Insulin therapy in type 2 diabetes (workshop)

1 Insulin therapy in type 2 diabetes (workshop) Krzysztof Strojek, MD PhD Bruce H.R. Wolffenbuttel, MD PhD 2 Relevant relationships (last years) Bv. Sponsorship or research support Bv. Honorarium or other (financial) compensation. Disclosure statement BHRW (Company) names Eur. Committee: KP7 EU grant (Meerdere) DiabetesFonds NL Juvenile Diabetes Research Foundation NWO Min VWS, AZ, Econ Affairs Provinces Groningen, Friesland, Drenthe Nierstichting (Kidney Foundation) Zon MW MENZIS EASD / EFSD AstraZeneca Becton Dickinson Eli Lilly Thermo Fisher Novo Nordisk Roche Sanofi Aventis Boehringer Ingelheim Bayer The complete presentation can be downloaded from http://www.gmed.nl/lectures Treatment of type 2 diabetes in 199: with each step treatment gets more complex Case 1: a 6 yr old teacher 3 1 2 3 Diet and exercise * 4 Sulphonylurea SU+metformin Insulin (± tablets) 4 A 6 year old male Type 2 diabetes since 1999, borderline hypertension, statin user, mildly obese Failing oral therapy (SU + metformin), HbA1c 8.9% FBG of 9 mmol/l, p.p. BG up to 1 mmol/l Teacher at a junior high school Sedentary work during the week, but likes to bicycle in the weekends Case 2: an elderly woman in a nursing home UKPDS epidemiologic study: better glycaemic control means fewer complications A 82 year old female Type 2 diabetes since 1989, hypertension, triple antihypertensives, myocardial infarction in 24, statin and aspirin user, mildly obese Failing oral therapy (SU + metformin), HbA1c 8.9% FBG of 9 mmol/l, p.p. BG up to 1 mmol/l Sedentary lifestyle Likes to go to the zoo with her grandchildren 6 Complications % 6 4 3 2 1% HbA1c = 33% eyes, kidney heart/bloodvessels 6, 7, 8, 9,, HbA 1c (%) ADA/EASD goals HbA1c < 7.% UKPDS 1998 1

What do doctors want to achieve with? What is success? 7 Reduce hyperglycaemic complaints (if any) Achieve (near) normoglycaemia: BG between and 8 mmol/l Prevent complications Avoid hypoglycaemia, especially in the elderly Can be easily adjusted in specific circumstances driving car, eating out, on holidays Can be easily administered by nurse if in nursing home 8 For the patient: it is a simple treatment has no side effects I can eat and drink all no injections please, and no fingerpricks I don t know what hypo is, but surely do not want it I still want to visit my grandchildren my neighbour went blind after starting insulin 1. Bring some simplicity 2. Discuss misconceptions and misbelieves Insulin treatment options in type 2 diabetes Choices, choices, choices... 9 Prandial / Intensified Conventional Basal Prandial / Intensified Conventional Basal Short acting insulin Usually 2 injections Short acting insulin Usually 2 injections (analog) prandially + mix of short acting insulin (analog) +/ oral agents (analog) prandially + mix of short acting insulin (analog) +/ oral agents and long acting insulin and long acting insulin NPH insulin? Glargine / Levemir? Regular or analog? 2/7? 3/7? /? NPH insulin? Glargine / Levemir? Continue which oral agents? SU? Metformin? TZD? Choices, choices, choices... Once daily insulin: basal injection always combined with oral agents 11 Prandial / Intensified Short acting insulin (analog) prandially + Conventional Usually 2 injections mix of short acting insulin (analog) Basal more than 2 combinations of insulin and oral agents are possible; +/ oral agents 12 metformin 3 dd 8 mg* gliclazide 2 3 dd 8 mg NPH insulin? Glargine / Levemir? Regular or analog? and long acting insulin so be smart, use only a few starter regimens in your daily practice, and gain experience with them, 2/7? 3/7? /? NPH insulin? Glargine / Levemir? while adjusting when needed by the patient Continue which oral agents? SU? Metformin? TZD? * or 2 dd mg 2

