Current principles of diabetes management

Current principles of diabetes management Prof. Martin Haluzík, MD, DSc. 3 Department of Medicine, General University Hospital and 1st Faculty of Medicine, Charles University in Prague, Czech Republic

Why do we need to treat DM? - To suppress the negative effects of excessive hyperglycemia (polydypsia, polyuria, weight loss) To prevent chronic microvascular (neuropathy, nephropathy, retinopathy) and macrovascular complications (MI, stroke, PVD) The ultimate goal is to prevent premature death and to enable the patient good quality of life (optimally without chronic complications)

Key challenges of type 2 diabetes 1. Diabetes is a progressive disease characterised by: Declining beta-cell function Deterioration of glycaemic control Increased risk of cardiovascular disease 2. As diabetes treatments are added to control glucose, physicians and patients face trade-offs such as: Hypoglycaemia Weight gain Complex treatment regimens (multiple daily dosing and need for self-monitoring of blood glucose)

T2DM is a complex disease associated with a high risk of CV complications 79 % of T2DM patients are overweight or obese 63 % of T2DM patients have arterial hypertension 70 % of T2DM patients have dyslipidemia Libby et al. Circulation 2002;106(22):2760 2763. Jacobs et al. Diabetes Res Clin Pract. 2005;70(3):263 269.

Hazard ratio Hazard ratio Higher HbA 1c predicts higher CV risk 10 Fatal and non-fatal MI 10 Fatal and non-fatal stroke p<0.0001 p=0.035 1 1 14% decrease per 1% reduction in HbA 1c 12% decrease per 1% reduction in HbA 1c 5 6 7 8 9 10 5 6 7 8 9 10 10 Amputation/death from PVD 10 Heart failure p<0.0001 p=0.021 1 1 43% decrease per 1% reduction in HbA 1c 16% decrease per 1% reduction in HbA 1c 5 6 7 8 9 10 5 6 7 8 9 10 HbA 1c (%) HbA 1c (%) Reference category (hazard ratio 1.0) is HbA 1c <6% with log linear scales CV, cardiovascular; HbA 1c, glycosylated haemoglobin; MI, myocardial infarction; PVD, peripheral vascular disease Stratton IM et al. BMJ 2000;321:405 412

STENO-2: Treatment targets Conventional Therapy Intensive Therapy 1993 1999 2000 2001 1993 1999 2000 2001 Systolic blood pressure (mmhg) < 160 < 135 < 140 < 130 Diastolic blood pressure (mmhg) < 95 < 85 < 85 < 80 HbA 1c (%) < 7.5 < 6.5 < 6.5 < 6.5 Fasting serum total cholesterol (mmol/l) < 6.5 < 4.9 < 4.9 < 4.5 Fasting serum triglycerides (mmol/l) < 2.2 < 2.0 < 1.7 < 1.7 Treatment with ACE-inhibitor irrespective of blood pressure No Yes Yes Yes Aspirin therapy: Known ischaemia Yes Yes Yes Yes Peripheral vascular disease No No Yes Yes No known CHD or peripheral vascular disease No No No Yes ACE, angiotensin-converting enzyme; CHD, coronary heart disease; HbA 1c, glycated haemoglobin Gæde P et al. Diabetologia 2016;59:2298 2307

Proportion of patients that died (%) Cumulative mortality (%) STENO-2: Mortality at 21 years follow-up 100 100 End of trial and start of intensification of conventional-therapy group patients treatment 80 HR: 0.55 95% CI: 0.36 0.83 p=0.005 75 Conventional Intensive 60 69 69% 50 13.3 years Median survival time 40 48 48% 25 Difference in median survival time of at least 7.9 years* 20 0 0 4 8 12 16 20 Years since randomisation 0 Conventional therapy Intensive therapy *No formal calculation possible as <50% mortality in intensive therapy group. CI, confidence interval; HR, hazard ratio Gæde P et al. Diabetologia 2016;59:2298 2307 Number at risk Intensive 80 76 66 58 54 43 Convention 80 78 65 45 34 24 al

