Insulin therapy in Type 2 Diabetes

Agenda: Initiation of Insulin therapy Evidence for Basal Insulin Selection Intensification of Insulin therapy Introduction of Insulin Glargine Introduction of Insulin Glulisine

Agenda: Initiation of Insulin therapy Evidence for Basal Insulin Selection Intensification of Insulin therapy Introduction of Insulin Glargine Introduction of Insulin Glulisine

Relative contribution (%) In T2DM contribution of fasting hyperglycaemia to overall glycaemia increases with worsening diabetes 290 patients with T2DM treated with diet or OHAs Baseline (normal) PG defined as 6.1 mmol/l (110 mg/dl) ― threshold defined by ADA as the upper limit of normal PG at fasting or preprandial times 100 70% Relative contribution (%) 50 This study analysed the diurnal glycaemic profiles of 290 patients with T2DM investigated at different levels of HbA1c. The patients were treated with diet or oral hypoglycaemic agents (not acarbose). Plasma glucose (PG) concentrations were determined at fasting and during postprandial and post absorptive periods. The areas under the curve above fasting PG concentrations and >6.1 mmol/l (110 mg/dl) were calculated for further evaluation of the relative contributions of postprandial and fasting PG increments to the overall diurnal hyperglycaemia. The value of 6.1 mmol/l (110 mg/dl) was chosen because this threshold has been defined as the upper limit of normal PG at fasting or preprandial times by the American Diabetes Association. The data were compared over quintiles of HbA1c. The main contributor to overall hyperglycaemia in patients with poorly controlled T2DM was found to be fasting hyperglycaemia. Fasting hyperglycaemia was the dominant factor in patients who were furthest from HbA1c target. Monnier L, et al. Diabetes Care 2003;26:881―5 Fasting 30% <7.3 7.3―8.4 8.5―9.2 9.3―10.2 >10.2 HbA1c (%) quintiles ADA=American Diabetes Association; OHA=oral hypoglycaemic agent; PG=plasma glucose. Adapted from Monnier L, et al. Diabetes Care 2003;26:881―5.

Treating fasting hyperglycaemia lowers the entire 24-hour plasma glucose profile 400 Type 2 diabetes 20 300 15 Plasma Glucose (mg/dL) 200 Hyperglycaemia due to increase in fasting glucose Plasma Glucose (mmol/L) 10 100 5 Normal Meal Meal Meal 6 10 14 18 22 2 6 Time of Day (h) Comparison of 24-hour glucose levels in control subjects vs patients with diabetes (p<0.001). Adapted from Hirsch I, et al. Clin Diabetes 2005;23:78–86.

To Initiate Insulin With A Basal Insulin Regimen In All Guidelines, It Is Recommended To Initiate Insulin With A Basal Insulin Regimen Start with basal insulin Basal-Plus or Basal-Bolus, Premix insulins are not for initiation, only for intensification (if needed) in a 2nd step Diabetes Care 2015;38:140–149

The Ideal Basal Insulin 1 injection daily covers 24 hours No peaks Low incidence of hypoglycaemia Good glycaemic control Less weight gain Safe Predictable Easy handling Injection at different sites Injection at different times No mixing necessary/clear solution High treatment satisfaction and acceptance The ideal long-acting insulin should safely provide a 24-hour, peakless profile, thereby mimicking the normal physiologic basal insulin profile The ideal long-acting insulin should help patients achieve target A1C levels with: Low incidence of hypoglycaemia Predictable Simple, once-daily injection High treatment satisfaction and acceptance

Basal Insulin Options Glargine and Detemir: Lasts up to 24 hours >50% of detemir patients need BID injections to reach glycemic targets Decreases risk of hypoglycemia (especially nocturnal) Less weight gain Less variability in effect Neutral Protamine Hagedorn (NPH): Lasts 10–16 hours Peaks 8–10 hours Less expensive May partly cover meal (e.g., breakfast if taken in morning) but can result in later hypoglycemia (e.g., early afternoon) Riddle et al. Diabetes Care. 26:3080-3086; 2003 Raskin et al Diabetes Care. 28:260-265; 2005

Agenda: Initiation of Insulin therapy Evidence for Basal Insulin Selection Intensification of Insulin therapy Introduction of Insulin Glargine Introduction of Insulin Glulisine