13 Once daily insulin: basal injection always combined with oral agents metformin 3 dd 8 mg beneficial for weight gain and/or insulin dose may increase risk hypo 14 Twice daily insulin mixture: for instance Humalog Mix 2 R / NovoMix 3 R metformin 3 dd 8 mg gliclazide 2 3 dd 8 mg fast acting long acting * or 2 dd mg 1 Pre prandial insulin injections Insulin aspart/lispro fast fast fast acting Cán work, but frequently basal insulin needed 16 Insulin aspart/lispro Basal bolus : 4 injections daily NPH/ Glargine/Detemir fast fast fast acting long acting Insulin therapy regimen should take into account lifestyle and other activities Starter insulin regimen in type 2 diabetes vary across Europe Results from the INSTIGATE study 17 18 % of patients 8 6 4 2 basal only premixed only short acting only basal-bolus other Germany France UK Greece Spain Smith H, et al. Diabetologia 28; 1 (suppl. 1): S443 3

19 Q. You have started basal insulin therapy. How long does the 'effect' last? 2 Simple starter regimens need intensification over time: lessons from DURABLE study LM2 LisPro Mix 2 Glargine Probability p=.4 between treatment difference Months of Maintaining HbA 1c Goal < 7.% Wolffenbuttel BHR, et al. EASD 2 21 Q. Three different regimens: basal insulin twice daily mix 3 times daily fast acting. What do patients like the most? 22 4T: long term effects 82% need to add fast acting insulin Holman R, et al. NEJM 29 23 4T: intensified insulin regimen gives lowest HbA1c Basal Biphasic Prandial 7.6±1. % 7.3±.9 %, p=.8 vs. biphasic 7.2±.9 %, p<.1 vs. biphasic/prandial Δ.8±1. 1.3±1.1 1.4±1. 24 but at a price of higher body weight, insulin dose and hypoglycaemia Change in BW (kg) Insulin dose (U) Hypo & HbA1c (%) 9 8 7 P<.1 Basal Biphasic Prandial +1.9 ± 4.2 42 (28 to 72) 2.3 +4.7 ± 4. * 48 (3 to 71).7 * +.7 ± 4.6 * # 6 (34 to 78) 12. * # & Grade 2 events/patient/year 6 3 6 9 12 Time (months) adapted from: N Engl J Med 27; 37: 1716 3 N Engl J Med 27; 37: 1716 3 4

NICE: better postprandial BG control with ultrafast acting insulin analog.... 2 Q. Do postprandial BG values matter? 26 FBG (mmol/l) 9 8 7 6 PPBG (mmol/l) 2 1 * * * * * HbA1c (%) 9 8 7 6 1 2 3 4 Time (yrs) HbA1c 7. HbA1c 7. 1 2 3 4 26 Time (yrs) 1 2 3 4 Time (yrs) * p<.2 374 Japanese pat s w. T2DM 3 injections fast acting insulin, NPH if needed Regular (Actrapid) vs Insulin aspart (NovoRapid) Nippon ultrapid Insulin & diabetic Complications Evaluation (NICE) adapted from: Nishimura et al. Diabetologia 28 (A1349)... does reduce c.v. events!! (MI, angina, PCI/CABG, TIA/CVA) But all patients had short duration of diabetes! Insulin treatment options in type 2 diabetes 27 C.V. events (%) 12 8 6 4 2 43% HR.7 CI:.34.9 (p<.2) 28 Prandial / Intensified Short acting insulin (analog) prandially + Conventional Usually 2 injections mix of short acting insulin (analog) and long acting insulin Basal +/ oral agents 1 2 3 4 6 Time (years) Summary of all studies What are the main differences? Nippon ultrapid Insulin & diabetic Complications Evaluation (NICE) ClinicalTrials.gov NCT7172 adapted from: Nishimura et al. Diabetologia 28 (A1349) Some general issues on insulin regimens 1 Some general issues on insulin regimens 2 29 Long acting insulin analogs vs. NPH insulin: fewer hypo's with better HbA1c reduction, and less variation of fasting glucose 3 Prandial / Intensified (basal bolus) Conventional (premixed) Basal (NPH / long acting) Fast acting insulin analogs give better ppbg control than regular insulin Combination with metformin reduces insulin dose and mitigates BW increase HbA1c PPBG control better (if OA s continued) better (3 % HbA1c 7.%) worse Simple starter insulin regimens need intensification within 14 to 16 months, because of HbA1c increase regimen difficult hypoglycaemia +++ slightly difficult ++ easy, continue OA s + weight gain +++ ++ + complications???

