1 When and how to start insulin: strategies for success in type diabetes Treatment of type diabetes in 199: with each step treatment gets more complex Bruce H.R. Wolffenbuttel, MD PhD Professor of Endocrinology & Metabolism University Medical Center Groningen The Netherlands e mail: bwo@int.umcg.nl 1 3 Diet and exercise * 4 Sulphonylurea SUmetformin Insulin (± tablets) 3 At diagnosis: Lifestyle metformin ADA/EASD type diabetes algorithm well validated therapies basal insulin sulphonylurea Step 1 Step Step 3 less well validated therapies pioglitazone pioglitazone sulphonylurea intensive insulin 4 Imagine your outpatient clinic next week: the first patient in front of you is... A year old male Type diabetes since 1999, borderline hypertension, statin user, mildly obese Failing oral therapy (SU metformin), HbA1c.9% FBG of 9 mmol/l, /,pp 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 GLP1 agonist basal insulin Imagine your outpatient clinic next week: the second patient in front of you is... UKPDS epidemiologic study: better glycaemic control means fewer complications A year old female Type diabetes since 199, hypertension, triple antihypertensives, myocardial infarction in 4, statin and aspirin user, mildly obese Failing oral therapy (SU metformin), HbA1c.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 Complications % 4 3 1% HbA1c = 33% eyes, kidney heart/bloodvessels,,, 9,, HbA 1c (%) ADA/EASD goals HbA1c <.% UKPDS 199 1
What do doctors want to achieve with? What is success? Reduce hyperglycaemic complaints (if any) Achieve (near) normoglycaemia: BG between and 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 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. Discuss misconceptions and misbelieves Insulin treatment options in type diabetes Choices, choices, choices... 9 Basal Basal Short acting insulin Usually injections Short acting insulin Usually 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? /? 3/? /? 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 Short acting insulin (analog) prandially Usually injections mix of short acting insulin (analog) Basal more than combinations of insulin and oral agents are possible; / oral agents 1 metformin 3 dd mg* gliclazide 3 dd 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, /? 3/? /? NPH insulin? Glargine / Levemir? while adjusting when needed by the patient Continue which oral agents? SU? Metformin? TZD? * or dd mg
13 Once daily insulin: basal injection always combined with oral agents metformin 3 dd mg beneficial for weight gain and/or insulin dose may increase risk hypo 14 Twice daily insulin mixture: for instance Humalog Mix R / NovoMix 3 R metformin 3 dd mg gliclazide 3 dd mg fast acting long acting * or dd mg 1 Pre prandial insulin injections Insulin aspart/lispro fast fast fast acting Cán work, but frequently basal insulin needed 1 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 1 1 Address patient reluctance: patients who perform self monitoring of blood glucose will more rapidly switch from tablets to insulin 3
Starter insulin regimen in type diabetes vary across Europe Results from the INSTIGATE study Simple starter regimens need intensification over time: lessons from DURABLE study 19 LM LisPro Mix ients % of pat basal only premixed only short acting only basal-bolus other 4 lity Probabil p=.4 between treatment difference Glargine Germany France UK Greece Spain Months of Maintaining HbA 1c Goal <.% Smith H, et al. Diabetologia ; 1 (suppl. 1): S443 Wolffenbuttel BHR, et al. EASD 4T: long term effects 4T: intensified insulin regimen gives lowest HbA1c 1 % need to add fast acting insulin Basal Biphasic Prandial.±1. %.3±.9 %, p=. vs. biphasic.±.9 %, p<.1 vs. biphasic/prandial Δ.±1. 1.3±1.1 1.4±1. 9 HbA1c ( (%) P<.1 Holman R, et al. NEJM 9 3 9 1 Time (months) adapted from: N Engl J Med ; 3: 11 3 3 but at a price of higher body weight, insulin dose and hypoglycaemia Basal Biphasic Prandial Change in BW (kg) Insulin dose (U) Hypo & 1.9 ±4. 4 ( to ).3 4. ± 4* 4. 4 (3 to 1). *. ±4. * # (34 to ) 1. * # & Grade events/patient/year N Engl J Med ; 3: 11 3 4 NICE: better postprandial BG control with ultrafast acting insulin analog.... FBG (mmol/l) HbA1c (%) 9 9 1 3 4 Time (yrs) HbA1c. HbA1c. 1 3 4 4 Time (yrs) PPBG (mmol/l) 1 * * * * * 1 3 4 Time (yrs) 34 Japanese pat s w. TDM 3 injections fast acting insulin, NPH if needed Regular (Actrapid) vs Insulin aspart (NovoRapid) Nippon ultrapid Insulin & diabetic Complications Evaluation (NICE) * p<. adapted from: Nishimura et al. Diabetologia (A1349) 4
