Limitations and opportunities of insulin therapy Luigi Meneghini June 8th, 2012

Outline Insulin need versus implementation Options for initiating insulin in T2DM Limitations & opportunities for more stable basal insulins Degludec pharmacodynamics and clinical studies Adding an incretin to basal insulin replacement

Metabolic Status at Diagnosis of Type 2 Diabetes Insulin resistance 40% 100 75 Beta-cell function 50% Beta Cell Function (%) 50 IGT 25 Postprandial Hyperglycemia Diabetes -12 -10 -6 -2 2 6 10 14 Years From Diagnosis Adapted from Lebovitz HE. Diabetes Reviews. 1999;7(3):139–153.

Glycemic Control with Monotherapy in the UKPDS Over 9 Years Short-acting insulin added in 44% by 9 years KEY POINT: While insulin is clearly most effective in maintaining FPG over time, overall glycemic control (as per A1C) still limited, underscoring need to address both fasting and prandial treatments Insulin treatment details: The initial insulinregimenconsistedof aonce-dailydose of long-acting or isophane insulin. If the daily dosewas above 14 U or if premeal or prebedtime FPG concentration was higher than 7 mmol/L (126 mg/dL), regular insulin was added to the regimen. Larger doses of insulin were used when FPG concentration was higher than6mmol/L(108mg/dL).The median insulin doses at 6 and 9 years from diagnosis of type 2 diabetes were 28 U and 34U, respectively. At 9 years, the median dose was 24 U in non obese and 53 U in obese subjects (BMI, #25 and "35 kg/m2, respectively). If hypoglycemia occurred, the doses were reduced. Although patients initially were treated with a basal insulin supply from long acting insulin, if home blood glucose monitoring or HbA1c levels were unsatisfactory, patients (44%) were transferred to mixtures of long- and short acting insulin or a twice-daily mixture at 9 years. Context Treatment with diet alone, insulin, sulfonylurea, or metformin is known to improve glycemia in patients with type 2 diabetes mellitus, but which treatment most frequently attains target fasting plasma glucose (FPG) concentration of less than 7.8 mmol/L (140 mg/dL) or glycosylated hemoglobin A1c (HbA1c) below 7% is unknown. Objective To assess how often each therapy can achieve the glycemic control target levels set by the American Diabetes Association. Design Randomized controlled trial conducted between 1977 and 1997. Patientswere recruited between 1977 and 1991 and were followed up every 3 months for 3, 6, and 9 years after enrollment. Setting Outpatient diabetes clinics in 15 UK hospitals. Patients A total of 4075 patients newly diagnosed as having type 2 diabetes ranged in age between 25 and 65 years and had a median (interquartile range) FPG concentration of 11.5 (9.0-14.4)mmol/L [207 (162-259)mg/dL], HbA1c levels of 9.1%(7.5%- 10.7%), and a mean (SD) body mass index of 29 (6) kg/m2. Interventions After 3 months on a low-fat, high-carbohydrate, high-fiber diet, patients were randomized to therapy with diet alone, insulin, sulfonylurea, or metformin. Main Outcome Measures Fasting plasma glucose and HbA1c levels, and the proportion of patientswho achieved target levels below7%HbA1c or less than 7.8mmol/L (140 mg/dL) FPG at 3, 6, or 9 years following diagnosis. Results The proportion of patientswhomaintained target glycemic levels declinedmarkedly over 9 years of follow-up. After 9 years of monotherapy with diet, insulin, or sulfonylurea, 8%, 42%, and 24%, respectively, achieved FPG levels of less than 7.8 mmol/L (140 mg/dL) and 9%, 28%, and 24% achieved HbA1c levels below 7%. In obese patients randomized to metformin, 18%attained FPG levels of less than 7.8 mmol/L (140 mg/dL) and 13% attained HbA1c levels below 7%. Patients less likely to achieve target levels were younger, more obese, or more hyperglycemic than other patients. Conclusions Each therapeutic agent, as monotherapy, increased 2- to 3-fold the proportion of patients who attained HbA1c below 7%compared with diet alone. However, the progressive deterioration of diabetes control was such that after 3 years approximately 50% of patients could attain this goal with monotherapy, and by 9 years this declined to approximately 25%. The majority of patients need multiple therapies to attain these glycemic target levels in the longer term. Turner RC et al. JAMA 1999; 281: 2005-2012