In 28, several long term clinical trials have reported their results 31 Q. Is intensified harmful? 32 What did they study? VADT 1. Can strict glycaemic control prevent cardiovascular complications? 2. Do we need to aim for HbA1c < 6.%? Macrovascular outcomes in ACCORD and ADVANCE: no difference between 'standard' and 'intensive' ACCORD showed high incidence of severe hypo 33 34 trial stopped early because of side effects with intensive R/ p<.1 intensive control arm stopped prematurely because of increased C.V. events Speculations on cause of increased mortality in ACCORD is answered in VADT substudy Diabetes duration determines the risk of c.v. events during intensive (insulin) therapy (VADT) 3 Coronary artery calcification (CAC) score measured in 31 VADT participants 4% had CAC score > 4 CAC predicted new events Intensive therapy is especially effective in low CAC score % with c.v. event 4 4 3 3 2 2 1 p<.1 std int < > CAC score 36 Risk 2 1 Benefit Deleterious 3 6 9 12 1 18 21 Diabetes duration (yrs) CAC=, (very high risk) RACED: Risk Factors, Atherosclerosis and Clinical Events in Diabetes adapted from: Reaven. ADA presentation VADT, June 28 adapted from: Duckworth. ADA presentation VADT, June 28 6

37 Diabetes metabolic syndrome Genes? 38 Hazard ratios for all cause mortality by HbA1c deciles oral combination insulin based therapies low grade inflammation treatment upregulation HPA -axis/ GH dietary factors? hypoglycaemia metabolic imbalances cardiac arrhythmia adverse effect on vasculature which is already damaged in diabetes acceleration of atherosclerosis ischaemia C.V. event Primary care database on diabetes treatment in England: 1. Those on insulin had more c.v. disease & renal insufficiency 2. With very low HbA1c, we observe an increase in mortality Currie CJ, et al. Lancet 2; 37: 481 89 Same HbA1c, different numbers of hypoglycaemia 39 Patient A: type 2 diabetes for years metformin 2dd mg, sitagliptin mg HbA1c 6.% no hypoglycaemia Patient B: type 2 diabetes for 8 years metformin 2dd mg, glargin 44 U at bedtime HbA1c 6.% 3 mild hypo's per week 1 severe hypoglycaemia per person per year 4 Q. Are we really sure about its safety? We know a lot about metabolic effects of various diabetes treatments, but almost nothing about their long term effects!! Insulin: the best there is?? Higher insulin dose is associated with more atherosclerosis 41 Insulin treatment in type 2 diabetes is associated with: Better glycaemic control Small improvements in dyslipidaemia Increase in body weight Hypoglycaemia 42 but also: Heart rhythm disturbances 1 Increase in BP 2,3 Inflammation of the vascular wall 4, Mitogenic effects 6,7 Inflammation of adipose tissue 8 related to hypoglycaemia sodium retention obesity & insulin resistance insulin growth factor influx macrophages 1. Chow E, et al. Diabetes 214; 63: 1738 47; 2. Kanoun F, et al. Diabetes Metab. 21; 27:69 7 3. Sarafidis PA, Am J Nephrol 27; 27: 44 4; 4. Andersson CX, et al. Diabetes Metab Res Rev 28; 24: 9 63. Barrett EJ, Liu Z. Rev Endocr Metab Disord 213; 14: 21 7; 6. Lundby A, et al. J Appl Toxicol. 214. doi:.2/jat.382 7. Rostoker R, et al. Endocr Relat Cancer 21; 22: 14 7; 8. Jansen HJ, et al, Diabetologia 213; 6: 273 81 Muis MJ et al. Atherosclerosis 2; 181: 18-192 7

