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Lantus® profile

1. Structure

2. Mechanism of action

3. Pharmacokinetics

Normal endogenous insulin secretion1

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Replicating the normal need1

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Basal/bolus regimen

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Insulin regimens

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Human insulin molecule

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Long-acting analogue - Glargine

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Insulin glargine was designed to provide a reliable, constant basal insulin concentration to control basal metabolism with one injection daily

Recombinant DNA origin of Lantus®

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Development of Lantus®

  1. Addition of 2 arginines to the B chain increased the stability of insulin hexamers, resulting in decreased solubility, slow absorption, and prolonged action
    • Found to be too insoluble, resulting in a bioavailability that was not good enough to maintain overnight blood glucose control
  2. Substituting the asparagine at position 21 on the A chain with glycine restored some of the solubility

Mechanism of Action

  1. Modifications made to form Lantus® alter its isoelectric point towards neutrality
  2. Less soluble at physiological pH
  3. Delay in solubilisation and dissociation into monomers
  4. Delayed and prolonged absorption
  5. Slow and smooth release

Mechanism of release

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  • Injection of an acidic solution (pH 4.0)
  • Precipitation of Lantus® in subcutaneous tissue (pH 7.4)
  • Slow dissolution of free
    Lantus® hexamers from precipitated Lantus® (stabilised aggregates)
  • Protracted action

Euglycaemic clamp technique

  1. To study time-action profiles of blood glucose-lowering drugs
  2. A constant insulin infusion increases peripheral glucose uptake and reduces endogenous glucose output, but glucose is infused to maintain the steady-state
  3. Predefined blood glucose level maintained after insulin infusion/injection by the adjustment of glucose infusion rate, which prevents the possibility of hypoglycaemia
  4. Amount of glucose necessary to neutralise the effect of the injected insulin represents the insulin-mediated glucose uptake
    • Measure of insulin sensitivity
    • Measure of glucose uptake

Insulin concentrations

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Blood glucose concentrations

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Glucose infusion rates

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Action Profile

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Comparison with insulin pump5

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Absorption profiles - arm / leg / abdomen

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Lantus® studies

1. Studies comparing insulin glargine v/s NPH
2. One pill, one shot
3. Treat to target
4. Flexible administration

Studies comparing insulin glargine v/s NPH

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Objectives

  1. Primary objectives
    • To compare the effects of Lantus® and NPH human insulin on glycohaemoglobin
    • To compare the safety of Lantus® and NPH human insulin
  2. Secondary objectives
    • To compare insulin glargine and NPH human insulin in terms of hypoglycaemia, FPG/FBG, blood glucose variability, other indicators of metabolic control, quality of life, and pharmacoeconomics

Clinical efficacy - Type 1 diabetes

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Clinical efficacy - Type 1 diabetes (ped)

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Clinical efficacy - Type 2 diabetes

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Hypoglycaemia

  • Lantus®vs. NPH
    • Type 2 diabetes
      • Overall number is low, as expected
        • Insulin glargine 4/548 patients
        • NPH 8/540 patients
    • Hypoglycaemia
      • Nocturnal hypoglycemia: Lesser events (Type 1 and 2) when used in combination with regular insulin, OADs or both
      • FPG was equal or better in all situations
      • Trials with Lispro did not reduce nocturnal hypos but gave better FPG

Consequences of hypoglycaemia

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Hypoglycaemic events

  1. Asymptomatic hypoglycaemia
    • A confirmed blood glucose <50 mg/dL (2.8 mmol/L) and without any symptoms of hypoglycaemia
  2. Symptomatic hypoglycaemia
    • Symptoms of hypoglycaemia are noted
  3. Severe hypoglycaemia
    • Requiring assistance from another person and blood glucose level <36 mg/dL (2.0 mmol/L) or prompt recovery after oral carbohydrate or intravenous glucose or glucagon administration
  4. Nocturnal hypoglycaemia
    • Characterised by symptoms of hypoglycaemia that occurred after bedtime injection but before the morning FBG was obtained

Summary of Safety (1)

  • Adverse events
    • No difference in adverse events (excludes hypoglycaemia)
    • Injection site reactions
      • insulin glargine 6.9%
      • NPH 5.4%
    • Antibodies to insulin glargine, human insulin and E. coli
      • No difference
    • Laboratory, ECG, Vital Signs
      • No difference

