Type 2 Diabetes Use of Insulin. Today 5/24/10. Robert J. Rushakoff, MD

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1 Type 2 Diabetes Use of Insulin Robert J. Rushakoff, MD Professor of Medicine University of California, San Francisco robert.rushakoff@ucsf.edu Today Quick Year in Review Why do some patients need to take insulin Insulin Basics Studies on Use of Insulin Actual Use of Insulin Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study Hazard ratios for progression to first large-vessel disease event by HbA 1c Lancet :

2 CVD Intervention Studies ADVANCE ACCORD VA ACCORD: Action to Control Cardiovascular Risk in Diabetes 10,251 Enrollees 60% male 40% female Mean age 62.2 Baseline HgA1c 8.1% BMI % macrovascular dx Duration DM: 10 years Majority of intensive group on 3-5 oral agents plus insulin Hypoglycemia 3 times greater in intensive group Primary and Secondary Outcomes The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:

3 ACCORD: Hazard Ratios for the Primary Outcome and Death from Any Cause in Prespecified Subgroups The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358: Epidemiologic Relationships Between A1C and All-Cause Mortality During a Median 3.4-Year Follow-up of Glycemic Treatment in the ACCORD Trial Diabetes Care May 2010 vol. 33 no Epidemiologic Relationships Between A1C and All-Cause Mortality During a Median 3.4-Year Follow-up of Glycemic Treatment in the ACCORD Trial Diabetes Care May 2010 vol. 33 no

4 Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus Mean Systolic Blood-Pressure Levels at Each Study Visit The ACCORD Study Group. N Engl J Med 2010; /NEJMoa Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus Lipid Values The ACCORD Study Group. N Engl J Med 2010; /NEJMoa

5 Effects of Intensive Blood-Pressure Control and Combination Lipid Therapy in Type 2 Diabetes Mellitus Kaplan-Meier Analysis of Primary Outcome in the ACCORD Study The ACCORD Study Group. N Engl J Med 2010; /NEJMoa The ACCORD Study Group. N Engl J Med 2010; /NEJMoa Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus The interpretation of the ACCORD BP results is complicated by the fact that the event rate observed in the standard-therapy group was almost 50% lower than the expected rate. The ACCORD Study Group. N Engl J Med 2010; /NEJMoa Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus Hazard Ratios for the Primary Outcome in Prespecified Subgroups The ACCORD Study Group. N Engl J Med 2010; /NEJMoa

6 Metformin and B12 Decrease in vitamin B12 levels. (decreased %) Metformin is thought to induce malabsorption of vitamin B12 and intrinsic factor in the ileum, an effect that can be reversed by increased calcium intake. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomized placebo controlled trial BMJ 2010;340:c2181 Metformin and B12 Anemia may be minimal to severe may present only as a peripheral neuropathy, possibly being misdiagnosed as diabetic neuropathy. 6

7 Incretin Drugs GLP Agonists Exenatide Liraglutide Semaglutide Albiglutide Taspoglutide Exenatide Lar Lixsenatide DPP 4 Inhibitors Vildagliptin Sitagliptin Saxagliptin Alogliptin Linagliptin Dutogliptin metogliptin Liraglutide Administer once daily at any time of day, independently of meals Inject subcutaneously in the abdomen, thigh or upper arm. The injection site and timing can be changed without dose adjustment Initiate at 0.6 mg per day for one week. This dose is intended to reduce gastrointestinal symptoms during initial titration, and is not effective for glycemic control. After one week, increase the dose to 1.2 mg. If the 1.2 mg dose does not result in acceptable glycemic control, the dose can be increased to 1.8 mg. When initiating liraglutide, consider reducing the dose of concomitantly-administered insulin secretagogues to reduce the risk of hypoglycemia Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26- week randomised, parallel-group, multinational, open-label trial (LEAD-6) Lancet :