Physicians delay intensifying therapy for months, especially initiating insulin 9.5% N=2319 N=3394 N=513 N=982 A1C>8% (mos) 4 17 12 26 A1C>7% (mos) 16 37 51 Brown et al. Diabetes Care 2004; 27: 1535

Options for Initiating & Intensifying Insulin Therapy in Type 2 Diabetes

Less hypoglycemia with basal initiation Insulin Initiation & Intensification Outcomes in T2DM at Baseline, 1 & 3 Years -1.3%* -1.4%* -1.2%* 3.0 5.5 1.7 Less hypoglycemia with basal initiation (events/pt/yr) * 2009 Background Evidence supporting the addition of specific insulin regimens to oral therapy in patients with type 2 diabetes mellitus is limited. Methods In this 3-year open-label, multicenter trial, we evaluated 708 patients who had suboptimal glycated hemoglobin levels while taking metformin and sulfonylurea therapy. Patients were randomly assigned to receive biphasic insulin aspart twice daily, prandial insulin aspart three times daily, or basal insulin detemir once daily (twice if required). Sulfonylurea therapy was replaced by a second type of insulin if hyperglycemia became unacceptable during the first year of the study or subsequently if glycated hemoglobin levels were more than 6.5%. Outcome measures were glycated hemoglobin levels, the proportion of patients with a glycated hemoglobin level of 6.5% or less, the rate of hypoglycemia, and weight gain. Results Median glycated hemoglobin levels were similar for patients receiving biphasic (7.1%), prandial (6.8%), and basal (6.9%) insulin-based regimens (P = 0.28). However, fewer patients had a level of 6.5% or less in the biphasic group (31.9%) than in the prandial group (44.7%, P = 0.006) or in the basal group (43.2%, P = 0.03), with 67.7%, 73.6%, and 81.6%, respectively, taking a second type of insulin (P = 0.002). Median rates of hypoglycemia per patient per year were lowest in the basal group (1.7), higher in the biphasic group (3.0), and highest in the prandial group (5.7) (P<0.001 for the overall comparison). The mean weight gain was higher in the prandial group than in either the biphasic group or the basal group. Other adverse event rates were similar in the three groups. Conclusions Patients who added a basal or prandial insulin-based regimen to oral therapy had better glycated hemoglobin control than patients who added a biphasic insulin-based regimen. Fewer hypoglycemic episodes and less weight gain occurred in patients adding basal insulin. 2007 Adding insulin to oral therapy in type 2 diabetes mellitus is customary when glycemic control is suboptimal, though evidence supporting specific insulin regimens is limited. In an open-label, controlled, multicenter trial, we randomly assigned 708 patients with a suboptimal glycated hemoglobin level (7.0 to 10.0%) who were receiving maximally tolerated doses of metformin and sulfonylurea to receive biphasic insulin aspart twice daily, prandial insulin aspart three times daily, or basal insulin detemir once daily (twice if required). Outcome measures at 1 year were the mean glycated hemoglobin level, the proportion of patients with a glycated hemoglobin level of 6.5% or less, the rate of hypoglycemia, and weight gain. At 1 year, mean glycated hemoglobin levels were similar in the biphasic group (7.3%) and the prandial group (7.2%) (P = 0.08) but higher in the basal group (7.6%, P<0.001 for both comparisons). The respective proportions of patients with a glycated hemoglobin level of 6.5% or less were 17.0%, 23.9%, and 8.1%; respective mean numbers of hypoglycemic events per patient per year were 5.7, 12.0, and 2.3; and respective mean weight gains were 4.7 kg, 5.7 kg, and 1.9 kg. Rates of adverse events were similar among the three groups. A single analogue-insulin formulation added to metformin and sulfonylurea resulted in a glycated hemoglobin level of 6.5% or less in a minority of patients at 1 year. The addition of biphasic or prandial insulin aspart reduced levels more than the addition of basal insulin detemir but were associated with greater risks of hypoglycemia and weight gain. 235 222 201 239 222 188 234 224 189 * P<0.05 Holman, et al. NEJM 2009;361:1736-47. Holman, et al. NEJM 2007;357: 1716-30