Insulin use and dose is associated with increased risk of CVD and mortality Insulin use and dose is associated with increased risk of CVD and mortality 43 In T2DM, exogenous insulin may be associated with increased risk of diabetes related complications 44 In T2DM, exogenous insulin may be associated with increased risk of diabetes related complications 12 12 Event rate (per 1, person years) 8 6 4 2 2.1 18. 19.3 34.6 42.7 4. 6.6 63.4 78.4 39.6 43. 44.3 4.9 6.9 71.6 81.4 8.6 9.3 Low dose Mid dose High dose Event rate (per 1, person years) 8 6 4 2 2.1 18. 19.3 34.6 42.7 4. 6.6 63.4 78.4 39.6 43. 44.3 4.9 6.9 71.6 81.4 8.6 9.3 Low dose Mid dose High dose Insulin + Insulin only and Insulin metformin insulin+metformin only All cause mortality Insulin + metformin Insulin only and insulin+metformin Combined endpoint Insulin only Insulin + Insulin only and Insulin metformin insulin+metformin only All cause mortality Insulin + metformin Insulin only and insulin+metformin Combined endpoint Insulin only Currie CJ, et al. J Clin Endocrinol Metab 213;98:668 677 Currie CJ, et al. J Clin Endocrinol Metab 213;98:668 677 4 Q. Who is (besides the patient) the most important person when starting? 46 Address patient reluctance: patients who perform self monitoring of blood glucose will more rapidly switch from tablets to insulin Factors for success in Once daily insulin: basal injection always combined with oral agents 47 Education: discuss expectations discuss 'insulin resistance' and teach SMBG discuss weight gain and hypoglycaemia (and how to avoid it) 48 metformin 3 dd 8 mg (2 dd mg) gliclazide 2 3 dd 8 mg Tailoring: choose two or three starter regimens, gain experience with them, and adjust if needed encourage insulin regimen which 'fits' the patient and can be adjusted to long term goals and lifestyle Insulin therapy = personalized medicine 1. continue oral agents 2. add 8 E long acting insulin at bedtime of breakfast 3. titrate on fasting BG 4. if hypoglycemia, reduce sulphonylurea dose. if daytime hyperglycemia, add 2nd injection of insulin 8

49 Twice daily insulin mixture: for instance Humalog Mix 2 metformin 3 dd 8 mg (2 dd mg) fast acting long acting Pre prandial insulin injections Insulin aspart/lispro fast fast fast acting 1. continue metformin 2. give 2/3 of insulin at breakfast and1/3 at dinner 3. titrate on BG before main meals / at bedtime, slower in the elderly 4. self monitoring mandatory. reduce dose in weekend when bicycling 1. continue metformin 2. give insulin at 4% breakfast, 2% lunch, 3% dinner 3. titrate on BG before main meals / at bedtime, slower in the elderly 4. self monitoring mandatory. frequently need for long acting insulin at bedtime 1 Basal bolus : maximal flexibility metformin 3 dd 8 mg (2 dd mg) 2 Insulin injection regimens in type 2 diabetes Continue oral agents Add long acting insulin bedtime Continue metformin Twice daily 2/7 mixture fast fast fast acting long acting Aspart/lispro NPH/ Glargine Add fast acting insulin when significant hyperglycemia Change % fast acting in mixtures when postprandial hyperglycemia Add 2nd fast acting insulin when significant hyperglycemia Add fast acting insulin at lunch when afternoon hyperglycemia 1. give 3 4% of insulin as long acting at bedtime 2. titrate on BG before main meals / at bedtime, later on p.p. BG 3. self monitoring mandatory 4. reduce dose when exercising / eating less Fast acting insulin before meals Long acting at bedtime Insulin injection regimens in type 2 diabetes 3 Basal Basal + 2/7 2/7 Biphasic 2/7 / Biphasic 4 Q. Is there an alternative to insulin therapy? 2/7 / Basal ++ Biphasic + long acting biphasic fast acting Multiple injections 9