8 Diabetic Patients Medication Underuse, Illness Outcomes, and Beliefs About Antihyperglycemic and Antihypertensive Treatments Perceived need for antihyperglycemic medication was associated with being younger, being prescribed insulin, and being prescribed multiple medications. Concern about antihyperglycemic medications was associated with being younger, African American, dissatisfied with information received about medication, and of low health literacy Diabetes Care January Medication Adherence OHA -- retrospective analysis: 36-93% remain on treatment for 6-24 months. Prospective electronic monitoring 67-85% to as prescribed. Insulin adherence in type 2 was 62-64%. Diabetes Care 27: , 2004 Patients with Type 2 DM who do not obtain at least 80% of their oral antihyperglycemic medications across 1 year are at a higher risk of hospitalization in the following year. Diabetes Care 27: ,

9 Medication Adherence Problems Paying Out-of Pocket Medication Costs Among Older Adults with Diabetes In past year: 19% cut back on medication for cost 11% cut back on DM meds 7% cut back at least once per month 28% reported forgoing food or other essentials to pay medication costs Diabetes Care 27: , 2004 Type 2 Diabetes: What to do when the pills don t work What does this mean? Why is it occurring? Changing goals Compliance Wrong diagnosis Problem with oral hypoglycemic agent Natural progression of disease Latent Autoimmune Diabetes In Adults Patients usually aged > 25 Clinical presentation masquerading as nonobese type 2 diabetes Initial control achieved with diet alone or diet and oral hypoglycemic agents Insulin dependency occurs within months but can take 10 years 9

10 Latent Autoimmune Diabetes In Adults Other features of type 1 diabetes: Low fasting and postglucagon stimulated C-peptide HLA susceptibility alleles ICA + Newly Diagnoses type 2 diabetics in Anti-GAD + UKPDS ICA 6% Anti GAD 10% both 4% Type 2 Diabetes: What to do when the pills don t work What does this mean? Why is it occurring? Changing goals Compliance Wrong diagnosis Problem with oral hypoglycemic agent Natural progression of disease Metformin and egfr 186 x (Creat / 88.4) x (Age) x (0.742 if female) x (1.210 if black) Current Guidelines call for discontinuation of Metformin serum creatinine >150 umol/l (1.7 mg/dl). Estimated GFR (egfr) being introduced as possible better measure of renal function than serum creatinine alone egfr of 36 ml/min per 1.73m 2 would be somewhat neutral to current use 10

11 Type 2 Diabetes: What to do when the pills don t work What does this mean? Why is it occurring? Changing goals Compliance Wrong diagnosis Problem with oral hypoglycemic agent Natural progression of disease Conventional Therapies Do Not Influence β-cell Failure: UKPDS HbA1c(%)! 10! Conventional!Chlorpropamide! Metformin! Insulin! Glibenclamide! 9! 8! 7! Overweight! cohort, median values! 6! 0! -1! 0! 2! 4! 6! 8! 10! Years from randomization! ß cell function (%)! 100! 80! 60! 40! 20! Non-Overweight! Overweight! 100! 80! 60! 40! 20! 0! 0! 0! 1! 2! 3! 4! 5! 6! 7! 0! 1! 2! 3! 4! 5! 6! 7! Years from randomization! Conventional! Sulphonylurea! Metformin! ß cell function (%)! UKPDS 34. Lancet 1998; 352: ! UKPDS 16: Diabetes 1995; 44: ! Insulins Available in the US Types and Action profile (h) Preparations Onset Peak Duration Rapid-acting Lispro/aspart/ glulisine Regular Intermediate-acting NPH U Long-acting Glargine Detemir

12 Insulin: Use and Adjustments Types and Preparations Timing Injection Glucose check Rapid-acting Lispro/aspart/ 10 min premeal 2 hour post meal glulisine and before next meal Regular 30 min premeal before next meal Intermediate-acting NPH Morning Pre-dinner Night Fasting Long-acting Glargine/detemir PM Fasting Insulin Basics Storage Current vial - room temperature Stored vials - refrigerate Mixing Clear short acting insulin (regular or lispro/ aspart) added to syringe first Glargine, detemir not mixed at all Insulin Basics Injection Sites Classic: Upper arms, thighs, abdomen Regular: best in abdomen - most reproducible Intermediate: best in abdomen and thighs Analogues: equal throughout 12