Cumulative incidence of death or CVD event (%) Median time to first CVD event or death (years) STENO-2: Time to first CVD event or death 100 End of trial and start of intensification of conventional-therapy group patients treatment 18 ETD: 8.1 years 95% CI: 4.0 12.6 75 16 14 16.1 50 Median CVD-free survival time 12 10 25 8 8.0 6 0 4 0 4 8 12 16 20 Years since randomisation 2 Number at risk Intensive 80 66 56 49 41 31 Convention 80 61 40 27 18 13 al CI, confidence interval; CVD, cardiovascular disease; ETD, estimated treatment difference Gæde P et al. Diabetologia 2016;59:2298 2307 0 Conventional therapy Intensive therapy

Lifestyle modifications in the treatment of T2DM - Stop smoking - Low calorie diet with restriction of simple carbohydrates (sweets, sugar drinks, sweet fruits), saturated fats, salt (patients with hypertension), no special diabetic foodstuffs! no food supplements! - Regular exercixe (optimally 10 000 steps/day) Long term goal decrease or at least maintenance of the current body weight (decrease of body weight of 5-10 % significantly decreases CV risk - fit-fat vs. unfit-unfat Repeated patients education needed

An average day at the outpatient clinic 56 years male 12 yrs T2DM BMI 31.6 Smoking Laser for DRP AMI 2 yrs earlier PNP Overt proteinuria HbA1c 8.9% 56 years male 4 yrs T2DM BMI 31.6 Never smoked No DRP No microalbuminuria No PNP Cycles to work HbA1c 8.9% Similar glycaemic targets?????

11 Inzucchi S E et al. Diabetes Care 2012;35:1364-79

Why the goals should not be the same or should they? Optimally, we would like to achieve euglycemia in all patients regardless of diabetes duration and complications The problem is that we cannot do that without risk of hypoglycemia, weight gain and other side effects of some of the current therapies It may well be that all diabetics would benefit from tight control if this can be done without major side effects

Major principles: The overall goal is to prevent or delay the development of micro- and macrovascular complications Early diagnosis and intensive pharmacological treatment immediately after diagnosis (metformin) target Hb1Ac 6-6.5 % In high-risk patients with long history of T2DM and unsatisfactory control the targets should be less ambitious (Hb1AC 7.0-8.5 %) Avoid hypoglycemia, weight gain Intensive life-style measures and education of patients (diet, body weight, physical activity) Intensive intervention of CV risk factors (BP, lipids, smoking cessation

New vs.old drugs: are we getting there? Old drugs Metformin Pioglitazone Sulphonylureas Glinides -glucosidase inhibitors Human insulins older insulin analogues New drugs DPP-4 inhibitors (gliptins) GLP-1 receptor agonists SGLT-2 inhibitors New insulin analogues

Targeting the ominous octet: initial triple combination vs. stepwise tretament intensification Design: 147 newly diagnosed T2DM patients randomized to: - Initial combination of metformin 2000 mg pioglitazone 45 mg exenatide 2 x 10 ug vs. - Stepwise intensification: metformin 1000 mg 2000 mg glipizide basal NPH insulin After 24 months of treatment: HbA1c: from 8,6 % (DCCT) to 6,1 % in initial triple combination vs. 6,6 % in stepwise intensification Hypoglycemia: 13,6 lower rate in initial triple combination Body weight: by 1,2 kg in initial triple combination vs. 3,6 kg in stepwise intensification DeFronzo et al, Diabetes, 2013; Abdul-Ghani et al, ADA, 2013

Experience with rosiglitazone: are diabetes medications associated with increased CV risk? Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that had borderline significance CV, cardiovascular Nissen SE et al. N Engl J Med 2007;156:2457 2471

The change in the paradigm of antidiabetic treatment goals From glucocentricity to reduction of CV risk and mortality CV, cardiovascular; HbA 1c, glycosylated haemoglobin