Hypoglycaemia limits further reduction of FPG with basal insulin Mean HbA1c [%] Mean annual fasting blood glucose [mmol/l] 12 Frequency of Hypoglycaemic Episodes [%] 10 8 6 4 40 30 20 3 5 7 9 11 n = 13,072 Yki-Jarvinen et al. Ann Int Med 1999

How do Pharmacodynamics of Basal Insulin Preparations Affect Outcomes

Pharmacodynamics of NPH versus Glargine Insulin Plasma glucose Pharmacodynamics of NPH versus Glargine Insulin Glucose infusion rate Lepore, et al. Diabetes 1999; 48 (suppl 1): A97 Bolli et al. The Lancet • Vol 356 • August 5 2000

Biologic activity over 24-hours more consistent for basal insulin analogs Insulin detemir Levemir® Offers a Consistent Blood Glucose Response This randomized, double-blind, parallel-group study (enrolled n=54, completed n=51) compared the within-subject variability of the glucose-lowering effect of Levemir® with insulin glargine and NPH in patients with type 1 diabetes Average A1C at baseline was 7.5% Each patient was randomly assigned to receive 4 subcutaneous injections of 0.4 unit/kg under euglycemic glucose clamp conditions on 4 identical study days Levemir®: n=18 Insulin glargine: n=16 NPH: n=17 The properties of each of the insulin preparations were recorded for 24 hours post-dose The graph reflects the individual time-action profiles over 24 hours GIR = Glucose Infusion Rate Heise et al. Diabetes 2004; 53 (6): 1614-1620 Reference Heise T, Nosek L, Rønn BB, et al. Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes. 2004;53:1614-1620.

Less hypoglycemia with basal analogues vs. NPH * * * * *P<0.05 Riddle et al. Diabetes Care 2003; 26: 3080–3086. Philis-Tsimikas et al. Clin Ther 2006; 28 (10).

Modeled risk of hypoglycemia based on achieved A1C levels Little S, et al. Diab Tech Ther 2011; 13 (S1)

Improving on current basal insulin analogs Extend duration of action Flat pharmacodynamic profile Reduced day-to-day variability

Molecular size determines rate of subcutaneous absorption Subcutaneous tissue Molecular size 6 kDa 36 kDa 72 kDa >5000 kDa Insulin association state Insulin High molecular weight forms Zn2+ Zn2+ Zn2+ Absorption Absorption rate Capillary membrane Rapid absorption Slow absorption Brange et al. Diabetes Care 1990;13:923–54 15

Insulin degludec from solution to subcutaneous depot Phenol Zn2+ Insulin degludec injected As phenol from the vehicle diffuses degludec hexamers link up via single side-chain contacts Long multi-hexamers assemble 16

Insulin degludec multi-hexamers visible with transmission electron microscopy SOLUTION SC DEPOT Main picture shows elongated IDeg structures in absence of phenol; inset (white box) shows absence of elongated IDeg structures in presence of phenol. Main picture shows elongated insulin degludec structures in absence of phenol; inset shows absence of elongated insulin degludec structures in presence of phenol Kurtzhals et al. Diabetes 2011;60(Suppl . 1):LB12 (Abstract 42-LB) (NN1250-1993 + MOA) 17

Insulin degludec: slow release following injection Subcutaneous depot Zn2+ Insulin degludec multi-hexamers Zinc diffuses slowly causing individual hexamers to disassemble, releasing monomers Monomers are absorbed from the depot into the circulation 18

Insulin degludec PD profile at steady state in T1D 2 4 6 8 10 12 14 16 18 20 22 24 Time (hours) 1 3 5 GIR (mg/kg/min) Mean profile, n=66 IDeg = 0.4 U/kg PD, pharmacodynamic Heise et al. Diabetologia 2011;54(Suppl. 1):S425

Terminal half-life & coefficient of variation at steady state Harmonic mean (h) CV (%) Terminal half-life (steady state) Degludec 24.5 23 Glargine 12.2 56 Degludec has a double as long half-life as insulin glargine. The long half-life is what makes the pharmacokinetic profiles flat and thereby gives the stable insulin 454 exposure during the 24 hour period between two doses over 24 hours.

