Why and how to intensify diabetes treatment in Type 2 diabetes

Transcription

1 Why and how to intensify diabetes treatment in Type 2 diabetes Strategic choices to be made... Päivi Maria Paldánius Novartis Pharmaceuticals

2 My disclosures Employee and share-owner of Novartis Worldwide Brand Medical Director Diabetes and Metabolism Research scientist at the Children s hospital, Helsinki University Central Hospital

3 Status: The world of diabetes as we know it today Variable patient journeys across the disease spectrum worldwide Multiple challenges requiring ample evidence (WHY) and management strategies (HOW) in diverse populations at different stages of disease Global challenges in diabetes management are equally faced locally, on all levels and various populations individualising treatment targets, often with multiple co-morbidities but access to different resource settings tackling clinical inertia, intensifying early enough or avoiding aggressive approach when applicable Converting the science from controlled studies into real-world settings Optimising therapy choices, verifying the future of T2DM management and access to care, for everybody 3

4 SCIENTIFIC RATIONALE

5 Proportional amount of nsulinin in relation to normal (%) Glucose mmol/l T2DM is a progressive disease with early onset of foundation for complications Postprandial glucose Fasting glucose NGT Pre diabetes (IFG / IGT) Diabetes 200 Insulin resistance Risk of diabetes Impaired islet cell function years Complications Insulin IFG: impaired fasting glucose; IGT: impaired glucose tolerance Adapted from International Diabetes Center. Type 2 Diabetes BASICS. Minneapolis, Minn: International Diabetes Center;

6 Complex disease: The Ominous Octet Gastrointestinal tissues Pancreas Adipose tissue Decreased insulin secretion Decreased incretin effect Increased lypolysis Islet-α cell Increased insulin secretion Hyperglycemia Increased glucose reabsorption Kidney Increased HGP Neurotransmission Dysfunction Decreased glucose uptake Liver Brain Muscle. Adapted from DeFronzo, R.A.. Diabetes. 2009; 58:

7 Insulin secretory response Insulin response to glucose in healthy individuals ED 50 Insulin capacity Glucose sensitivity Glucose concentration (mmol/l) ED 50 =effective dose at 50% Adapted from Ireland JT et al. Diabetes today: a handbook for the clinical team. Ed. HM + M Publishers. 1979, pp15 6; Adapted from Davidson MB. West J Med 1985;142:

8 Insulin secretory response Insulin response to glucose in individuals with high capacity but low sensitivity (IGT) ED 50 High insulin capacity Reduced glucose sensitivity Glucose concentration (mmol/l) ED 50 =effective dose at 50%; IGT=impaired glucose tolerance Adapted from Ahrén B. Diabetes 2009;58:726 31; Adapted from Davidson MB. West J Med 1985;142:

9 < < % of reference category % of reference category Loss of insulin sensitivity is an early phenomenon even within normoglycaemic range (N=6414) Ref. NFG IFG Diabetes 1st phase insulin secretion Ref. NFG IFG Diabetes 1st phase insulin secretion MatsudalSI InsAUC 30 /GluAUC MatsudalSI InsAUC 30 /GluAUC 30 0 InsAUC 120 /GluAUC InsAUC 120 /GluAUC 120 Fasting plasma glucose [mm] OGTT 2-hour plasma glucose [mm] AUC, area under curve; IFG, impaired fasting glucose; Ins, insulin; NFG, normal fasting glucose, OGTT, oral glucose tolerance test Stančáková A et al. Diabetes 58: ,

10 Isolated IFG and IGT: differences in pathophysiology? How do we, if at all, address this in newly-diagnosed T2DM patients? Liver Pancreas IIFG Hepatic glucose production Insulin sensitivity IIGT Hepatic glucose production +/- Insulin sensitivity +/- Insulin secretion (fasting, 1 st phase) Insulin secretion (1 st phase) Muscle Insulin sensitivity Insulin sensitivity IFG, impaired fasting glucose; IGT, impaired glucose tolerance; IIFG, isolated impaired fasting glucose; IIGT, Isolated impaired glucose tolerance; Adapted from Laakso M. et al. Diabetologia 51:502-11, 2008; Stancakova A, et al. Diabetes 58: ,