Summary of Safety (2)

  • Weight
    • Type 1 diabetes
      • insulin glargine 0.3 kg
      • NPH 0.5 kg
    • Type 2 diabetes
      • Insulin glargine 0.9 kg
      • NPH 1.2 kg

One pill, one shot

Improved glycaemic control and reduced nocturnal hypoglycaemia in patients with Type 2 diabetes with morning administration of insulin glargine compared with NPH insulin

Primary study objective

To determine whether a simple regimen of one injection and one pill can provide safe and effective glycaemic control

Study design and methods

  • Open-label, controlled, randomised, parallel-group, multicentre, multinational study
  • Titration of insulin dose by predefined titration regimen with fasting blood glucose (FBG) target of <5.6 mmol/L (100 mg/dL)
  • Screening phase (1-4 weeks) was followed by a 24-week treatment phase
  • Visits at weeks 1, 2, 3, 4, 6, 8, 12, 18 and endpoint

Treatment regimen

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Primary efficacy variable

  • Baseline to endpoint change in HbA1c in the three treatment arms
    • Bedtime insulin glargine vs bedtime NPH insulin
    • Morning insulin glargine vs bedtime NPH insulin
    • Morning insulin glargine vs bedtime insulin glargine

Secondary efficacy variables

  • Proportion of patients achieving HbA1c
  • Baseline to endpoint change in FBG
  • Percentage of patients experiencing nocturnal hypoglycaemia

Patients

  • Inclusion criteria
    1. Men and women with Type 2 diabetes
    2. Aged ≥75 years
    3. Treatment with OADs for at least 6 months
      • Any sulfonylurea, as monotherapy or in combination with Metformin or Acarbose
      • Previous sulfonylurea dose ≥ Glimepiride 3 mg
    4. No pretreatment with any insulin in the 3 months prior to study
    5. HbA1c between 7.5% and 10.5%
    6. FBG ≥6.7 mmol/L (≥120 mg/dL)

Baseline characteristics

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Primary variable: change in HbA1c

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Primary variable: change in HbA1c

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Responder rates (HbA1c ≤8.0%)

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Nocturnal hypoglycaemia rates

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Conclusions

  • The simple regimen of one-pill (Glimepiride), one-shot (insulin glargine) can provide good glycaemic control without significant safety concerns in patients with Type 2 diabetes
  • When insulin glargine is used as the once-daily basal insulin, whether administered in the morning or at bedtime, more patients achieve adequate glycaemic control than with NPH insulin
  • This improved glycaemic control with insulin glargine is achieved with significantly less nocturnal hypoglycaemia compared with NPH insulin

Treat-to-target

  • The majority of patients do not reach glycaemic control targets (HbA1c <7%)
  • Adding basal insulin to oral hypoglycaemic agents (OADs) improves glycaemic control in Type 2 diabetes
  • Insulin dose adjustments to achieve targets are limited by hypoglycaemia, especially nocturnal hypoglycaemia
  • More aggressive, 'treat-to-target' insulin regimens are needed to achieve 'treatment success' (i.e. HbA1c <7%) in a greater number of patients

Primary study objective

To compare the abilities of insulin glargine and NPH insulin to restore glycaemic control to target HbA1c

Study design and methods

  • Open-label, 24-week, randomised, parallel-group, multicentre, multinational (USA and Canada) study
  • Insulin glargine was compared with NPH insulin given at bedtime, in patients inadequately controlled on 1 or 2 oral agents
  • Insulin dosage adjusted weekly by a forced-titration schedule seeking fasting plasma glucose (FPG) ≤5.5 mmol/L (100 mg/dL)

Treatment regimen Subjects (n=764) were randomised to receive

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Insulin starting dose: 10 IU/day

Dose titration target: FPG

Forced titration regimen

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Efficacy variables

  • Primary
    • Percentage of patients reaching HbA1c ≤7% without symptomatic nocturnal hypoglycaemia documented by plasma glucose ≤4 mmol/L (≤72 mg/dL) at 24 weeks
  • Secondary
    • FPG
    • HbA1c levels
    • Hypoglycaemia

