GP Time In Time Out Session

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GP Time In Time Out Session

• Dr K R Narayanan

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Case 1

• 69 ?
• T2 DM since 1995
• Alcohol excess (15 U/W)
• 74 Kg BMI32
• Ex-smoker, BP122/80
• HbA1c8.8, TC6.0
• GGT113

• Rx
• Bezalip MR 400mg OD
• Gliclazide 160mg BD
• MF MR 500 mg BD
• Amitriptyline 10mg OD
• Refuses Insulin
• Cannot tolerate statins

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South of Tyne Type 2 Diabetes Management
Guidelines 2010
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Acknowledgements

• Dr Colin Bradshaw GP and PBC Diabetes Lead South
  Tyneside
• Dr Henry Choi GP and PBC Diabetes Lead Sunderland
• Helen Ramsey Nurse Practitioner and PBC Diabetes
  Lead Gateshead
• Anne-Marie Bailey Prescribing Advisor NHS SoTW
  Medicines Management Team
• Dr Terence Aspray Care of the Elderly Consultant
  City Hospitals Sunderland
• Dr John Parr Consultant Diabetologist South
  Tyneside District General Hospital
• Dr Shahid Wahid Consultant Diabetologist South
  Tyneside District General Hospital
• Dr Rahul Nayar Consultant Diabetologist City
  Hospital Sunderland
• Dr Peter Carey Consultant Diabetologist City
  Hospital Sunderland
• Dr Kilimangalam Narayanan Consultant
  Diabetologist Gateshead Health Foundation Trust
• Gillian Johnson Regional Programme Manager NHS
  Diabetes

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South of Tyne Guidance
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INCRETINS

• GLIPTINS
• Inhibit DPP IV
• Prolong action of native GLP 1

• GLP 1 MIMETICS
• Resistant to cleavage by DPP IV
• Half life prolonged
• Liraglutide vs Exenatide
• OD
• Better S/E profile
• Better homology to human GLP 1

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GLP-1 effects in humans
GLP-1 secreted upon the ingestion of food
5.Brain promotes satiety and reduces appetite4,5
2.a-cell suppresses postprandialglucagon
secretion1
3.Liver reduces hepatic glucose output2
1.?-cellenhances glucose-dependent insulin
secretion in the pancreas1
4.Stomach slows the rate of gastric emptying3
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8

• Gliptins are DPP IV inhibitors
• Prolong endogenous GLP 1 action

• GLP 1 therapies
• Resistant to endogenous DPP IV action

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Pioglitazone and Gliptins

• Dual therapy
• 2nd line instead of SU
• 2nd line instead of MF
• 3rd line would be insulin

• Triple therapy
• SoT guidelines
• 3rd line after MFSU instead of insulin
• 4th line would be insulin

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Pioglitazone or Gliptins?

• Pioglitazone preferable to gliptins if
• Marked insulin insensitivity is suspected
• Gliptin is contraindicated
• Poor response or intolerance to gliptin in the
  past
• Continue only if 0.5 drop in HbA1c at end of
  6/12
• Do not use if C/I

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Where do we stand with Pioglitazone?

• Pros
• Insulin sensitiser
• Stabilise ß-cell function
• Minimal risk of hypos

• Cons
• Weight gain and fluid retention
• Delayed onset of action
• OR of 1.45 for fractures
• Use FRAX
• CV risk
• ? for pioglitazone
• Juurlink et.al. (BMJ 2009)
• Retrospective Cohort
• Death and HF less with pioglitazone

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Pioglitazone or Gliptins?

• Gliptins preferable to glitazones if
• Further weight gain would cause significant
  problems
• Glitazone is C/I
• Poor response to or did not tolerate glitazone in
  the past
• Not for initial monotherapy
• Continue only if 0.5 fall in HbA1c at 6 months

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Sitagliptin studies
Study Duration HbA1c Weight A/E
Add to MF Charbonnel Raz 24 vs P 30 vs P -0.65 -1.00 -0.6 similar -0.5 similar Similar Similar
Add to MF Nuack 52 vs glipizide -0.67 similar -0.8 cv gain Lower hypos
Add to pio Rosenstock 24 vs P -0.7 -0.6 similar Similar
Add to SU Hermansen 24 vs P -0.9 0.7 Similar
Add to SUMF Hermansen 24 vs P -0.6 0.7 Similar
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Which Gliptin?
Sitagliptin Vildagliptin Saxagliptin
HbA1c fall MF 0.65 1.00 1.10 0.5 0.72
Weight Neutral with no difference between agents Neutral with no difference between agents Neutral with no difference between agents
Hypos (cv placebo) Similar with no difference between agents Similar with no difference between agents Similar with no difference between agents
Dose 100 mg OD 50 mg BD MF 5 mg OD
Cost 28 days 37 for pio 33 32 (same for combination tablet) 32
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Cautions and S/E Gliptins

• C/I allergy, moderate to severe renal
  impairment, pregnancy
• S/E nausea, nasopharyngitis, SJ syndrome, hypos
  with SU
• For Vildagliptin
• Monitor LFTs
• Caution in CCF and in the elderly
• ?