Question to the audience Case 3. A diabetes problem in clinical practice perverted by reimbursement issues For a patient with type 2 diabetes, intolerant to metformin, failing gliclazide + sitagliptin, HbA1c 7.9%, BMI 3 kg/m 2, I would prescribe: 1. a GLP1 agonist like exenatide 2. basal insulin (glargine) 3. twice daily premix insulin (LisPro mix 2) 4. multiple daily insulin injections 6 Type 2 diabetes, 9 years, treated by G.P. Weight 9 kg BMI 3 kg/m2 intolerant to metformin gliclazide + sitagliptin simvastatin normal blood pressure, normal lipds HbA1c 7.9% What is the best treatment for me at this moment? Question to the audience The case of mrs. E., 9 years 7 For a patient with type 2 diabetes, intolerant to metformin, failing gliclazide + sitagliptin, HbA1c 7.9%, BMI 3 kg/m 2, I would prescribe: 1. a GLP1 agonist like exenatide 2. basal insulin (glargine) 3. twice daily premix insulin (LisPro mix 2) 4. multiple daily insulin injections 8 Type 2 diabetes Weight 9 kg BMI 3 kg/m 2 intolerant to metformin gliclazide + sitagliptin simvastatin normal blood pressure How is reimbursement of insulin and GLP1 agonists arranged in your country? In The Netherlands, this is only reimbursed when BMI > 3 kg/m 2 Goal: improving control but wants to loose weight The case of mrs. E., 9 years Woman, 9 years, type 2 diabetes 9 Type 2 diabetes Weight 9 kg BMI 3 kg/m 2 intolerant to metformin gliclazide + sitagliptin simvastatin normal blood pressure 6 Type 2 diabetes, since 6 yrs Weight 9 kg BMI 3 kg/m 2 intolerant for metformin; R/ gliclazide + sitagliptin simvastatin normal bloodpressure Goal: glycaemic improvement but wants to loose weight Does not consider insulin to be an option Goal: improving control but wants to loose weight start of exenatide bid, pays for it herself Euro per month Weight 7 kg (BMI 2) stop sitagliptin; start GLP1 rec. agonist, is paying this HERSELF Euro per month Weight 7 kg (BMI 2) No hypo s No side effects

Man, 7 years, type 2 diabetes Insulin or GLP1 agonist as a first step after failure on oral agents? 61 Type 2 diabetes, since 6 years Weight 114 kg BMI 3.6 kg/m 2 metformin & glimepiride; atorvastatin 3 BP lowering drugs Goal: glycaemic improvement bnu wants to loose weight (not gain it) Does not consider insulin a good option 62 1 patients DM2 age 3 7 years HbA 1c 7 11% (SU+MF) BMI 2 4 kg/m 2 Exenatide 2 dd mcg 2 dd mcg decrease dose of glimepiride start liraglutide 1.2 mg Weight 7 kg (BMI 33.4) stable medication dose! No hypo s No side effects Randomized study 13 countries 4 8 12 16 2 24 28 32 36 4 44 48 2 Time (weeks) Novomix 3 2 dd sc Nauck M., et al. Diabetologia 27 Exenatide: lower body weight and postprandial BG Obesity a risk factor for many chronic disorders 63 Exenatide 64 Metabolic consequences Diabetes Cardiovascular disease Difference.4 kg Insulin Dynamic consequences Arthrosis/arthritis/gout Pulmonary complaints Sleep apnoea Esophageal reflux Cancer Various types of cancer Other Gall stones Alzheimer s disease Cognitive disturbances - - -1 kg during GLP1 RA therapy = Outcome of car accidents fewer long-term sequelae?? Postoperative complications Possible scenarios regarding body weight benefit of GLP1 agonists New drugs are more expensive than old drugs 6 Body weight (kg) 9 9 Insulin therapy (weight ) Scenario 1 Scenario 2 (best one) Scenario 3 66 Price per month: SU: 3 4 Euro, Metformin: 3 4 DPP4 i & SGLT2 remmer: 4 Insulin: 7 GLP1 RA: 8 2 3 Time (years) Short term costs vs long term benefits Possible benefits of long term reduction of excess body weight: 'Metabolic' / 'Dynamic' / 'Cancer' / 'Other'? Miele LG 11