Patients

  • Inclusion criteria
    • Men and women with Type 2 diabetes
    • Aged 30-70 years
    • Insulin naïve
    • Receiving treatment with 1 or 2 OADs
      • Sulfonylureas
      • Metformin
      • Thiazolidinediones
    • BMI 26-40 kg/m2
    • HbA1c 7.5-10%
    • FPG ≥7.8 mmol/L (140 mg/dL)
    • Negative GAD antibody measurement

Baseline characteristics

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Baseline to endpoint change in HbA1c

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Baseline to endpoint change in FPG

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Mean basal insulin dose at endpoint

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Episodes of symptomatic nocturnal hypoglycaemia

Number of symptomatic nocturnal hypoglycaemia events

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Primary variable

Patients reaching HbA1c

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Symptomatic hypoglycaemia by time of day

Percentage of patients experiencing ≥1 episode of symptomatic hypoglycaemia

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Symptomatic hypoglycaemia by time of day

Number of episodes of symptomatic hypoglycaemia by hour

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Summary of results

  • Structured titration of bedtime basal insulin co-administered with OADs can restore HbA1c to the target level of ≤7% in most patients
  • Bedtime insulin glargine, when used as the basal insulin instead of NPH insulin, causes significantly fewer nocturnal hypoglycaemic events
  • The use of bedtime insulin glargine as a basal insulin results in more patients attaining HbA1c levels of ≤7% without nocturnal hypoglycaemia, compared with NPH insulin

Flexible administration

Once-daily insulin glargine is effective and safe regardless of whether injected before breakfast or dinner, or at bedtime

Primary study objective

  • To determine if appropriately titrated insulin glargine, combined with insulin lispro, provides similar glycaemic contrul in patients with Type 1 diabetes, whether injected:
    • Before breakfast (06:00-09:00)
    • Before dinner (18:00-20:00)
    • At bedtime (21:00-24:00)

Study design and methods

  1. Open-label, randomised, parallel-group, multicentre, multinational study
  2. Evaluate glycaemic control of titrated insulin glargine given either before breakfast, before dinner or at bedtime in combination with prandial insulin lispro
  3. Conducted in 9 European countries
  4. Screening phase (1-4 weeks) was followed by a 24-week treatment phase
  5. Visits at weeks 1, 2, 3, 4, 6, 8, 12, 18 and endpoint

Treatment regimen

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Primary efficacy variable

Demonstrate equivalent efficacy between all three treatment groups, based on HbA1c at endpoint

Secondary efficacy variables

  1. Insulin doses (insulin glargine and lispro)
  2. 24-hour blood glucose profile
  3. Incidence of hypoglycaemia
  4. Responder rates:
    • % patients reaching HbA1c

Patients

  • Inclusion criteria
    • Confirmed Type 1 diabetes
    • Aged 18-65 years
    • At least 1 year of intensified insulin treatment (basal-bolus regimen)
    • Treatment with a basal insulin plus fast-acting insulin analogue for at least 6 months
    • HbA1c 5.5-9.8% at screening visit

Baseline characteristics

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Primary variable: HbA1c

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Daily insulin glargine doses

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24-hour blood glucose profiles

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Responder rates

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Incidence of nocturnal hypoglycaemia

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Symptomatic hypoglycaemia by time-of-day

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Conclusions

  1. Insulin glargine, in combination with insulin lispro, provides equivalent glycaemic control regardless of whether administered before breakfast, dinner or at bedtime
  2. Nocturnal hypoglycaemia is significantly lower with breakfast administration compared with dinner and bedtime administration of insulin glargine
  3. This more flexible injection regimen of insulin glargine (pre-breakfast, pre-dinner or at bedtime) allows adjustments of insulin doses to individual needs

References

1. Lee W,Zinman B ,From Insulin to Insulin analogues:progress in treatment of Type 1 diabetes.Diabetes reviews 1998;6(2):73-88.
2. Exp.Opin Invest Drugs 1999;8(3):308.
3. The textbook of Diabetes ,edition2,1997,Pickup & Williams,Blackwell science,page75.
4. Linkeschoma R et al.Diabetes ,1999;Suppl 1:A97 abs 0417.
5. Lepore M et al.Diabetes 2000;49:2142-8.

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