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Oral Agents in Management ofType 2 Diabetes
Nemanja Stojanović
Consultant Endocrinologist
Queen’s Hospital, Romford
We will talk about
• T2DM in general…• Metformin• Sulphonylureas + PPG regulators• α-Glucosidase Inhibitors• Statistics• Glitazones and meta- analysis• DPP-4 inhibitors and meta- analysis• GLP-1 analogues
Definition
– Fasting plasma glucose 7mmol/l- 2 occasions
– 2 h plasma glucose or random glucose of 11.1 mmol/l
BM’s
Fasting Beforelunch
Beforedinner
Beforebed
Normal 3.9 4.4 4.9 5.0
Type 2 DM 8.2 13.4 13.1 10.7
Type 2 DM 6.8 8.7 6.8 6.2
Type 1 DM 3.1 4.1 4.2 10.2
Normal 24h profile
T1DM: Relationship between HbA1c and Mean Glucose
HbA1c Mean Glucose (mmol/l)
6% 7.5
7% 9.5
8% 11.5
9% 13.5
10% 15.5
11% 17.5
12% 19.5 Dia Care2002: 25: 275-8
“Drug therapies are
replacing a lot of medicines
as we used to
know it…”
George W Bush
Treatment
Diet, Exercise
Medications:Metformin
SulphonylureasPPGs
Acarbose
Metformin
NH
NH2 C NH2
Guanidine
Galega officinalis
CH3
CH3
N C NH
NH
C
NH
NH2
Metformin
Metformin : Non- Glycaemic Effects
• Abdominal obesity- stabilizes body weight; reduces weight gain and can facilitate weight loss
• Reduces progression of IGT to type 2 diabetes
• Dyslipidaemia: VLDL-TG, LDL-C, HDL-C
• Procoagulant state: PAI-1,fibrinogen and platelet aggregation
Metformin : contraindications
• Cr> 150 umol/l• Hypoxic states
- CCF/acute heart failure- sepsis- Severe COPD
• Severe liver disease • Alcoholism• History of lactic acidosis• Radiological contrast
Insulin Secretaguoges
• SU
• Repeglanide
• Nateglinide
• Glibenclamide
Insulin Secretaguoges: Concerns
• Hypoglycemia
• Weight gain
• Cardiovascular disease risk
α-Glucosidase Inhibitors
• Take within 15' of a major meal
• Increase the dose gradually
• SE/benefit dose 50mg tds
α-Glucosidase Inhibitors: Side effects
• Deranged LFT’s high doses
• Ileus Japanese.
• Contraindications:- IBD- Malabsorption- Bowel obstruction- Liver failure- Cr clearance<25 ml/min
Thiazolidinediones
Pharmacokinetics of TZD’s
Pioglitazone
Rosiglitazone
Thiazolidinedions (Glitazones)
• Reduce HbA1c by
1-2%
• Peripheral vascular resistance : 4mmHg in 24-h mean systolic and diastolic blood pressure
• Lipids
- Convert small, dense LDL particles to large, buoyant LDL particles
- Increase plasma HDL cholesterol
- Decrease plasma triglycerides if they are elevated (>200 mg/dl)
Pioglitazone vs Rosiglitazone
Pioglitazone Rosiglitazone p
HbA1c - 0.7% - 0.6% NS
Cholesterol 5.7± 0.1% 15.9± 1% <0.001
LDL 15.7±1.9% 23.3± 1.9% <0.02
HDL 14.9± 1.2% 7.8± 1.3% <0.001
Non HDL 3.8±1.3% 18.6± 1.3% <0.001
Trigs -12±3 % 14.9±3.1% <0.001
Dia Care 2005: 1547-54
Rosiglitazone
Before We Start
• Rofecoxib
• Muraglitazar
• Rosiglitazone
• Rofecoxib= Vioxx
• SE Nissen
Odds Ratio
• Odds of an event occurring in a patient in the experimental group relative to that of a patient in the control group
Confidence Interval and Odds Ratio
• Odds ratio, for the result to be statistically significant, the 95% confidence interval should not overlap 1 (i.e. the odds ratios within the confidence interval should all be >1 or <1, the no difference point)
Nissen SE, Wolski K. N Engl J Med 2007;356:2457-2471
• Analysed 42 out of 48 trials • 6 trials without CVS events ruled out of analysis• Trial duration ≥ 24 weeks • No time to event analysis• Mean age 57 years
n MI CVS Death
p
Avandia 15560 Odds Ratio 1.43
Odds Ratio 1.64
0.03
No Avandia 12283 95%CI
1.03-1.98
95%CI
0.98- 2.740.06
Nissen SE, Wolski K. N Engl J Med 2007;356:2457-2471
Caution about use…Limitations of the study acknowledgedMay increase CVS risk
RECORD TrialInterim analysis at 3.9 yrs
• Non- inferiority Study !!• 4447 patients- 40- 75 years- A1c 7.1-9%- BMI> 25
• 2220 Rosi + Met or SU • 2227 Met + SU
Primary Outcomes
- Myocardial infarction- Congestive heart failure- Stroke- TIA- Unstable angina- Unplanned CVS
revascularization- Amputation of extremities- Death from CVS cause
RECORD Study : Problems
• Expected event rate 11% p.a.
• Actual event rate 2% p.a.
• Expected study dropout rate 2% p.a.
• Actual study dropout rate 3% p.a.