13 Insulin and Glucose Patterns Normal Glucose Insulin mg/dl µu/ml B L S Time of Day B L S Time of Day Polonsky, et al. N Engl J Med. 1988;318: Insulin Regimens Relative Insulin Level 12pm Breakfast Lunch Dinner Time Insulin Regimens Relative Insulin Level AM NPH 12pm Breakfast Lunch Dinner Time 13

14 Insulin Regimens Relative Insulin Level NPH PM NPH 12pm Breakfast Lunch Dinner Time Profiles of glucose over 24 hours both before (broken line) and after (solid line) treatment of a group of individuals with type 2 diabetes with a single injection of neutral protamine Hagedorn insulin at bedtime titrated to control fasting glucose. The glucose curve is shifted downward, with nearly normal fasting levels achieved but also with persistence of postprandial increments Diabetes Care 18 (1995), pp Insulin Regimens Relative Insulin Level NPH BID NPH 12pm Breakfast Lunch Dinner Time 14

15 Insulin Regimens Relative Insulin Level NPH regular BID R and NPH 12pm Breakfast Lunch Dinner Time Insulin Regimens Relative Insulin Level regular NPH BID R and NPH 12pm Breakfast Lunch Dinner Time Insulin Regimens Relative Insulin Level regular NPH TID R and hs NPH 12pm Breakfast Lunch Dinner Time 15

16 Insulin Regimens Relative Insulin Level Lispro/aspart Long analogue BID lispro/aspart 12pm Breakfast Lunch Dinner Time Insulin Regimens Relative Insulin Level NPH TID lispro/aspart/glulisine and hs NPH Lispro/aspart/ glulisine 12pm Breakfast Lunch Dinner Time 16

17 Insulin Regimens Relative Insulin Level NPH TID lispro/aspart/glulisine and bid NPH Lispro/aspart/ glulisine 12pm Breakfast Lunch Dinner Time Insulin Regimens Relative Insulin Level glargine PM glargine 12pm Breakfast Lunch Dinner Time Correcting Fasting Hyperglycemia 300 Uncontrolled A1C ~9% Controlled A1C <7% PG (mg/dl) 200 A1C ~6% 100 Normal A1C 5% 6% Time of Day Adapted with permission from Cefalu WT. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel Dekker; 2002:1 17

18 Insulin Regimens Relative Insulin Level TID lispro/aspart/glulisine and hs glargine glargine Lispro/aspart/ glulisine 12pm Breakfast Lunch Dinner Time Insulin Regimens Insulin pump Relative Insulin Level Lispro/aspart/ glulisine 12pm Breakfast Lunch Dinner Time 18

19 Three-year efficacy of complex insulin regimens in type 2 diabetes. Holman R et al. N Engl J Med 2009;361: Three-year efficacy of complex insulin regimens in type 2 diabetes. Changes from Baseline to 3 Years in Glycated Hemoglobin, Fasting Plasma Glucose, Postprandial Glucose, and Body Weight and the Rate of Hypoglycemia Holman R et al. N Engl J Med 2009;361:

20 Three-year efficacy of complex insulin regimens in type 2 diabetes. Holman R et al. N Engl J Med 2009;361: Attainment of glycaemic goals in type 2 diabetes with once-, twice-, or thrice-daily dosing with biphasic insulin aspart 70/30 (The study) Diabetes Obes Metab Jan;8(1): Attainment of glycaemic goals in type 2 diabetes with once-, twice-, or thrice-daily dosing with biphasic insulin aspart 70/30 (The study) Diabetes Obes Metab Jan;8(1):