... does reduce c.v. events!! (MI, angina, PCI/CABG, TIA/CVA) But all patients had short duration of diabetes! Insulin treatment options in type diabetes vents (%) 1 43% HR. CI:.34.9 (p<.) Short acting insulin (analog) prandially Usually injections mix of short acting insulin (analog) Basal / oral agents C.V. e 4 and long acting insulin 1 3 4 Time (years) Summary of all studies What are the main differences? Nippon ultrapid Insulin & diabetic Complications Evaluation (NICE) ClinicalTrials.gov NCT1 adapted from: Nishimura et al. Diabetologia (A1349) Some general issues on insulin regimens 1 Some general issues on insulin regimens Long acting insulin analogs vs. NPH insulin: fewer hypo's with better HbA1c reduction, and less variation of fasting glucose (basal bolus) (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 Simple starter insulin regimens need intensification within 14 to 1 months, because of HbA1c increase HbA1c (if OA s continued) (3 % HbA1c.%) PPBG control better better worse regimen difficult slightly difficult easy, continue OA s hypoglycaemia weight gain complications??? In, several long term clinical trials have reported their results 9 Is intensified harmful? 3 What did they study? VADT 1. Can strict glycaemic control prevent cardiovascular complications?. Do we need to aim for HbA1c <.%?
Macrovascular outcomes in ACCORD and ADVANCE: no difference between 'standard' and 'intensive' Speculations on cause of increased mortality in ACCORD is answered in VADT substudy 31 trial stopped early because of side effects with intensive R/ 3 Coronary artery calcification (CAC) score measured in 31 4 VADT participants 4 3 4% had CAC score > 4 3 CAC predicted new events Intensive therapy is especially effective in low CAC score h c.v. event % with 1 p<.1 std int < > CAC score CAC=, (very high risk) RACED: Risk Factors, Atherosclerosis and Clinical Events in Diabetes adapted from: Reaven. ADA presentation VADT, June Diabetes duration determines the risk of c.v. events during intensive (insulin) therapy (VADT) Diabetes metabolic syndrome Genes? 33 Deleterious 34 treatment low grade inflammation Risk 1 hypoglycaemia upregulation HPA -axis/ GH Benefit 3 9 1 1 1 1 Diabetes duration (yrs) dietary factors? metabolic imbalances adverse effect on vasculature which is already damaged in diabetes cardiac arrhythmia acceleration of atherosclerosis ischaemia C.V. event adapted from: Duckworth. ADA presentation VADT, June 3 Is intensified harmful? No, if started early in course of disease No, but don't use in those with severe c.v. cv disease 3 Factors for success in Education: discuss expectations discuss 'insulin resistance' and teach SMBG discuss weight gain and hypoglycaemia (and how to avoid it) 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
Once daily insulin: basal injection always combined with oral agents Twice daily insulin mixture: for instance Humalog Mix 3 metformin 3 dd mg ( dd mg) gliclazide 3 dd mg 3 metformin 3 dd mg ( dd mg) fast acting long acting 1. continue oral agents. add E long acting insulin at bedtime of breakfast 3. titrate on fasting BG 4. if hypoglycemia, reduce sulphonylurea dose. if daytime hyperglycemia, add nd injection of insulin 1. continue metformin. give /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 39 Pre prandial insulin injections Insulin aspart/lispro fast fast fast acting 4 Basal bolus : maximal flexibility metformin 3 dd mg ( dd mg) fast fast fast acting long acting Aspart/lispro NPH/ Glargine 1. continue metformin. give insulin at 4% breakfast, % 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. give 3 4% of insulin as long acting at bedtime. titrate on BG before main meals / at bedtime, later on p.p. BG 3. self monitoring mandatory 4. reduce dose when exercising / eating less Insulin injection regimens in type diabetes Insulin injection regimens in type diabetes 41 Continue oral agents Add long acting insulin bedtime Continue metformin Twice daily / mixture 4 Basal / / Biphasic Add fast acting insulin when significant hyperglycemia Change % fast acting in mixtures when postprandial hyperglycemia Basal / / Biphasic i Add nd fast acting insulin when significant hyperglycemia Add fast acting insulin at lunch when afternoon hyperglycemia Basal / / Biphasic Fast acting insulin before meals Long acting at bedtime long acting biphasic fast acting Multiple injections
Take home messages on 43 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 1 months, because HbA1c increase