Obesity a risk factor for many chronic disorders QALY vs. Costs 67 Can a 1 kg reduction of body weight reduce weight related morbidities? Metabolic consequences Diabetes Cardiovascular disease Dynamic consequences Arthrosis/arthritis/gout Pulmonary complaints Sleep apnoea Esophageal reflux Cancer Various types of cancer Other Gall stones Alzheimer s disease Cognitive disturbances Outcome of car accidents Postoperative complications 68 Expected QALYs prior to the first event A 64.4 64.38 64.36 64.34 64.32 64.3 64.28 64.26 8% Men 7% 64.24 2 23 2 27 29 Expected medication cost per QALY (USD/QALY) Δ 6.% B 68.44 68.42 68.4 68.38 68.36 68.34 Women 7% 6.% 68.32 met+sulf+insulin 68.3 8% met+dpp IV+insulin 68.28 met+glp 1+insulin met+insulin 68.26 2 23 2 27 29 Expected medication cost per QALY (USD/QALY) QALYs vs. cost incurred by the four different treatment regimens as a function of glycemic control goal. Comparison of the expected QALYs vs. the expected medication cost per QALY incurred from diagnosis to first event (diabetes related complication or death) for men (A) and women (B). Each of the four treatments is compared as the glycemic control goal is varied from 6.% (48 mmol/mol) to 8% (64 mmol/mol). Results are presented using HbA1c of 6.% (48 mmol/mol) ( ), 7% (3 mmol/mol) ( ), and 8% (64 mmol/mol) ( ) as the glycemic control goal Zhang Y, et al. Diabetes Care 214;37:1338-134 Making decisions in type 2 diabetes Progression of type 2 diabetes makes treatment choices / regimens more complicated 69 second line drug features 7 Failure on oral agents (OA) Lifestyle intervention (healthy food, weight reduction, physical activity) Metformin (metabolic control, less c.v. events, no hypoglycaemia, no weight increase Sulphonylurea Glinides Thiazolidines α GIucosidase inh. DPP 4 inhibitors GLP1 agonists hypo, weight gain hypo, safe in renal insuff. edema, c.v.d., bladder pp. BG, GI side effects no hypo, neutral weight injections, weight loss MF+OA+ GLP1ag MF+GLP1ag+ basal insulin MF+OA+ basal insulin MF+PreMix Insulin Insulin injections, weight gain, BG measurements MF+GLP1ag +BBT (?) Not approved yet MF+ BasalBolus Take home messages on 71 Intensive BG lowering: dangerous in long term diabetics and those with (severe) c.v. disease Long acting analogs vs. NPH insulin: fewer hypo's with better HbA1c reduction, and less variation of fasting glucose Fast acting analogs: better ppbg control than regular insulin, which may reduce c.v. complications Intensive insulin treatment: more hypoglycaemia, weight gain Simple starter insulin regimen: intensification within 14 to 16 months, because HbA1c increase 12