What�s new in diabetes by 6t592n

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									What’s new in diabetes

         Robert Schmidli
   MB, ChB, FRACP, MRCP, PhD
       Consultant Physician
   Diabetes and Endocrinology
Topics

     Patient management
     Thiazolidenediones
     Prevention of diabetes
     Long-acting insulin analogues
    Case history
   53 year-old male schoolteacher
   Type 2 diabetes 8 years
   Increasing need for medication
   Medications (well tolerated):
          Gliclazide 160mg bd
          Metformin 1g tds
   BMI 35
   BGLs 8-12 mmol/l
   HbA1C 8.5%
Options

         Lifestyle intervention
         Acarbose
         Thiazolidenediones
         Orlistat
         Insulin
   Natural history of type 2
   diabetes (UKPDS)
            9
                    Conventional Therapy
                            (diet)

            8
HbA1c (%)




                                                Intensive Therapy
                                               (sulfonylurea or insulin)
            7

                                                                           6.2%
            6
                0
                    0        3          6           9          12           15
                              Years from randomisation
Therapy of type 2 diabetes
           Oral (metformin) +
                 insulin



            Oral combination
      sulphonylurea  glucobay/TZD



      Oral monotherapy (metformin)




       Lifestyle, BP, lipids, smoking
   Benefits - drawbacks
Lifestyle            Effective if well-motivated

Acarbose             Often effective
                     Flatulence
Thiazolidenediones   Not covered by PBS
                     Effectiveness as triple therapy
Orlistat             Cost
                     Modest benefit
Insulin              Patient resistance
                     Weight gain, hypoglycaemia
Case 2
   60 year old retired woman
   Diagnosed 6 months ago HbA1C 10.5%
   Lifestyle changes - 6kg
   Medications:
       Gliclazide 160mg bd
       Diarrhoea on Metformin 500mg/day
   BMI 32
   BGLs 6-11
   HbA1C 8.5%
Options
   Lifestyle
   Thiazolidenedione
       Expect 1%  HbA1C
       Highly variable response
   Acarbose – side effects
   Insulin – not indicated
Thiazolidenediones – mode of
action
 Activate PPAR-g (peroxisome proliferator-activated receptor –
 gamma) receptors.
                                   
 Increases transcription of proteins regulating glucose and lipid
 metabolism.

                                   

 Amplifies actions of insulin in liver and peripheral tissues.

                                   

 Improve glycaemic control with no increase in endogenous insulin
 secretion.


Gillies and Dunn 2000
TZDs – precautions
   Troglitazone – liver failure
   > 4,000 treated with Pioglitazone
    worldwide – no evidence liver disease
   LFTs 2 monthly 1 yr, then periodically
   Avoid in cardiac failure
   Dilutional anaemia – FBE at initiation
TZDs – “official” indications
   Inadequate control – HbA1C > 7.0
   Dual therapy – intolerance to
    sulphonylurea or metformin
   Dual therapy with insulin – intolerance
    to metformin
   HbA1C must come below 8.5%
When to use a TZD
   Intolerance to Metformin
   Raised serum creatinine (> 0.15
    mmol/l) on Metformin
   Severe sulphonamide allergy
   Poor control despite large insulin doses
   Severe hypertriglyceridaemia
   Unwilling to start insulin
         Pioglitazone: efficacy
       HbA1c at week 26 (% points)      FPG at week 26 (mmol/l)
                                                                      Pioglitazone dose
1.0                                  0.5
                                                                           7.5 mg
                                     0.0                                   15 mg
0.5                                                                        30 mg
                                     -0.5                                  45 mg
0.0
                                     -1.0
                                                                        † p<0.05 vs placebo
-0.5                                 -1.5
                                              †
                                     -2.0
-1.0
                  †     †                           †    †
                                     -2.5

-1.5
                                     -3.0
                              †

-2.0                                 -3.5
                                                                  †
          Difference from placebo           Difference from placebo
    Rosiglitazone: efficacy
         8.5



             8.0
Mean HbA1c
   (%)




             7.5                       RSG 8 mg/day
                                            n= 160



             7.0


                   0   6   12     18   24            30
                             Months          Jones 2000
Patient 3
   56 year old male stockbroker
   Fasting BGL 6.5 on insurance medical
   No hyperglycaemic symptoms
   Father had type 2 diabetes
   BMI 35
Questions

     Does he have diabetes?

  What treatments are available?
Options
   Lifestyle
   Metformin
   Thiazolidenedione
   Acarbose
   Ramapril
Definition of diabetes
   Requires TWO of:
       Fasting BGL > 7.0mmol/l
       Post-glucose BGL > 11.1mmol/l

                   OR

   ONE of the above in the presence of
    symptoms
Diabetes Prevention Program
(DPP) study
   IGT: n = 3234
   No therapy vs metformin vs lifestyle
   Mean follow-up 2.8 years
   >7% weight loss target
   150min exercise target
   Individualised program
   Cost: $104,000,000 !!
Results
             Reductions
             Metformin
              31%
             Lifestyle
              58%
        Acarbose and IGT:
        STOP-NIDDM Trial
   IGT: N=714 Acarbose, 715 placebo, 3.3y
    follow-up
   100mg Acarbose tds
   Dropouts:               45                           42
                                     40
       Acarbose: 31%                35      32
       Placebo: 19%          % to 25
                                     30