Basal insulin initiation in T2DM IDeg OD + metformin ± DPP-4 (n=773) Insulin-naïve patients with type 2 diabetes (n=1030) IGlar OD + metformin ± DPP-4 (n=257) Inclusion criteria Type 2 diabetes ≥6 months Insulin naïve treated with metformin ± SU, DPP-4 or acarbose for ≥3 months HbA1c 7.0–10.0% BMI ≤40 kg/m2 Age ≥18 years 52 weeks Randomised 3:1 (IDeg OD:IGlar OD) Open label Insulin degludec administered with main evening meal Insulin glargine administered according to label DPP-4, dipeptidyl peptidase-4 inhibitor SU, sulphonylurea OD, once daily Data on file: NN1250-3579; Accepted for presentation at ADA 2012

Pre-breakfast plasma glucosea Weekly titration algorithm for insulin degludec and insulin glargine in T2DM Pre-breakfast plasma glucosea Adjustment mmol/L mg/dL U <3.1b <56b –4 3.1–3.9b 56–70b –2 4.0–4.9 71–89 5.0–6.9 90–125 +2 7.0–7.9 126–143 +4 8.0–8.9 144–161 +6 ≥9.0 ≥162 +8 a Mean of 3 consecutive days’ measurements for up titration. b Unless there is obvious explanation for the low value, such as a missed meal

Serum IDeg concentration Proportion of Day 10 level (%) Insulin degludec steady state is reached within 2–3 days of once-daily dosing 1 2 3 4 5 6 7 8 9 10 20 30 40 50 60 70 80 90 100 110 120 Days since first dose Serum IDeg concentration Proportion of Day 10 level (%) Relative serum IDeg trough concentrations during initiation of once-daily (0.4 U/kg) dosing in patients with T1DM Values are estimated ratios and 95% CI relative to day 10 Heise T et al. IDF 2011 21st World Congress Abstract Book. IDF: Dubai, 2011; Poster 1453

Pharmacokinetics of insulin steady state Receptor activation & insulin clearance Absorption from the SC depot

No difference in HbA1c decrease over time between degludec & glargine Degludec (n=773) Glargine (n=257) Treatment differences are derived from an LSMeans-based model 0.0 Time (weeks) Mean±SEM; FAS; LOCF Comparisons: Estimates adjusted for multiple covariates Data on file: NN1250-3579; Accepted for presentation at ADA 2012

No difference in overall confirmed hypoglycaemia HYPOGLYCEMIA BG < 56 mg/dl or severe 18% (ns) Degludec (n=773) Glargine (n=257) Please note that after 26 weeks of the 52-week trial, visit (and therefore, reporting) frequency decreased. Statistics based on FAS Time (weeks) SAS Comparisons: Estimates adjusted for multiple covariates Data on file: NN1250-3579; Accepted for presentation at ADA 2012

Lower nocturnal confirmed hypoglycaemia with insulin degludec Degludec (n=773) Glargine (n=257) 36% p<0.05 Please note that after 26 weeks of the 52-week trial, visit (and therefore, reporting) frequency decreased. Statistics based on FAS Time (weeks) SAS Comparisons: Estimates adjusted for multiple covariates Data on file: NN1250-3579; Accepted for presentation at ADA 2012 27

Forced flexible insulin degludec study design Degludec OD Flexible ±OADs (n=229) (metformin/SU/pioglitazone) Patients with type 2 diabetes (n=687) Degludec OD Fixed ±OADs (n=228) (metformin/SU/pioglitazone) Glargine OD ±OADs (n=230) (metformin/SU/pioglitazone) Inclusion criteria Type 2 diabetes ≥6 months Previously treated with OADs and/or basal insulin HbA1c: OADs only 7–11% Basal insulin ± OADs 7–10% BMI ≤40 kg/m2 Age ≥18 years 26 weeks Open label Birkeland et al. IDF 2011:P-1443; Bain et al. IDF 2011:O-0508; Birkeland et al. Diabetologia 2011;54(suppl. 1):S423; Atkin et al. Diabetologia 2011;54(suppl. 1):S53; Meneghini et al. Diabetes 2011;60(suppl. 1A):LB10 (NN1250-3668)