21 Attainment of glycaemic goals in type 2 diabetes with once-, twice-, or thrice-daily dosing with biphasic insulin aspart 70/30 (The study) Diabetes Obes Metab Jan;8(1): Advancing Insulin Therapy in Type 2 Diabetes Previously Treated With Glargine Plus Oral Agents Prandial premixed (insulin lispro protamine suspension/lispro) versus basal/bolus (glargine/ lispro) therapy Daily Insulin Dose Entry BBT 55 ± 28 units [0.6 ± 0.3 units/kg] PPT 52 ± 24 units [0.5 ± 0.2 units/kg] Conclusion 146 ± 85 units [1.4 ± 0.8 units/kg] 123 ± 69 units [1.2 ± 0.5 units/kg] Diabetes Care 2008 vol Insulin Therapy in Type 2 Diabetes: What is the evidence Mariëlle J. P van Avendonk and Guy E. H. M Rutten Diabetes, Obesity and Metabolism epub. 21

22 Insulin Therapy in Type 2 Diabetes: Bottom Line Basal Insulin Premixed Insulin Basal Bolus Insulin Therapy in Type 2 Diabetes: Bottom Line Basal Insulin Continuing metformin and/or sulphonylurea after start of therapy with basal long-acting insulin results in better glycemic control with less insulin requirements, less weight gain and less hypoglycemic events. Long-acting insulin analogues in combination with oral medication are associated with similar glycemic control but fewer hypoglycemic episodes compared with NPH insulin. Insulin Therapy in Type 2 Diabetes: Bottom Line Premixed Insulin Most of the trials demonstrated better glycemic control with premix insulin therapy than with a long-acting insulin once daily, but premix insulin causes more hypoglycemic episodes. Analogue premix provides similar HbA1c, but lower postprandial glucose levels compared with human premix, without increase in hypoglycemic events or weight gain. 22

23 Insulin Therapy in Type 2 Diabetes: Bottom Line Basal Bolus Drawing conclusions from the limited number of studies concerning basal-bolus regimen seems not possible. Some studies showed that rapid-acting insulin analogues frequently result in a better HbA1c or postprandial glucose without increase of hypoglycemia than regular human insulin. Insulin Therapy in Type 2 Diabetes: Bottom Line A once-daily basal insulin regimen added to oral medication is an ideal starting point. All next steps, from one to two or even more injections per day should be taken very carefully and in thorough deliberation with the patient, who has to comply with such a regimen for many years Starting Insulin Patient Barriers Using insulin as a threat Fear of injections Weight gain Insulin meaning they have bad diabetes and now will get complications or die Worsening of atherosclerosis Patient leaves and does not come back 23

24 Starting Insulin Home glucose Monitoring Reinforce basic diet Discuss reasons that the oral agents are no longer adequate to control their diabetes Teach insulin techniques Starting Insulin Not at goal on Sulfonylurea, Metformin, Thiazolidinedione, DPP 4 inhib, and/or GLP angonist Option 1: Start am or hs glargine or hs detemir Start at about 10 Units Titrate up by 2-8 units every 5-7 days based on fasting glucose level.? Which other drugs to continue 24

25 When to go to > 1 shot per day HgA1c >7 or your goal Morning or evening glucose remains > 140 mg/dl Options Split the glargine or detemir Glucose in AM at goal; Glucose before dinner >140 (pm shot) Glucose in PM at goal; Glucose in AM >140 (am shot) Add premeal lispro/aspart/glulisine Change to bid premixed insulin 70/30, 75/25 Questions DC sulfonylurea Continue metformin? Thiazolidinedione Premixed Insulins Insulin Name First Component Second Component Component Ratio First:Second Humulin 70/30 Human NPH Human Regular 70:30 Humalog 50/50 lispro protamine lispro 50:50 Humalog 75/25 lispro protamine lispro 75:25 Novolin 70/30 Human NPH Human Regular 70:30 Novolog 70/30 aspart protamine aspart 70:30 25

26 Starting Insulin Patient on Sulfonylurea, Metformin and Thiazolidinedione Option 2: Start bid insulin pre mixed Start at about 20 U am, 10 U pm Titrate up by 2-8 units every 5-7 days based on fasting and pre dinner glucose levels. DC of sulfonylurea. Continue metformin,?? Thiazolidinedione 26