   Significant reversion   diabetes 20
                                     15
    to normal glucose                10
                                      5
    tolerance                         0
                                          Acarbose    Placebo
                                             24% reduction
Troglitazone & IGT (post GDM)
TRIPOD study
   133 Hispanic women with previous GMD
    given Troglitazone or placebo
   Median 30 months follow-up
   Diabetes development:
       Troglitazone:   5.4%    55% reduction
       Placebo:        12.1%
   Protection maintained 8 months after
    Troglitazone stopped
Ramapril and type 2 diabetes
HOPE study
   Nondiabetic subjects > 55y:
       2837 Ramapril  10mg/day
       2883 placebo
   Development of diabetes in 4.5 years
   Ramapril:  3.6%
                          33% reduction
   Placebo:   5.4%
Diabetes prevention:
Conclusions
   Lifestyle alone more effective than any
    drug regimen
   Combined treatment may give
    additional benefit
   Risk : Benefit not known
   Drug treatment not currently
    recommended
Long-acting insulin analogues
                                       Relationship between control
                                       and hypoglycaemia
                                      100
                                                                    Hypoglycaemia
    hypoglycaemia/complications (%)




                                      90                            Complications
                                      80
           Risk of developing




                                      70
                                      60
                                      50
                                      40
                                      30
                                      20
                                      10
                                       0
                                            5.5   6.0   6.5   7.0    7.5    8.0    8.5   9.0   9.5   10.0   10.5
                                                                           HbA1C
DCCT Research Group. N Engl J Med 1993;329:977–986
        Hypoglycaemia-associated autonomic
        failure
                  Excessive/inappropriate
                          insulin



                                                   Hypoglycaemia




                        Vicious cycle                     Autonomic /      Hormonal response
                                                      neurogenic symptom      (adrenaline)
                                                           responses


                                                                           Counter-regulatory
                                                                               response



                                            hypoglycaemia risk



Cryer PE. Diabetologia 2002;45(7):937–48
       Insulin Glargine
 A chain
  1           5               10              15                  Gly
                                                               20 Asn   Substitution

 B chain
 1            5              10
                             10               15
                                              15          19                 25               30

                                                                                  Extension
     Substitution: asparagine at position A21 replaced by glycine                                 Arg Arg

       Provides stability

     Extension: addition of 2 arginines at the C-terminus of the B
      chain
       Soluble at slightly acidic pH

Lantus® (insulin glargine) Approved Product Information
McKeage K et al. Drugs. 2001;61:1599-1624.
       Levemir (insulin Detemir)


                                                          Phe        Gly
                                                   Phe                       Arg
                                             Tyr                                    Glu
                                     Thr                                                   Gly
                              Pro                                                                Cys
                       Lys
           Thr                                                                                         Val
           Lys                                       Asn       Cys
                             B29             A21
                                                                      Tyr                                  Leu
A1   Gly                                                                   Asn                               Tyr
     Ile                                                                    Glu                              Leu   •Recently
     Val
     Glu
                                                                            Leu
                                                                           Gln
                                                                                                             Ala
                                                                                                             Glu
                                                                                                                   available in UK
      Gln
                                                                      Tyr                                    Val   and Germany
           Cys                                                 Leu                                           Leu
                                                                                                                   •Binds avidly to
                 Cys   Thr     Ser     Ile     Cys       Ser
                                                                                                           His


                                                                                               Gly
                                                                                                     Ser
                                                                                                                   albumin
                                                                                         Cys
                               B1                              Gln         His     Leu
                                      Phe      Val   Asn
              Glargine – mechanism of
              action
            The mechanics of sustained release1,2



                                                                Injection of an acidic solution (pH 4.0)3
                                                                          
                                                                Microprecipitation of insulin glargine
                                                                in subcutaneous tissue (pH 7.4)3
                                                                           
                                                                Slow dissolution of free insulin glargine
                                                                hexamers from microprecipitates
                                                                (stabilized aggregates)3
                                                                         
                                                                Protracted action3


1. LANTUS® (insulin glargine) Approved Product Information 2. McKeage K, et al. Drugs. 2001;61:1599–1624.
3. Kramer W. Exp Clin Endocrinol Diabetes. 1999;107(suppl. 2):S52–S61.
Detemir – mode of action
    Pen

                                HSA
                   HSA
             HSA
 Absorptio          HSA
                                                   Receptor
         n                               HSA      interaction
                                            HSA
                   Capillary

                                      Distribution
                               HSA
                                                      IR
                                      HSA: human serum albumin
 Glargine: profile compared to
 other insulins
                                      NPH                  Continuous subcutaneous insulin
                                      Ultralente           infusion by insulin pump
                                                           Insulin glargine
                          4                                                                24

                                                                                           20
                          3
          Infusion rate




                                                                                                (µmol/kg/min)
          (mg/kg/min)




                                                                                                 Infusion rate
                                                                                           16

                          2                                                                12

                                                                                           8
                          1
                                                                                           4

                          0                                                                0
                              0                    10                    20           30
                                                 Time (hours)
                                                                                   n=20
                                  Subcutaneous insulin
Adapted with permission from Lepore M, et al. Diabetes 2000:49;2142–8.
     Long-acting analogues:
     summary

   24-hour duration of action
   Peak-less profile
   Lower, more stable fasting BGL
   Once-daily injection (usually)
   Reduced risk of nocturnal hypoglycaemia
   Lower HbA1C in some studies
   Clear solution: more consistent delivery

								
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