Timing of flexible insulin degludec administration 29 Timing of flexible insulin degludec administration Mon Tue Wed Thu Fri Sat Sun morning morning morning 8h 8h 40h 40h 40h 8-12 AND 36-40 hours between insulin administration evening evening evening evening 24h

No difference in A1C between flexible degludec and fixed dosing Degludec Flexible OD Degludec OD Glargine OD Treatment differences are derived from an LSMeans-based model 0.0 Time (weeks) Birkeland et al. IDF 2011:P-1443; Bain et al. IDF 2011:O-0508; Birkeland et al. Diabetologia 2011;54(suppl. 1):S423; Atkin et al. Diabetologia 2011;54(suppl. 1):S53; Meneghini et al. Diabetes 2011;60(suppl. 1A):LB10 (NN1250-3668) 30

Nocturnal hypoglycemia No difference in hypoglycemia between flexible degludec and fixed dosing Degludec Flexible OD Degludec OD Glargine OD Overall hypoglycemia Nocturnal hypoglycemia 23%(ns) 18%(ns) cumulative events/patient/yr cumulative events/patient/yr Time (weeks) Birkeland et al. IDF 2011:P-1443; Bain et al. IDF 2011:O-0508; Birkeland et al. Diabetologia 2011;54(suppl. 1):S423; Atkin et al. Diabetologia 2011;54(suppl. 1):S53; Meneghini et al. Diabetes 2011;60(suppl. 1A):LB10 (NN1250-3668)

Insulin Lispro Pegylation = 20-40 kDa

Pegylated Lispro Insulin PD

Fasting vs. post-prandial contribution to A1C: baseline & after basal insulin Fasting hyperglycemia Post-prandial hyperglycemia OBJECTIVE To determine the relative contributions of basal hyperglycemia (BHG) versus postprandial hyperglycemia (PPHG) before and after treatment intensification in patients with glycated hemoglobin A1c (A1C) >7.0% while on prior oral therapy. RESEARCH DESIGN AND METHODS Self-measured, plasma-referenced glucose profiles and A1C values were evaluated from participants in six studies comparing systematically titrated insulin glargine with an alternative regimen (adding basal, premixed, or prandial insulin, or increasing oral agents). Hyperglycemic exposure (>100 mg/dL [5.6 mmol/L]) as a result of BHG versus PPHG was calculated. RESULTS On prior oral therapy, 1,699 participants (mean age 59 years, diabetes duration 9 years) had mean fasting plasma glucose (FPG) of 194 mg/dL (10.8 mmol/L), and mean A1C was 8.7%. BHG contributed an average of 76–80% to hyperglycemia over the observed range of baseline A1C levels. Adding basal insulin for 24 or 28 weeks lowered mean FPG to 117 mg/dL (6.5 mmol/L), A1C to 7.0%, and BHG contribution to 32–41%. Alternative regimens reduced FPG to 146 mg/dL (8.1 mmol/L), A1C to 7.1%, and the contribution of BHG to 64–71%. BHG contributions for patients with A1C averaging 7.6–7.7% were 76% at baseline and 34 and 68% after adding basal insulin or other therapies, respectively. CONCLUSIONS When A1C is >7.0% despite oral therapy, BHG routinely dominates exposure. Intensified therapy reduces A1C and changes this relationship, but BHG amenable to further intervention still accounts for one-third of total hyperglycemia after basal insulin treatment and two-thirds after alternative methods. Basal insulin Riddle, et al. Diabetes Care 2011; 34 (12): 2508-2514