27 A 1c Control in a Primary Care Setting: Self-titrating an Insulin Analog Pre-mix (INITIATEplus Trial) Am J Med ;122(11): A 1c Control in a Primary Care Setting: Self-titrating an Insulin Analog Pre-mix (INITIATEplus Trial) Am J Med ;122(11):

28 Adjust to Target in Type 2 Diabetes: Comparison of a simple algorithm with carbohydrate counting for adjustment of mealtime insulin glulisine Diabetes Care Diabetes Care Adjust to Target in Type 2 Diabetes: Comparison of a simple algorithm with carbohydrate counting for adjustment of mealtime insulin glulisine Diabetes Care

29 Amylin 37-amino acid β-cell hormone that is co-secreted with insulin in response to meals Acts as a neuroendocrine hormone that binds to specific receptors in the hindbrain, including area postrema Has both glucoregulatory and anorexigenic actions decreases the rate of gastric emptying suppresses hepatic glucose output by inhibiting glucagon secretion Anti-obesity effects in diet-induced obese (DIO) rodents: Reductions in food intake Reductions in body fat, with preservation of lean mass Pramlintide: Soluble Analog of Human Amylin Adapted from Weyer C, et al. Curr Pharm Des 2001; 7: Mack C, et al. Diabetes 2003; 52: A389. Schmitz O, et al. Diabetes 2004; 53:S233-S2381. A T T C N C K Amide Y T L S S N S V N T G Human amylin A I T Q R L A G A N F F L V H S S N N Pramlintide or Mealtime Insulin Added to Basal Insulin Treatment for Patients With Type 2 Diabetes Diabetes Care :

30 DIGAMI2 (European Heart J. Prepublication Feb 2005) Group 1 IV insulin then long term SQ insulin Group 2 IV insulin then standard treatment Group 3 Standard treatment Mortality Effect of different updated glucose lowering treatments on mortality and morbidity Mellbin, L. G. et al. Eur Heart J : Insulin Treatment and Risk of Cancer 1. Hemkens LG, Grouven U, Bender R et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 2009;52: Jonasson JM, Ljung R, Talbäck M, Haglund B, Gudbjörnsdòttir S, Steineck G. Insulin glargine use and short-term incidence of alignancies a population based follow-up study in Sweden. Diabetologia 2009;52: Currie CJ, Poole CD, Gale EAM. The influence of glucose lowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009;52: Colhoun HM, SDRN Epidemiology Group. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia 2009;52:

31 Insulin Treatment and Risk of Cancer Four studies Studies involve convoluted statistical manipulation of epidemiologic data There are fundamental internal disagreements and multiple inconsistencies. Does Diabetes Therapy Influence the Risk of Cancer? German study 1 : N=127,031 Glargine vs human insulin - a decrease in all cancers with Glargine After adjusting for dose, a dose-dependent increase in cancer risk was found for treatment with glargine compared with human insulin (P<.0001): the adjusted HR was 1.09 for a daily dose of 10 IU, 1.19 for 30 IU, and 1.31 for 50 IU No increased risk was found for aspart or lispro compared with human insulin did not take into account body mass index and the duration of time that the patients were on insulin. time on insulin was very short, only about 1.6 years, 1. Hemkens LG, et al. Diabetologia doi: /s Does Diabetes Therapy Influence the Risk of Cancer? 4 Large Observational Studies Swedish study 1 : N=114,841 No statistically significant difference in cancer incidence between patients on insulins other than glargine, and those on glargine plus other insulins Women on glargine alone, however, had a higher risk of breast cancer than those on insulins other than glargine, with an RR of Jonasson JM, et al. Diabetologia doi: /s