11 Unmet medical need - silent disorder early in the disease course Classic signs or symptoms of diabetes might only appear after several years of hyperglycaemia disease is present 9 to 12 years before diagnosis by the time diabetes is diagnosed, up to 80 85% of β-cell function may have already been lost CV risk factors present and micro/macrovascular disease progressing prior to any symptoms or diagnosis an estimated delay of 5 years in diabetes diagnosis is associated with significantly worse incidence of all-cause mortality, diabetes-related death, and any diabetesrelated complication (UKPDS) Harris MI et al. Diabetes Care. 1992; 15: ; Bagust A et al. QJM. 2003;96: ; DeFronzo RA. Diabetes. 2009;58: ; Colagiuri S et al. Diabetes Care. 2002;25:

12 Insulin secretory response Insulin response to glucose in patients with T2DM Reduced glucose sensitivity Reduced insulin capacity ED 50 Insulin capacity Glucose concentration (mmol/l) ED 50 =effective dose at 50% Adapted from Davidson MB. West J Med 1985;142:219 29; Adapted from Turner RC, Holman RR. Lancet 1976;1:

13 Treatment of T2DM: A therapeutic approach based upon pathophysiology? Pancreas Adipose tissue (+) TZD GLP-1 analogues DPP-4 inhibitors Sulphonylureas Increased HGP Impaired insulin secretion (-) Metformin TZD Hyperglycaemia Increased lipolysis (+) TZD Metformin (-) TZD Decreased glucose uptake Liver Muscle DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; HGP, hepatic glucose production; T2DM, type 2 diabetes mellitus; TZD, thiazolidinedione Adapted from: DeFronzo RA. Diabetes. 2009;58:

14 Pathophysiology-based algorithm Treatment of type 2 diabetes based upon pathophysiology Lifestyle + Triple Combination TZD + Metformin + Exenatide HBA1c < 6% Comparison of the ADA and pathophysiological-based algorithms ADA Pathophysiology-based Durability No Yes β cell preservation No Yes Hypoglycemia Yes No Weigh gain Yes No Del Fronzo, R.A. Diabetes. 2009; 58:

15 Median HbA1c (%) Targeting: Achieving early glycaemic control which may generate a good legacy effect 9 8 Conventional Metformin 7 6 Legacy effect 0 UKPDS Holman et al Difference in HbA1c was lost after first year but patients in the initial intensive arm still had lower incidence of any complication: 24% reduction in microvascular complications 15% reduction in MI 13% reduction in all-cause mortality MI, myocardial infarction Diabetes Trials Unit. UKPDS Post Trial Monitoring. UKPDS 80 Slide Set. Available at: Accessed 12 September, 2008; Adapted from Holman RR, et al. N Engl J Med. 2008; 359: ; UKPDS 33. Lancet. 1998; 352:

16 Median glycated haemoglobin level (%) Long term benefits of glucose control The VADT follow up (better late than never?) 10.0 Standard therapy Intensive therapy Year since start of study VADT was a multi-site, randomised, controlled trial in patients (N=1,791) who had a suboptimal response to therapy for T2D. Patients received either intensive (n=892) or standard glucose control (n=899) (patients with a BMI of 27 were started on metformin and rosiglitazone; those with a BMI of <27 were started on glimepiride and rosiglitazone. The intensive-therapy group were started on maximal doses, and the standard-therapy group were started on half of these doses. Insulin was added if patients in the intensivetherapy group did not achieve HbA1c <6% and if patients in the standard-therapy group did not achieve HbA1c <9%. Further changes in medication were based on protocol guidelines and local assessment). Median follow-up was 5.6 years. The primary outcome (major CV events) was non-significantly lower in the intensive-therapy group compared with the standard-therapy group. Long-term follow-up data is being collected from national data registries. BMI=body mass index 16 Hayward et al. N Engl J Med 2015;372: ; Duckworth et al. N Engl J Med 2009;360:129 39

17 Long term benefits of glucose control The VADT follow up Effect of intensive glucose control on the rate of major cardiovascular events and mortality* Outcome Standard therapy Intensive therapy Events No. of participants/ total no. Rate per 1000 person-yr Events No. of participants/ total no. Rate per 1000 person-yr Hazard Ratio (95% CI) P Value Primary outcome: major cardiovascular event 288/ / ( ) 0.04 Secondary outcome Death from cardiovascular causes 83/ / ( ) 0.42 Death from any cause 258/ / ( ) 0.54 *The primary outcome was the time of the first major cardiovascular event (a composite of heart attack, stroke, new or worsening congestive heart failure, amputation for ischaemic gangrene, or death from cardiovascular causes) and was analysed in the survey cohort. Mortality outcomes were analysed in the complete cohort. VADT was a multi-site, randomised, controlled trial in patients (N=1,791) who had a suboptimal response to therapy for T2D. Patients received either intensive (n=892) or standard glucose control (n=899) (patients with a BMI of 27 were started on metformin and rosiglitazone; those with a BMI of <27 were started on glimepiride and rosiglitazone. The intensive-therapy group were started on maximal doses, and the standard-therapy group were started on half of these doses. Insulin was added if patients in the intensivetherapy group did not achieve HbA1c <6% and if patients in the standard-therapy group did not achieve HbA1c <9%. Further changes in medication were based on protocol guidelines and local assessment). Median follow-up was 5.6 years. The primary outcome (major cardiovascular events) was non-significantly lower in the intensive-therapy group compared with the standard-therapy group. Long-term follow-up data is being collected from national data registries. CI=confidence interval 17 Hayward et al. N Engl J Med 2015;372: ; Duckworth et al. N Engl J Med 2009;360:129 39