Exenatide added to basal insulin glargine improves control in T2DM A1C 8.3-8.5% Insulin 0.5 u/kg BMI 33-34 -1.0% +20u +1.0kg -1.7% +13u -1.8kg BACKGROUND: Insulin replacement in diabetes often requires prandial intervention to reach hemoglobin A₁(c) (HbA₁(c)) targets. OBJECTIVE: To test whether twice-daily exenatide injections reduce HbA₁(c) levels more than placebo in people receiving insulin glargine. DESIGN: Parallel, randomized, placebo-controlled trial, blocked and stratified by HbA₁(c) level at site, performed from October 2008 to January 2010. Participants, investigators, and personnel conducting the study were masked to treatment assignments. (ClinicalTrials.gov registration number: NCT00765817) SETTING: 59 centers in 5 countries. PATIENTS: Adults with type 2 diabetes and an HbA₁(c) level of 7.1% to 10.5% who were receiving insulin glargine alone or in combination with metformin or pioglitazone (or both agents). INTERVENTION: Assignment by a centralized, computer-generated, random-sequence interactive voice-response system to exenatide, 10 µg twice daily, or placebo for 30 weeks. MEASUREMENTS: The primary outcome was change in HbA₁(c) level. Secondary outcomes included the percentage of participants with HbA₁(c) values of 7.0% or less and 6.5% or less, 7-point self-monitored glucose profiles, body weight, waist circumference, insulin dose, hypoglycemia, and adverse events. RESULTS: 112 of 138 exenatide recipients and 101 of 123 placebo recipients completed the study. The HbA₁(c) level decreased by 1.74% with exenatide and 1.04% with placebo (between-group difference, -0.69% [95% CI, -0.93% to -0.46%]; P < 0.001). Weight decreased by 1.8 kg with exenatide and increased by 1.0 kg with placebo (between-group difference, -2.7 kg [CI, -3.7 to -1.7]). Average increases in insulin dosage with exenatide and placebo were 13 U/d and 20 U/d. The estimated rate of minor hypoglycemia was similar between groups. Thirteen exenatide recipients and 1 placebo recipient discontinued the study because of adverse events (P < 0.010); rates of nausea (41% vs. 8%), diarrhea (18% vs. 8%), vomiting (18% vs. 4%), headache (14% vs. 4%), and constipation (10% vs. 2%) were higher with exenatide than with placebo. LIMITATIONS: The study was of short duration. There were slight imbalances between groups at baseline in terms of sex, use of concomitant glucose-lowering medications, and HbA₁(c) levels, and more exenatide recipients than placebo recipients withdrew because of adverse events. CONCLUSION: Adding twice-daily exenatide injections improved glycemic control without increased hypoglycemia or weight gain in participants with uncontrolled type 2 diabetes who were receiving insulin glargine treatment. Adverse events of exenatide included nausea, diarrhea, vomiting, headache, and constipation OBJECTIVE To determine variables associated with glycemic and body weight responses when adding exenatide to basal insulin-treated type 2 diabetes. RESEARCH DESIGN AND METHODS Exploratory subgroup analyses based on baseline A1C, disease duration, and BMI of a 30-week study comparing exenatide twice daily to placebo, added to optimized insulin glargine (intent-to-treat analysis: 137 exenatide; 122 placebo). RESULTS Exenatide participants had greater A1C reductions compared with optimized insulin glargine alone, irrespective of baseline A1C (P < 0.001). Exenatide participants with longer diabetes duration and those with lower BMI had greater A1C reductions (P < 0.01). Exenatide participants lost more weight, regardless of baseline A1C or BMI (P < 0.05). Exenatide participants with longer diabetes duration lost the most weight (P < 0.001). CONCLUSIONS Exenatide added to optimized basal insulin was associated with improved glycemic control and weight loss, irrespective of baseline A1C, diabetes duration, and BMI. Changes were evident in modestly obese patients and in those with longer diabetes duration. Longer diabetes duration and lower BMI had greater A1C reductions. Longer diabetes duration also lost the most weight. Minor hypoglycemia 25% (EXE) vs 29% (PLB) Buse, et al. Ann Intern Med. 2011;154:103-112. Rosenstock, et al. Diabetes Care 2012; 35(5):955-8. Epub 2012 Mar 19.

Effective combinations of basal replacement and GLP-1 Ras Conclusions Ultra-long acting basal insulin with improved consistency & less hypoglycemia Effective combinations of basal replacement and GLP-1 Ras Smarter & simpler approaches to treatment Ultimately, more intensive insulin regimens may be required (see Figure 3.) Dashed arrow line on the left-hand side of the figure denotes the option of a more rapid progression from a 2-drug combination directly to multiple daily insulin doses, in those patients with severe hyperglycaemia (e.g. HbA1c ≥10.0-12.0%). Consider beginning with insulin if patient presents with severe hyperglycemia (≥300-350 mg/dl [≥16.7-19.4 mmol/l]; HbA1c ≥10.0-12.0%) with or without catabolic features (weight loss, ketosis, etc). Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]