DPP-4i DPP-4i Saxagliptin and cardiovascular outcomes in patients with T2DM Alogliptin after acute coronary syndrome in patients with T2DM DPP-4i GLP-1RA Effect of sitagliptin on cardiovascular outcomes in T2DM Lixisenatide in acute coronary syndrome, a longterm cardiovascular end point trial of lixisenatide vs placebo SGLT2i GLP-1RA Empagliflozin, cardiovascular outcomes and mortality in T2DM Liraglutide and cardiovascular outcomes in T2DM GLP-1RA GLP-1RA SUSTAIN 6: cardiovascular and other long-term outcomes with semaglutide in subjects with T2DM FREEDOM-CVO: placebo-controlled cardiovascular outcomes study examining the safety of ITCA 650 vs placebo DPP-4i, dipeptidyl peptidase 4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; SGLT2i, sodium glucose co transporter 2 inhibitor; T2DM, type 2 diabetes mellitus

SAVOR-TIMI-53 1 EXAMINE 2 T2DM; HbA 1c 6.5 12.0%; 40 years + CVD; 55 (men) or 60 (women) years + CV risk factors (n=16,492) Saxagliptin (2.5 or 5 mg/day) + standard of care Placebo + standard of care T2DM; HbA 1c 6.5 11.0%; ACS within 15 90 days (n=5,380) Alogliptin (6.25, 12.5 or 25 mg/day) + standard of care Placebo + standard of care TECOS 3 ELIXA 4 T2DM; HbA 1c 6.5 8.0%; 50 years; CVD history (n=14,671) Sitagliptin (100 or 50 mg/day) + standard of care Placebo + standard of care T2DM; HbA 1c 5.5 11.0%; ACS within 180 days (n=6,068) Lixisenatide (10 or 20 mg/day) + standard of care Placebo + standard of care ACS, acute coronary syndrome; CI, confidence interval; CV, cardiovascular; EXAMINE, Examination of Cardiovascular Outcomes: Alogliptin vs. Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome; HR, hazard ratio; MI, myocardial infarction; SAVOR TIMI-53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus Thrombolysis in Myocardial Infarction 53; T2DM, type 2 diabetes; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin; T2DM, type 2 diabetes; UA, unstable angina 1. Sciria et al. N Engl J Med 2013;369(14):1317 1326; 2. White et al. N Engl J Med 2013;369(14):1327 1335; 3. Green et al. N Engl J Med 2015;16;373(3):232-242; 4. Pfeffer MA et al. N Engl J Med 2015;373:2247 2257

Patients with event (%) EMPA-REG OUTCOME Study design and inclusion criteria EMPAGLIFLOZIN 25 mg once daily Placebo EMPAGLIFLOZIN 10 mg once daily 20 Time to first occurrence of CV death, non-fatal MI, or non-fatal stroke Hazard ratio (95.02% CI): 0.86 (0.74 0.99) p=0.04 for superiority Placebo once daily 15 Screening Placebo run-in Randomisation (1:1:1) Treatment period Median duration: 2.6 years Median observation time: 3.1 years End of treatment Followup +30 days 10 N=7028 T2DM with established CV disease Age: 18 years; 20 years in Japan; 65 years in India Drug-naive and HbA 1c 7.0 to 9.0% or stable background antidiabetes therapy* and HbA 1c 7.0 to 10.0% BMI 45.0 kg/m 2 and egfr 30 ml/min/1.73m 2 5 0 Empagliflozin Placebo 0 6 12 18 24 30 36 42 48 Primary endpoint Three-point MACE time to first occurrence of: CV death, non-fatal MI, or non-fatal stroke Month No. at risk Empaglifl 4687 4580 4455 4328 3851 2821 2359 1534 370 ozin Placebo 2333 2256 2194 2112 1875 1380 1161 741 166 *Except pioglitazone in Japan; Excluding silent MI Background glucose-lowering therapy unchanged in first 12 weeks, then adjusted at the investigator s discretion to achieve desired glycaemic control BMI, body mass index; CI, confidence interval; CV, cardiovascular; egfr, estimated glomerular filtration rate; HbA 1c, glycosylated haemoglobin; MACE, major adverse cardiovascular event; MI, myocardial infarction; T2DM, type 2 diabetes mellitus Zinman B et al. Cardiovasc Diabetol 2014;13:102; Zinman B et al. N Engl J Med 2015;373:2117 2128