Glargine vs NPH Insulin Title Subtitle Glargine vs NPH Insulin 6 NPH 5 Glargine 4 Glucose utilization rate (mg/kg/h) 3 2 1 10 20 30 Time (h) after SC injection End of observation period Lepore, et al. Diabetes. 1999;48(suppl 1):A97. 10

Insulin Glargine vs. NPH in Treat-to-Target Trial: HbA1c and Hypoglycemia 21% risk reduction p <0.02 16 9.0 14 NPH + OAD 8.5 Insulin glargine + OAD 12 8.0 Events per patient per year 10 42% risk reduction p <0.01 HbA1c (%) 8 7.5 6 7.0 4 This slide illustrates that in normal individuals, glucose excursions following meals are modest and kept within a very narrow range. Therefore, defense against hyperglycemia is very aggressive. In patients with type 2 diabetes who have established fasting hyperglycemia, postprandial glycemic excursions are exaggerated. The NPH in this study was given at bedtime, and the difference in hypoglycemia very well could be due to variable absorption 6.5 2 4 8 12 16 20 24 Overall Nocturnal Weeks Hypoglycemia Riddle et al. Diabetes Care 2003;26:3080-6.

Summary Real-life studies with insulin glargine have shown: Significantly lower risk of hypoglycemia vs NPH Significantly greater reduction in HbA1c vs NPH and detemir Significantly better persistency with treatment vs NPH and detemir Sustained long-term glycemic control Significantly reduced risk of MI vs NPH These data confirm the importance of verifying RCTs in a real-life clinical setting.

To reach the high level of Lantus® efficacy, 55% of insulin detemir patients needed twice daily injections n=275 n=268 p=ns Rosenstock J, et al. Diabetologia 2008;51:408–16. Rosenstock J, et al. Diabetologia. 2008 ;51(3):408-416. For internal use only

77% higher insulin detemir dose was required to achieve the high level of Lantus® efficacy 0.44 0.78 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1 Mean daily dose (U/kg) Lantus® Insulin detemir QD or BID +77% IU/kg U/kg n=248 n=227 Rosenstock J, et al. Diabetologia. 2008 ;51(3):408-416.

3-fold increase in injection site reactions with insulin detemir Overall safety: The only between-drug difference was more cutaneous adverse reactions with insulin detemir 3-fold increase in injection site reactions with insulin detemir 3-fold increase n=4 n=13 Allergic reactions and skin disorders were also more frequent in insulin detemir patients. Rosenstock J, et al. Diabetologia. 2008 ;51(3):408-416.

T2D Patients inadequately controlled with insulin Detemir benefit from switching to Glargine Prospective multinational study in T2D Patients not controlled with insulin Detemir+OAD Change in mean HbA1c in T2D Patients treated with glargine consisted of patients previously treated with Detemir once daily or twice daily A.G Lievers et al. Diabetes Stoffw Herz 2013; 22:141-147

T2D Patients inadequately controlled with insulin Detemir benefit from switching to Glargine Prospective multinational study in T2D Patients not controlled with insulin Detemir+OAD Change in mean FBG in T2D Patients treated with glargine consisted of patients previously treated with Detemir once daily or twice daily A.G Lievers et al. Diabetes Stoffw Herz 2013; 22:141-147

Patients with ≥1 hypoglycaemia event (%) Hypoglycemia in The Last Month under Glargine Patients with ≥1 hypoglycaemia event (%) Incidence rate of hypoglycaemia reported during the last 4 weeks of previous insulin detemir treatment and for the last 4 weeks of insulin glargine treatment, respectively. A.G Lievers et al. Diabetes Stoffw Herz 2013; 22:141-147

Agenda: Initiation of Insulin therapy Evidence for Basal Insulin Selection Intensification of Insulin therapy Introduction of Insulin Glargine Introduction of Insulin Glulisine

Time To Intensify: Failing Basal Insulin How To Define It 1st step for everybody Insulin titration on FPG Fix fasting first FPG at target despite a well titrated basal insulin HbA1c > 7.5 to 8% Post-prandial glucose increments from pre-prandial are not addressed on basal insulin. A « PRANDIAL ISSUE » may explain why HbA1c remains high despite a good titration