18 INTERVAL: Ambitious mean target reductions set by the investigators, independent of the baseline factors - no true individualisation in most of the patients; too late to target lower glycaemia? Mean (SD) Baseline HbA 1c, % 7.9 (0.72) Mean reduction (SD) Range Overall (0.54) -4.4 to -0.1 HbA 1c 8% (0.35) -2.4 to -0.1 HbA 1c >8% (0.65) -4.4 to -0.2 In this elderly cohort (70+ years old, mean age 75), the mean individualized HbA 1c targets set by the investigators were around 7.0% for both the treatment groups, 0.9% (range 4.4 to 0.1) lower than the mean baseline HbA 1c of 7.9%. Strain WD et al. Lancet May 23. [Epub ahead of print]

19 IMPORTANCE OF EARLY INTENSIFICATION ESPECIALLY IN YOUNGER PATIENTS 19

20 Why early intervention - especially in younger patients with most to gain Diabetes is affecting a younger population more than ever before due to increased rates of obesity and an increased shift to western lifestyles There is a growing epidemic of people with T2DM below the age of 50 T2DM is more aggressive in younger patients with earlier disease onset these patients should still have a long life expectancy and a good QoL Majority will be in developing countries or those less prepared to address the increasing incidence of T2DM Yet, also more developed countries seem less prepared as knowledge alone doesn t lead to appropriate action 20 20

21 Despite having detailed knowledge, we don t follow even the most established evidence-based recommendations* You must sit down if you: 1. Are still smoking 2. Don t sleep at least seven hours every night 3. Haven t exercised at least five times a week for 30 min 4. Took an elevator instead of stairs to this meeting 5. Have been talking into your mobile while driving 6. Don t brush your teeth at least twice a day *references to applicable individual recommendations available per request while this is a conceptual exercise for demonstration of human dimensions of inertia in absence of motivation 21

22 If clinical inertia was an intervention associated with this increased risk of complications, it would rapidly be withdrawn pending safety analyses. However, the lack of appropriate escalation of treatment is accepted in every day practice. Strain WD et al. Clinical Inertia in Individualising Care for Diabetes: Is There Time to do More in Type 2 Diabetes? Diabetes Ther DOI /s

23 INERTIA- clinical inertia- patients/physician inertia In the study of physics, INERTIA describes resistance to movement When applied to medicine, the word inertia is similarly used to describe resistance to change More specifically, it is the difference between the medical care that could be aspired to and what is actually achieved Clinical inertia can and usually is being implemented by both the treating physician and the patient CLINICAL INERTIA is a failure to initiate or intensify treatment in a timely manner in people with diabetes whose health is likely to improve with this intensification 23

24 HbA 1c (%) The true numbers behind conventional treatment intensification (in those with HbA1c > 7.0%) OAD* monotherapy OAD Dual therapy OAD triple combination OAD + insulin % 8.7% 9.1% 9.7% years 7.2 years 6.7 years HbA 1c = 7% 6 Duration of diabetes *OAD = oral antidiabetic Adapted from Adapted from Del Prato S et al Int J Clin Pract ;59(11): Khunti K, et al. DiabCare 2013;36:

25 Real-world data: HbA1c at treatment intensification (mono to dual therapy) The point at which combination therapy is prescribed varies by region, but is consistently higher than the guideline recommendation of 7.0% (or even 6.5%) Bader G et al. ADA abstracts 2449-PO. 72nd Scientific Sessions: 2012;June: 61(suppl 1). 2. Inzucchi SE et al. Diabetologia 2012;55:

26 5,0 4,4 5,1 3,8 3,8 3,6 7,4 7,3 13,1 11,0 7,6 10,0 6,5 6,7 6,4 8,9 9,3 9,6 8,3 6,5 12,1 10,3 18,3 18,6 19,8 Proportion of patients (%) 22,6 32,0 37,7 36,2 38,4 36,2 42,9 41,2 45,2 52,9 51,5 48,3 47,6 50,5 49,4 44,7 48,0 51,0 50,0 49,0 57,2 68,9 67,5 Contributing also to an unnecessary high prevalence of complications at monotherapy failure (which could have at least partially been preventable)? 80,0 Hypertension 70,0 Lipids Disorders Macrovascular 60,0 Microvascular 50,0 40,0 30,0 20,0 10,0 0,0 Vildagliptin (28442) Comparator (15349) Vildagliptin (1661) Comparator (740) Vildagliptin (15582) Comparator (6491) Vildagliptin (3065) Comparator (781) Vildagliptin (2513) Comparator (2266) Vildagliptin (5621) Overall East Asia Europe Latin America Middle East India Comparator (5071) 26

27 The impact of a 12 month inertia on outcomes a T2DM cohort of 110,543 UK patients, treated between May 1990 and January 2010 Patients with HbA1c 7.0% not receiving therapy intensification within 1 year 26% of all patients At 5.3 years, significantly increased risk of: MI 67% (CI %) Stroke 51% (CI 25 83%) HF 64% (CI 40 91%) Composite CVE 62% (CI 46 80%) Paul et al. Cardiovasc Diabetol 2015;14:100 doi: /s x 27

28 HbA1c (%) Modern approach to hyperglycaemia 10 Diet and exercise 9 OAD monotherapy OAD combinations OAD up-titration OAD + basal insulin OAD + multiple daily insulin injections 8 7 ACTION POINT: HbA 1c = 7% 6 0 OAD, oral antidiabetes drug Del Prato S et al Int J Clin Pract ;59(11): Duration of diabetes HbA 1c = 6.5% 28

29 HbA1c (%) ADOPT study: progression of hyperglycaemia in T2DM with monotherapy 8.0 Treatment difference (95% CI) Rosiglitazone vs metformin: 0.13 ( 0.22 to 0.05); p=0.002 Rosiglitazone vs glyburide: 0.42 ( 0.50 to 0.33); p< Annualised slope (95% CI) Rosiglitazone: 0.07 (0.06 to 0.09) Metformin: 0.14 (0.13 to 0.16)* Glyburide: 0.24 (0.23 to 0.26)* Time (years) *Significant difference rosiglitazone vs other treatment groups with Hochberg adjustment. Kahn SE, et al. N Engl J Med. 2006;355:

30 ADOPT study: progression of hyperglycaemia in T2DM with monotherapy -would early intervention with a combination be the answer? It is not known how the initial difference in the glycaemic control would evolve over time No long-term data related to the effect of combination therapies on the durability of glycaemic control are available in patients with more preserved β-cell function, i.e. newly diagnosed, or treatment-näive patients with mild hyperglycaemia. Guidelines don t, so far, advocate early combinations 30

31 Profiles of Anti-diabetic Medications: we have a good arsenal of tools for lowering of glycaemia... Source: Garber et al. Endocr Pract.2016;22:

32 ...while there are multiple barriers to effective and sustainable T2DM care Weight gain Induced by life-style or anti-diabetic therapies Fear and/or events of hypoglycaemia Mostly induced by anti-diabetic therapies Poor adherence to therapy and lifestyle advise Clinical inertia and lack of individualisation In the Time2DoMore programme main reasons triggering a change in treatment were hypos or lack of glycaemic control, often due to lack of compliance with diet and exercise regimen. UKPDS. Lancet 1998; 352 (9131): , Amiel SA et al. Diab Med 2008; 25(3):245-54, Guisasola AF. Diabetes Obes Metab 2008;10: S1:25-32, Weyer C et al. J Clin Invest 1999; 104(6): , Khunti K et al. Diabetes Care 2013;36(11): , Strain WD et al. Diabetes Res Clin Pract. 2014;105:

33 Selecting the appropriate therapeutic agent for individual patients... o Reduction in HbA1c o Risk of hypoglycemia o Impact of pathophysiologic mechanisms o (DO I REALLY CARE...?) o Changes in body weight, lifestyle, sexual function... o CV risk vs. QoL vs... o Safety profile vs tolerability o Friendly use: tailored for me and to my busy life... o Cost vs immediate vs longterm benefit Adapted from Nathan DM, et al. Diabetes Care 2009;32:

34 Time to do more signposts The health outcomes for people with diabetes are a function of the communication between the healthcare professionals and people with diabetes acting as a team It is the duty of that team to establish realistic shared goals and a contract in order to achieve these objectives Individualising care needs to be personalised to all aspects of the needs of the person with diabetes, not simply chasing glycaemic, blood pressure or lipid targets We call on purchasers and providers to incentivise good management in early disease in order to optimise quality of life for people with diabetes 2014 Novartis Pharma AG - Time 2 Do More is a trademark owned by Novartis AG Adapted from: Strain WD et al. Diabetes Res Clin Pract. 2014;105:

35 THE FUTURE 35

36 Randomize GRADE study - The Glycaemia Reduction Approaches for Diabetes: a comparative Effectiveness study 2000 Drug-naive subjects T2DM < 3 years HbA1c 6.5-9% 5500 Met-treated or drug-naive (after 2000 drug-naive randomized) HbA1c 6.5-9% Met run-in: initiate and/or titrate Met to 1000 (min) to 2000(max) mg/day 1000 sequential therapy 1000 early combination therapy 5500 combination therapy SU SU 1100 TZD TZD 1100 DPP-IV 200 GLP Randomize 200 DPP-IV GLP Randomize Insulin Insulin Comparison of sequential vs early combination therapy in 2000 subjects, 1000 per group Comparison of combination therapies in 6500 subjects, 1300 per group The primary metabolic outcome will be time to failure defined as HbA1c >7%, subsequently confirmed, after having been treated with metformin and started on the second randomly assigned medication (intention-to-treat) DPP-IV, dipeptidyl peptidase IV; GLP-1, glucagon like peptide-1, Met, metformin; OAD, oral anti-diabetic drug; SU, sulphonylurea; T2DM, type 2 diabetes mellitus; TZD, thiazolidinedione Clinicaltrial.gov NCT

37 Randomization MET 500mg /d MET 1000mg/d MET 1500mg /d VERIFYING THE FUTURE: Vildagliptin Efficacy in combination with metformin For early treatment of T2DM Period 1 Period 2 Period 3 Vilda 50 mg bid + MET ad 1000 mg bid Vilda 50 mg bid + MET ad 1000 mg bid + (basal) insulin HbA1c > 7.0% (twice) At investigator discretion Screening Run-in : 3 wks Placebo bid + MET ad 1000 mg bid Vilda 50 mg bid + MET ad 1000 mg bid + (basal) insulin Visits every 3 monthly 5 years Patient population: ADOPT- like design, 2000 patients with newly diagnosed (<24 mo) T2DM and HbA1c % Period 1 is double-blinded (until end of the study), period 2 is single-blinded and Period 3 is open label intensification of treatment with OAD instead of insulin in Period 3 leads to discontinuation Primary objectives (co-primaries): Initial treatment failure rate and rate of loss in glycaemic control (HbA1c) over time Other end-points: Progression of and change in HbA1c, FPG, safety and tolerability, 2 hr meal AUC glucose and annual 2 hr meal ISR/G ClinicalTrials.gov Identifier: NCT Del Prato S et al, Diabet Med May 23. doi: /dme

38 Potential implications VERIFY is the first study to investigate the long-term clinical benefits of initial combination treatment versus the standardof-care MET monotherapy followed by addition of OAD addressing key pathophysiological features of the disease at diagnosis It will provide valuable data on the durability of glycaemic control, beta-cell function, insulin resistance, safety and tolerability It will explore for early changes in the vasculature of patients with T2DM early in the course of the disease Addressing primary clinical objective for treatment of hyperglycaemia It has potential to change the way we treat type 2 diabetes and its complex pathophysiology in the future 38

39 My perspective on optimal T2DM treatment selection criteria Early intervention and timely maintenance of glycaemic control at all stages still remains the most effective way to reduce the burden of long-term complications A modern approach to achieve an ideal risk-to-benefit ratio requires prompt intervention aiming at individualised treatment targets and a careful selection of medications to treat diabetes or its complications

40 Effective treatment of type 2 diabetes requires multiple interventions but also drugs used in combination to correct multiple pathophysiological defects Treatment should be based on known pathogenic abnormalities (not simply on reduction of glycaemia) and started early in the natural history of T2DM to prevent progressive β-cell failure Optimal therapy of T2DM should also target these multiple mechanisms without increased risk of hypoglycaemia, weight gain or other tolerability issues which in turn induce reduce adherence and worse outcomes

41 Thank you for your attention.