Patients with event (%) EMPA-REG OUTCOME: CV death 9 Placebo 8 7 6 Hazard ratio (95% CI): 0.62 (0.49 0.77) p<0.001 5 Empagliflozin 4 3 2 1 0 0 6 12 18 24 30 36 42 48 Month Number at risk Empagliflozi 4687 4650 4608 4556 4128 3079 2617 1722 414 n Placebo 2333 2303 2280 2243 2012 1503 1281 825 177 CI, confidence interval; CV, cardiovascular Zinman B et al. N Engl J Med 2015;373:2117 2128

Patients with event (%) EMPA-REG OUTCOME: Hospitalisation for heart failure 7 6 5 Hazard ratio (95% CI): 0.65 (0.50 0.85) p=0.002 Placebo 4 3 Empagliflozin 2 1 0 0 6 12 18 24 30 36 42 48 Month Number at risk Empagliflozi n 4687 4614 4523 4427 3988 2950 2487 1634 395 Placebo 2333 2271 2226 2173 1932 1424 1202 775 168 CI, confidence interval; CV, cardiovascular Zinman B et al. N Engl J Med 2015;373:2117 2128

Patients with an event (%) LEADER Study design and inclusion criteria Time to CV death, non-fatal MI, or non-fatal stroke Placebo Liraglutide 0.6 1.8 mg OD + standard of care Placebo + standard of care Safety follow up Safety follow up 20 2 0 15 1 5 Hazard ratio (95% CI) 0.87 (0.78 ; 0.97) p<0.001 for non-inferiority p=0.01 for superiority P la c e b o Placebo 2 weeks Duration 3.5 5 years 30 days N=9340 T2DM, HbA 1c 7.0% Antidiabetic drug naïve; OADs and/or basal/premix insulin Age 50 years; established CV disease or chronic renal failure or age 60 years and risk factors for CV disease Primary endpoint Time from randomisation to first occurrence of a composite CV outcome (CV death, non-fatal MI, or non-fatal stroke) 10 1 0 5 Patients at risk Liraglutide 4668 Placebo L ir a g lu t id e 0 0 6 121 2 181 8 242 4 30 3 0 3 36 6 42 4 2 484 8 545 4 4672 4593 4588 Time from randomisation (months) 4496 4473 4400 4352 4280 4237 4172 4123 4072 4010 3982 3914 Liraglutide 1562 1543 424 407 The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, non-fatal myocardial infarction, or nonfatal stroke. The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months CV, cardiovascular; HbA 1c, glycosylated haemoglobin; MI, myocardial infarction; OAD, oral antidiabetic drug; OD, once daily; T2DM, type 2 diabetes mellitus Marso SP et al. N Engl J Med 2016;375:311 322

Subjects with an event (%) Semaglutide is an investigational product and not currently approved SUSTAIN 6 Study design and inclusion criteria Semaglutide 1.0 mg Semaglutide 0.5 mg Placebo 1.0 mg 15 10 Time to first occurrence of CV death, non-fatal MI or non-fatal stroke Hazard ratio (95% CI) 0.74 (0.58 0.95) Events: 108 semaglutide; 146 placebo p<0.001 for non-inferiority p=0.02 for superiority Placebo, 8.9% Placebo 0.5 mg Dose escalation * 4 8 weeks Maximum trial duration 104 weeks Follow-up 5 weeks 5 Semaglutide, 6.6% 3297 patients T2DM with HbA 1c 7.0% 0 2 OADs ± basal or pre-mix insulin 0 0 8 16 24 32 40 48 56 64 72 80 88 96 104 109 Time since randomisation (weeks) Primary endpoint Time from randomisation to first occurrence of a MACE, defined as CV death, non-fatal MI, or non-fatal stroke Semaglutid e Number of patients at risk 1648 1619 1601 1584 1568 1543 1524 1513 Placebo 1649 1616 1586 1567 1534 1508 1479 1466 *Fixed dose-escalation: starting dose 0.25 mg for 4 weeks, escalated to 0.5 mg for 4 weeks until maintenance dose (0.5 mg or 1.0 mg); CV, cardiovascular; HbA 1c, glycosylated haemoglobin; MACE, major cardiovascular adverse event; MI, myocardial infarction; OAD, oral antidiabetic drug; T2DM, type 2 diabetes mellitus. Marso SP et al. N Engl J Med 2016;375:1834 1844