How To Intensify: Failing Basal Insulin Prandial Issue 1st step for everybody Insulin titration on FPG Fix fasting first HbA1c remains above target despite a good titration of basal insulin The“prandial” issue Intensification of insulin therapy usually consists of additional prandial injections: at each meal (basal-bolus) or at the main meal ( the “basal +” concept)

How to intensify: the guidelines After basal insulin, How to intensify: the guidelines Updated 2015 HbA1c > target The ADA/EASD position statement endorsed the addition of 1 to 3 injections of a rapid-acting insulin analog before meals. As an alternative, the statement mentioned premixed insulins.

Agenda: Initiation of Insulin therapy Evidence for Basal Insulin Selection Intensification of Insulin therapy Introduction of Insulin Glargine Introduction of Insulin Glulisine

A Long-Acting Basal Insulin Analogue Insulin Glargine A Long-Acting Basal Insulin Analogue Insulin glargine is an insulin analogue. It is a B31-B32-Di-Arg human insulin with further substitution of asparagine in position A21 by glycine. These changes result in a shift of the electronic point from 5.4 in native insulin toward a pH of 4.0 in insulin glargine. As a result, insulin glargine precipitates at physiological pH in SC tissue after injection, which delays its absorption. G l y A s n - A-Chain 1 5 2 3 r g B-Chain Extension Substitution

Mechanism of Action Injection of an acidic solution (pH 4.0) Clear Solution pH4 pH 7.4 Precipitation Dissolution Capillary Membrane Insulin in Blood Hexamers Dimers Monomers 10-3 M 10-5M 10-8 M Injection of an acidic solution (pH 4.0) Precipitation of insulin glargine in subcutaneous tissue (pH 7.4) Slow dissolution of free insulin glargin hexamers from micro precipitates (stabilized aggregates) Protracted action

PHARMACOKINETICS : Slow dissolution of the Glargine hexamers at the injection site results in a relatively constant release with no pronounced peak over a period of up to 24 hours. Onset of action = 2 hours Peak = flat Duration = 24 hours

Figure 3. Approach to starting & adjusting insulin in T2DM Start: 10U/day or 0.1-0.2 U/Kg/day Adjust: 10-15% or 2-4 U 0nce-twice weekly to reach FBG target. For hypo: Determine & address cause; ↓dose by 4 units or 10-20% Basal insulin alone is usually the optimal initial regimen, beginning at 0.1-0.2 U/kg body weight, depending on the degree of hyperglycemia. It is usually prescribed in conjunction with 1-2 non-insulin agents, although insulin secretagogues (sulfonylureas, meglitinides) are typically stopped once more complex regimens beyond basal insulin are utilized. In patients still not at target after basal insulin has been adequately titrated, and the patient is willing to take >1 injections, there are several options. First, consider GLP-1 receptor agonists (see Fig. 2). The combination of basal insulin + GLP-1RA is becoming well established after several studies confirmed its efficacy on par with more complex multi-dose insulin regimens, but with less hypoglycemia and with weight loss instead of weight gain. If such an approach is not possible or has been tried and proven unsuccessful, there are 3 possible advanced insulin regimens: Adding 1 injection of a rapid acting insulin analogue before the largest meal, Adding 2-3 injections of a rapid acting insulin analogue before 2-3 meals, or Using premixed insulin BID Each approach has its advantages and disadvantages. The figure describes the number of injections required at each stage, together with the relative complexity and flexibility. Once a strategy is initiated, titration of the insulin dose is important, with dose adjustments made based on the prevailing BG levels as reported by the patient. Comprehensive education regarding self-monitoring of BG, diet, exercise, and the avoidance of, and response to, hypoglycemia are critical in any patient on insulin therapy. Diabetes Care 2015;38:140; Diabetologia 2015;10.1077/s00125-014-3460-0