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Where do we stand with gliptins?

• Pros
• Well tolerated
• Low risk of hypos
• Weight neutral
• Oral agent
• Promotion of ß-cell mass
• Licensed for second or third line Rx
• Sitagliptin can be used with insulin

• Cons
• May alter immune system
• ? risk of some infections
• Caution in renal impairment
• Effect on long term mortality/morbidity unclear

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Back to our case.

• 69 ?
• T2 DM since 1995
• Alcohol excess (15 U/W)
• 74 Kg BMI32
• Ex-smoker, BP122/80
• HbA1c8.8, TC6.0
• GGT113

• Rx
• Bezalip MR 400mg OD
• Gliclazide 160mg BD
• MF MR 500 mg BD
• Amitriptyline 10mg OD
• Refuses Insulin
• Cannot tolerate statins

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Back to our case

• GLYCAEMIC CONTROL
• Third line oral agent
• GLIPTIN
• GLITAZONE
• ACARBOSE
• GLP 1 analogues

• LIPID PROFILE
• Have we achieved all we can?
• Further lifestyle measures?
• Improved HbA1cbetter CV risk

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GLP 1 mimetics/analogues

• Add to metformin and SU where insulin would be
  considered as the next option if -
• BMI35 with problems associated with high weight
• Inadequate glucose control
• BMIlt35 and insulin unacceptable or weight loss
  would benefit other co-morbidities
• Continue only if 1 HbA1c fall and 3 loss in
  weight at 6 months
• Currently not licensed for use with insulin
• Liraglutide licensed for use with pioglitazone

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Liraglutide versus Exenatide (1)

• Liraglutide effect and action in diabetes LEAD
  trial 6
• Open label, MN, parallel group trial
• 26 weeks
• 464 patients with T2DM on MF and/or SU with HbA1c
  7-11 and BMI45
• Randomised to receive liraglutide 1.8mg OD or
  exenatide 10 mcg BD

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Liraglutide versus Exenatide (2)
Liraglutide Exenatide
Change in HbA1c plt0.0001 - 1.1 - 0.8
Change in body weight NS - 3.24 - 2.87
achieving HbA1clt7.0 p0.0015 54 43
S/E nausea lt10 after 5 weeks 10 at 26 weeks
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ABCD Exenatide AuditPresented at DUK, Dr Ryder

• 6717 patients, 3054 data complete
• Data collected over 1 year
• HbA1c drop 9.41 ? 8.65 (1.00)
• Weight loss 114 ? 109 (5-10 kgs)
• S/E
• 28 had GI S/E
• 7.2 stopped Rx
• 7 cases of pancreatitis (0.18)

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Liraglutide NICE TA-2010

• TRIPLE THERAPY
• Indications as before

• DUAL THERAPY
• With MF or SU
• Additional SU/MF not tolerated/CI AND
• Additional glitazone/gliptin not tolerated/CI
• 1.8 mg not recommended

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Statins in T2 DM

• JBS2 SIGN, NICE
• All gt40 yrs grade A
• 18-39 yrs with associated problems
• Evidence
• CARDS, ASCOT, HPS
• Strong evidence in T2DM
• 1 mmol/l ? 21 RR

Simvastatin 40 mg
Simvastatin 80 mg
Atorvastatin 80 mg OR Simvastatin 80 mg
Ezetimibe 10 mg
Age 10 yr risk NNT
30 1.1 364
40 2.5 160
50 5.7 70
70 23 17
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Statins in T1 DM

• JBS2 SIGN, NICE
• All gt40 yrs grade B
• 18-39 yrs with associated problems
• Evidence
• CARDS, ASCOT, HPS
• Less strong evidence
• 1 mmol/l ? same ? in events ns

CONCLUSION In younger patients with type 1 DM
absolute risk is low but risk is higher
compared to age matched people without DM
Age 10 yr risk NNT
20-29 0.24 1667
30-39 0.87 460
40-49 5.28 76
60-69 28.3 14
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Aspirin as Primary Prevention in DM

• Over the age of 50
• On anti-HT with BPlt145/90 OR
• Strong family h/o premature IHD OR
• CV risk score 20 over 10 years using UKPDS
  risk engine

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Case 2

• 71 ?
• T2 DM since 2008
• IHD 1989
• HT 1988
• BMI28
• Macroproteinuria
• eGFR68
• TC2.7

• Rx
• Lisinopril 40mg OD
• Irbesartan 300 mg OD
• Atenolol 50mg OD
• BDZ 2.5mg OD
• Adalat retard 90mg OD
• Simvastatin 10mg OD
• What other info do you want?
• What are the priorities in management?

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Diabetic NephropathyBurden of Illness

• Incidence
• Diabetic nephropathy develops in around 25 of
  patients with type 2 diabetes
• People with diabetes account for 25 of those
  entering renal replacement therapy
• Mortality
• Microalbuminuria indicates a substantially
  increased mortality risk in patients with type 2
  diabetes
• Patients with type 2 diabetes and high levels of
  albumin have a mortality rate 148 higher than
  control.