Ongoing and planned CVOTs in diabetes SUSTAIN 6 (Semaglutide, GLP-1RA) n=3297; duration ~2.8 years Q3 2016 - RESULTS CANVAS-R (Canagliflozin, SGLT2i) n=5826; duration ~3 years Completion Q1 2017 VERTIS CV (NCT01986881) (Ertugliflozin, SGLT2i) n=8000; duration ~6.3 years Completion Q4 2019 ALECARDIO (Aleglitazar, PPAR-αγ ) n=7226; follow-up 2.0 years Termin. Q3 2013 RESULTS EMPA-REG OUTCOME (Empagliflozin, SGLT2i) n=7000; duration up to 5 years Q2 2015 - RESULTS CANVAS (Canagliflozin, SGLT2i) n=4418; duration 4+ years Completion Q1 2017 DECLARE-TIMI-58 (Dapagliflozin, SGLT2i) n=17,276; duration ~6 years Completion Q2 2019 EXAMINE (Alogliptin, DPP4i) n=5380; follow-up ~1.5 years Q3 2013 RESULTS ELIXA (Lixisenatide, GLP-1RA) n=6000; duration ~4 years Q1 2015 RESULTS FREEDOM (ITCA 650, GLP-1RA in DUROS) n=4000; duration ~2 years Q2 2016 - COMPLETED REWIND (Dulaglutide, QW GLP-1RA) n=9622; duration ~6.5 years Completion Q3 2018 CREDENCE (cardio-renal) (Canagliflozin, SGLT2i) n=3700; duration ~5.5 years Completion Q1 2020 SAVOR TIMI-53 (Saxagliptin, DPP-4i) n=16,492; follow-up ~2 years Q2 2013 RESULTS LEADER (Liraglutide, GLP-1RA) n=9341; duration 3.5 5 years Q2 2016 - RESULTS EXSCEL (Bydureon, QW GLP-1RA) n=14,000; duration ~7.5 years Completion Q2 2018 HARMONY OUTCOME (Albiglutide, QW GLP-1RA) n~9400; duration ~4 years Completion Q2 2019 TECOS (Sitagliptin, DPP-4i) n=14,000; duration ~4 5 years Q4 2014 - RESULTS DEVOTE (Insulin degludec, insulin) n=7637; duration ~5 years Q3 2016 - COMPLETED CARMELINA (Linagliptin, DPP-4i) n=8000; duration ~4 years Completion Q1 2018 CAROLINA (Linagliptin, DPP-4i vs SU) n=6000; duration ~8 years Completion Q1 2019 2013 2014 2015 2016 2017 2018 2019 2020 2021 DPP-4i GLP-1RA SGLT2i Insulin PPAR-αγ CVOT, cardiovascular outcomes trial; DPP-4i, dipeptidyl peptidase 4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; QW, once weekly; SGLT2i, sodium glucose co transporter 2 inhibitor; SU, sulphonylurea ClinicalTrials.gov. Accessed February 17, 2017.

ADA/EASD consensus statement HbA1c 9% ( 75mmol/mol) Hypeglycemia HbA1c 10-12% ( 86-108 mmol/mol) Inzucchi SE et al Diabetologia 2015;10.1077/s00125-014-3460-0

Long-term effects of bariatric surgery (Swedish obese subjects study) Body weight Cumulative mortality Sjostrom et al, J Int Med, 2012

Conclusions Early diagnosis and good control from the start is critically important to prevent complications The different targets for high risk patients with long history of T2DM may be needed to avoid side effects of therapy At the moment, there are 3 antidiabetic medications with confirmed reduction of composite CV outcome vs placebo + standard of care: empagliflozin, liraglutide, and semaglutide Even with the positive effects of some antidiabetic treatments on CV outcomes, good control of other CV risk factors is still necessary Early combinational therapy might improve the long-term outcomes better than the stepwise intensification as suggested in the current algorithms

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