Dosing

Titration

Insulin Glargine Injection in Special Populations Desired blood glucose levels, as well as the doses and timing of antidiabetic medications, must be determined individually Pediatric safe for 2 years old type 1 patients Elderly Initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemic reaction Obese patients No differences in safety and efficacy between insulin glargine and NPH human insulin Renal or hepatic Careful glucose monitoring and dose impairment adjustments of insulins may be necessary Safety and effectiveness of Lantus® (insulin glargine) have been established in patients with type 1 diabetes aged 6 to 15 years. Administration to paediatric patients aged <6 years has not been studied.1,2 Based on the results of a study in paediatric patients, the dose recommendations for changeover to Lantus are the same as described for adults1 In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycaemic reactions1 Subgroup analyses based on patients with a body mass index up to 49.6 kg/m2 did not show any differences in safety and efficacy between Lantus and NPH human insulin1 Although studies have not been performed in patients with diabetes and renal or hepatic impairment, Lantus requirements may be diminished because of a reduced capacity for gluconeogenesis and reduced insulin metabolism, similar to observations found with other insulins.1,2 Some studies with human insulin have shown increased circulating levels of insulin in patients with renal or liver failure. Careful glucose monitoring and dose adjustments of insulin, including Lantus, may be necessary in patients with renal or hepatic dysfunction1 Insulin requirements may be altered during intercurrent conditions such as illness, emotional disturbances, or stress. Dose adjustments of Lantus and other insulins or oral hypoglycaemic agents may be required if the patient’s weight or lifestyle changes or other circumstances arise that increase susceptibility to hypoglycaemia or hyperglycaemia1,2 Lantus® (insulin glargine) EMEA Summary of Product Characteristics. 2002. 1. Lantus® (insulin glargine) US Prescribing Information. Bridgewater, NJ: Aventis Pharmaceuticals; 2002. 2. Lantus® (insulin glargine) EMEA Summary of Product Characteristics. Bridgewater, NJ: Aventis Pharmaceuticals; 2002.

Agenda: Initiation of Insulin therapy Evidence for Basal Insulin Selection Intensification of Insulin therapy Introduction of Insulin Glargine Introduction of Insulin Glulisine

Molecular structure of insulin Glulisine (Apidra®) Becker RH. Diabetes Technol Ther 2007;9:109–21. A chain Human 3BLys-29BGlu-insulin B chain Gly 1 5 10 15 20 S Gln Ile Cys Phe His Leu 25 30 Pro Lys Thr Ala Glu = substitution Asn x --- -- stabilising agent Polysorbate 20 complexing agent Zinc   Function Components GLU ASP Qualitative composition buffering agent Trometamol LIS RHI Zinc-free formulation Insulin glulisine is a modified version of endogenous human insulin produced by recombinant DNA technology using Escherichia coli. Insulin glulisine differs from endogenous human insulin by two amino acid substitutions on the B chain: asparagine in position B3 replaced with lysine lysine at position B29 replaced with glutamic acid. The two amino acid substitutions discourage self-association (no formation of hexamers in solution) and enhance the solubility of insulin glulisine at physiologic pH, which allows rapid absorption of monomers from the tissue after subcutaneous injection. Reference Becker RH. Diabetes Technol Ther 2007;9:109–21.

RA-insulins uptake from subcutaneous tissue Zn2+ RA-insulin analogues: LIS ASP T T T T T T T T T Phenol Phenolic residues ( ) , Zn2+ atoms ( ) Phenolic residues ( ) Zn2+ atoms ( ) Structures R-format Hexamers T-format Dimer Monomer RA-insulin analogue: GLU No added zinc Polysorbate 20 (Tween 20) Capillary Brange J, et al. Diabetes Care 1990:13;923–54. Becker RH. Diabetes Technol Ther 2007;9:109–21.

Apidra® offers convenience tailored to fit a patient’s lifestyle. Apidra® is an ideal partner for Lantus Apidra® offers convenience tailored to fit a patient’s lifestyle.

Take home massage: Insulin may be initiated after failure of mono or combination non-insulin therapies, when symptomatic, glucose toxicity, or at the request of the individual with diabetes. Basal Insulin alone, is the best option for Insulin initiation. The Basal Plus strategy is a flexible, ‘patient friendly’, stepwise approach to managing progressive diabetes in clinical practice.

Apidra® is an ideal partner for Lantus Take home massage: Lantus: The once daily peakless basal Insulin, easy to initiate and titrate. Apidra® offers convenience tailored to fit a patient’s lifestyle. Apidra® is an ideal partner for Lantus

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