32 Does Diabetes Therapy Influence the Risk of Cancer? 4 Large Observational Studies Swedish study 1 : N=114,841 In Sweden, an increased risk of breast cancer was reported only in women who used glargine insulin alone, but not in those women who used glargine insulin plus other types of insulin 1. Jonasson JM, et al. Diabetologia doi: /s Does Diabetes Therapy Influence the Risk of Cancer? (cont) Scottish study 1 : N=49,197 4 Large Observational Studies Glargine with rapid-acting insulin had a slightly lower rate of cancer progression than did human insulin (HR 0.8, P<.26), but glargine alone had a higher overall rate (HR 1.55, P=.045) The number of site-specific cancers was small, but more cases of breast cancer were noted with glargine alone, compared with nonglargine insulins (HR 3.39, P=.004) 1. Colhoun HM; for the SDRN Epidemiology Group. Diabetologia doi: / s Does Diabetes Therapy Influence the Risk of Cancer? (cont) Scottish study 1 : N=49,197 4 Large Observational Studies Glargine overall, no increase in cancer Breast Cancer no increase for all glargine users Breast Cancer - Increase for glargine only - only 6 cases 1. Colhoun HM; for the SDRN Epidemiology Group. Diabetologia doi: / s

33 Does Diabetes Therapy Influence the Risk of Cancer? (cont) UK study 1 : N=62,809 4 Large Observational Studies Metformin monotherapy carried the lowest risk of cancer; adjusted HR was 1.08 for metformin + sulfonylurea, 1.36 for sulfonylurea monotherapy, and 1.42 for insulin-based regimens; adding metformin to insulin reduced progression to cancer (HR 0.54); risk for patients on basal human insulin alone vs glargine was 1.24 Compared with metformin, insulin therapy increased the risk of colorectal (HR 1.69) or pancreatic cancer (HR 4.63) but did not influence the risk of breast or prostate cancer; sulfonylureas were associated with a similar pattern of risk as insulin 1. Currie CJ, et al. Diabetologia doi: /s Insulin Treatment and Risk of Cancer Many types of cancer are increased in diabetic patients Recent retrospective observational studies suggest that longacting insulin analog glargine may increase and that biguanide metformin may decrease cancer risk The evidence provided by these studies is weak and disputable because of many experiment and analysis limitations. Therefore it is possible neither to confirm nor to exclude the effect of these drugs on cancer in diabetic patients. While waiting for more careful studies we have no evidencebased rationale for changing treatment approach to diabetic patients Drug Cost Comparison Drug and Dose Cost/month Glucose Strips (2 per day) $66 Sulfonylurea Generic $4-14 Brand $50 Rapaglinide 2 mg tid/nateglinide 120 tid $193/164 Acarbose 100 mg tid $88 Metformin 1000 bid Generic $ 4-32 Brand $161 Rosiglitazone 8 mg qd $266 Pioglitazone 45 mg/d $245 Sitagliptin/Saxagliptin $207/190 Exenatide 10mcg /Liraglutide 1.2mg $271/280 Colesevelam 3750 mg/d $224 Bromocriptine 2.5-5mg $ Glargine, 45 U/d /(pen) $150/182 Salsalate 4g/d $50 24 hour fitness center $35 YMCA $65 33

34 Drug Cost Comparison Glargine (45 Drug units/d), and Dose metformin, glimepiride Cost/month 1-2 checks per day $226 Glucose Strips (2 per day) $66 Glargine (45 units/d), metformin, glimepiride Sulfonylurea Generic $4-14 Exenatide (10 bid) Brand $ checks per day $497 Rapaglinide 2 mg tid/nateglinide 120 tid $193/164 Acarbose 100 mg tid $88 Glargine (45 units/d), metformin, glimepiride Metformin 1000 bid Generic $ 4-32 symlin Brand $ checks per day $537 Rosiglitazone 8 mg qd $266 Pioglitazone 45 mg/d $245 Novolog 70/30 (80 Units/d), metformin Sitagliptin/Saxagliptin $207/190 2 checks per day $423 Exenatide 10mcg /Liraglutide 1.2mg $271/280 Colesevelam 3750 mg/d $224 Glargine (45 units/d), Lispro 50 units/d, Bromocriptine 2.5-5mg $ Metformin Glargine, 45 U/d /(pen) $150/182 4 checks per day $507 Salsalate 4g/d $50 Metformin, glimepiride, pioglitazone 24 hour fitness center $35 Sitagliptin 1-2 checks per day $526 YMCA $65 34