360:129-139.

Changes in Median Glycated Hemoglobin Level, According to Year since the Start of the Study. The primary outcome was the time to the first major cardiovascular event (a composite of heart attack, stroke, new or worsening congestive heart failure, death from cardiovascular causes, or amputation for ischemic gangrene). Hayward RA et al. N Engl J Med 2015;372:2197-2206.

Time course of glycemic control: Bad glycemic legacy 1 Figur 2 fra ref 1. Ref 1: Del Prato S. Diabetologia 2009;52:1219 26

Behandle bredt og intensivt

Nytter intervention hos diabetespatienten? 1 STENO 2 studiet 1 Figur 3 A-C fra ref 1 Ref 1: Gæde P et al. NEJM 2008;;358 (6):580

Individualisering af behandling

Forebyggelse af kardiovaskulær sygdom ved diabetes 1 Livsstil intervention 1 Sygdomsspecifik patientuddannelse Diætvejledning Fysisk aktivitet Rygeafvænning Farmakologisk intervention 1 Lipidsænkende behandling Antihypertensiv behandling Antiglykæmisk behandling 53 Ref 1: Guidelines for type 2- diabetes 2014 revision. Publiceret online af Dansk Endokrinologisk Selskab (www.endocrinology.dk) og Dansk Selskab for Almen Medicin (www.dsam.dk)

2012 by American Diabetes Association Silvio E. Inzucchi et al. Dia Care 2012;;35:1364-1379

Behandling og behandlingsmål for hyperglykæmi 1 Ref 1: Guidelines for type 2- diabetes 2014 revision. Publiceret online af Dansk Endokrinologisk Selskab (www.endocrinology.dk) og Dansk Selskab for Almen Medicin (www.dsam.dk)

Type 2- diabetes er en kompleks sygdom 1 Nedsat insulinsekretion Bugspytkirtlens β-celler Nedsat inkretineffekt Mave-tarmkanalen Øget lipolyse Fedtvæv Øget glukagonsekretion Bugspytkirtlens α-celler GLP1-analog DPP4-hæmmer GLP1-analog DPP4-hæmmer Sulfonylurinstof Glitazon Øget glukosereabsorption Nyrerne GLP1-analog DPP4-hæmmer Hyperglykæmi Selektiv SGLT2- hæmmer Biguanid Biguanid Glitazon Øget glukoseproduktion Leveren Nedsat glukoseoptagelse Muskelvæv Neurotransmitter dysfunktion Centralnervesystemet Figuren er fremstillet af AstraZeneca på baggrund af : Ref 1: Defronzo, RA. From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus. Diabetes. 2009; 58:773 795, Bailey C. Diabetes Met;2010;193-9, Forxiga (dapgagliflozin) produktresume januar 2015, Victoza (liraglutid ) produktresume nov 2014.

Guidelines for Type 2-diabetes 1 Ref 1: Guidelines for type 2-diabetes 2014 revision. Publiceret online af Dansk Endokrinologisk Selskab (www.endocrinology.dk) og Dansk Selskab for Almen Medicin (www.dsam.dk)

Sequential insulin strategies in type 2 diabetes. Silvio E. Inzucchi et al. Dia Care 2012;;35:1364-1379 2012 by American Diabetes Association