British Diabetic Association Report, April
1997. Jarrett RJ, et al. Diabetic Med 1984 (1)
17-19.
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CVD Mortality by Urinary Protein Excretion in
Type 2 Diabetes
1.0
0.9
Survival curves for CVD mortality
A
0.8
B
0.7
0.6
C
Overall plt0.001
0.5
0
0
10
20
30
40
50
60
70
80
90
Months
U-Prot urinary protein concentration
Miettinen H et al. Stroke. 1996 27 20332039.
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Micro and macroalbuminuria

• Microalbuminuria
• (31-299 mg/day)
• ACR gt2.5 in men
• ACRgt3.5 in women
• Macroalbuminuria
• gt300 mg/24 hour

• Exercise
• Pregnancy
• Poor sugar control
• CCF
• Hypertension
• UTI

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Albuminuria

• Marker for CV disease and nephropathy

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Natural History of Type 2 Diabetic Nephropathy
Clinical type 2 diabetes
Functional changes
Structural changes
Rising blood pressure
Microalbuminuria
Proteinuria
Rising serum creatinine levels
End-stage renal disease
Cardiovascular death
Onset of diabetes
2
5
10
20
30
Years
Renal haemodynamics altered, glomerular
hyperfiltration Glomerular basement membrane
thickening ?, mesangial expansion ?,
microvascular changes /-
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Strategies to prevent progression of diabetic
nephropathy

• Extremely good BP control ? also ? UAER
• lt130/75 in type 1
• lt140/80 in type 2
• Individualise target
• Good glycaemic control
• ACEI/ARB but be prepared to use multiple agents
• CV risk reduction to reduce mortality

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Slower Decline in Renal Function with Lower
Blood Pressure Goals
Results of studies ³ 3 years in patients with
type 2 diabetic nephropathy
Bakris GL. Diabetes Res 1998 39(suppl) S35-S42.
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What about primary prevention?

• Good glycaemic control
• DCCT 2.2 vs 3.4 per year developed µalb
• UKPDS 23 vs 34 had µalb at 12 yrs
• But does not abolish it
• Use of RAS inhibitors
• Losartan, candesartan, enalapril
• Unable to reduce µalb over 5 yrs

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Back to our case......

• Consider other causes of proteinuria
• Refer to renal team if
• e-GFRlt30 OR
• If e-GFR falls by gt 4 ml/min/year
• CV risk reduction
• Aspirin, Simvastatin to 40 mg
• Individualise BP target
• Achieve target HbA1c
• Ensure digital retinal screening is up to date

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Case 3

• 65 ?
• T2 DM 2001
• HT
• BMI30.4, Xsmoker
• HbA1c10.5
• TC4.6
• ACR Normal

• Rx
• Glimiperide 4 mg OD
• Glucophage SR 2 g OD
• What next?
• Not keen on insulin

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Case 4

• 87 ? very active
• T2 DM 1992
• HT
• Macroproteinuria
• Impaired vision
• BMI26.4, BP182/80
• HbA1c6.9

• Rx
• MF 3 gm/day
• Gliclazide 320 mg/day
• Perindopril 8mg OD
• Irbesartan 300mg OD

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Case 4 continued

• 06/2007 eGFR 36 so MF stopped
• 08/07 HbA1c 9.8 so pio started
• 06/08 HbA1c 7.9 but BMI ? 29.1 and BP? 176/100
• 10/2010 pio stopped and MF re-started as eGFR 40
• Now HbA1c 8, 146/56, eGFR 43

• Rx
• Gliclazide 320, MF 500
• Perindopril, irbesartan
• Frusemide 40, amlodipine 5
• Bisoprolol 5
• What could have been done different?
• What now?

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Case 5

• 65 ?
• T2 DM 2004
• HT
• NAFLD
• BMI33, BP 140/80
• HbA1c11.1

• Rx
• MF 3 gm
• Gliclazide 320 mg
• Ramipril 5 mg
• Simvastatin 40 mg
• What are the options?

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Case 6

• 61 ?
• T2 DM 2000
• HT, OA
• Smoker
• BMI47.2, BP140/90
• HbA1c7.9, TC5.9

• Rx
• Aspirin, perindopril
• Atenolol, frusemide
• Orlistat trial X
• Novomix 30 52 BD
• MF 2 gm/day
• Can we do anything to help her lose weight?

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Case 6 continued

• Role of insulin sensitisers
• Pioglitazone added in Feb 2010

HbA1c BMI Insulin dose
2/2010 7.9 47.2 104
7/2010 7.4 47 64
3/2011 5.9 43 44 ? 32
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Drug Cost for 28 days
Glucophage SR 1000 4.26 (67p for 850mg)
Sitagliptin 100 33.26
Pioglitazone 45 36.96
Gliclazide 320 4.24
Insulin glargine 1500 units 39.00
Exenatide 10 mcg 68.24 (78.48 for Liraglutide)
DIABETES DRUG COSTS ACROSS SOUTH OF TYNE 6.9
million 7.2