• As a result the study is underpowered
RECORD: Conclusion
• Rosiglitazone association with an increased risk of heart failure acknowledged
• As the study was underpowered, it is nit possible to determine whether the drug was associated with an increase in the risk of myocardial infarction
Pioglitazone
PROactive
• 5238 patients• HbA1c above 6.5%• At least one of the following - Previous MI- Previous CVA- PTCA- ACS> 3months prior to the study entry- History of intermittent claudication
Lancet; 366: 1279-89
PROactive
• Primary Endpoints
- Composite of all cause mortality, MI, CVA, unstable angina,
PTCA, Revascularisation procedures, amputations
• Secondary Endpoints
• Time to death of any of the disease endpoints
- MI- CVA- Unstable angina etc
Lancet; 366: 1279-89
PROactive
• NNT 49 over 3 years to prevent an event
• 21 first MI would be saved in 1000 patients started on pioglitazone
• Heart failure was increased in pioglitazone group( Odds ratio 1.38), but LVF mortality was equal
Pioglitazone Meta-analysis
• 16390 Patients
• Pioglitazone n= 8554; Control n= 7836
• Primary Endpoint: Composite of Death, Non-fatal MI and Non-fatal CVA
• Secondary Endpoint Heart Failure
Pioglitazone did well…
• Primary endpoint Pioglitazone 4.4% vs Control 5.5% p=0.05
• HR= 0.82; CI 0.72- 0.94
• Time to event apparent after 1 year
• Heart Failure: Pioglitazone 2.3% vs Control 1.8% p=0.02 HR 1.4
• No difference in fatal
HF!!!
The PERISCOPE Trial
• 547 patients randomised: pioglitazone vs glimepiride
• Age 35- 85
• HbA1C 6-9%
• Angiographic Coronary a stenosis 20-50%
• Target vessel stenosis had to be less than 50% throughout 4cm segment
JAMA 2008; 299: 1561- 73
The PERISCOPE Trial
JAMA 2008; 299: 1561- 73
Glimepiride n=273
Pioglitazone n= 270
p
Smokers 53 (19.4%) 31 (11.5%) 0.01
Ex Smokers 119 (43.6%) 147 (54.5%) nsNever smoked 99 (36.4%) 89 (33%) ns
Prior MI 70 (25.6%) 83 (30.7%) ns
BP 250 (91.6%) 225 (83.3%) 0.02
Insulin 63 (23.1%) 49 (18.1%) ns
Glimepiride Pioglitazone
LS mean (CI)
P valueΔ from baseline
LS mean (CI)
P valueΔ from baseline
p
% atheroma Volume
0.73
(0.33- 1.12)
< 0.001 -0.16 (-0.57-0.25)
0.44 0.002
Max atheroma thickness
0.011 0.054 -0.011 0.06 0.006
Normalized atheroma Volume
-1.5
(-4.5 to 1.54)
0.34 -5.5
(-8.7 to -2.4)
<0.01 0.06
Ath Vol in 10mm most diseased segment
-2.1
(-3.3 to -0.84
0.01 -2
(3.3 to -0.67)
0.003 0.93
Glimepiride Group End
Glimepiride Group Baseline Pioglitazone Group Baseline
Pioglitazone Group End
Pioglitazone Group EndGlimepiride Group End
Glimepiride Group Baseline Pioglitazone Group Baseline
ACCORD Trial
• Intensive glycaemic management
• Target HbA1c 6.4%
• Stopped a month ago…
• Increased mortality in active treatment group
• Analysis is awaited
New Kids on the Block
DPP-4 inhibitors
GLP-1 mimetics
Of Men and Mice
• Dipeptidyl Peptidase – 4 (DPP-4)
degrades
- Glucose-dependent Insulinotropic Peptide (GIP):improves glycaemic control in mice
- Glucagon Like Peptide 1 ( GLP-1): improves glycaemic control in mice and men
DDP-4 Knock Out Mice
• Improved glucose tolerance
• Elevated GLP-1 and GIP levels
• Resistance to diet induced obesity and hyperglycaemia
DDP-4 Knock Out Mice
• Increased pain threshold
• Reduced stress like responses
• Reduced number of CD4 cells in spleen
• Immune and inflammatory responses increased in experimental arthritis
DPP-4 other Biological Activities
• Loss of DPP-4 in tumours: > aggressive behaviour
• Implicated in control of immune and lymphocyte function
• Cell migration
Sitagliptin Studies
Added to Duration nStarting
A1c Δ A1c placebo
Metformin 6 months 701 8.00% -0.65% yes
Metformin 1 year 1172 7.50% -0.70% yes
vs Metformin+ Glipizide Less hypos Weight loss
Pioglitazone 6 months 353 8.00% -0.70% yes
Vildagliptin Studies
Added to Duration nStarting
A1c Δ A1c placebo
Metformin 12+40 wk 107(72) 7.80% -0.70% yes
Metformin 24wks 544 8.40% (50mg) -0.7% yes
(100mg) -1.1%
Pioglitazone 26 weeks 592 8.70% -1.90% yes
Insulin 24 weeks 296 8.90% -0.50% yes
Indications
• Sitagliptin
• In addition to - TZD OR- Metformin OR- SU ± Metformin
- Dose 100mg OD
• Vildagliptin
• In combination with
- TZD OR- Metformin
- SU: 50mg OD
50 mg BD
Exenatide
• GLP-1 analogue
• 5-10 ug BD
• Injection
• Licensed with SU/Metformin or in combination
• Induces ~2kg weight loss
Exenatide
• HbA1c reduction ~ 1%
• FPG reduction of 1.5mmol/l
• Reduction in postprandial hyperglycaemia
• Rare hypos
• Nausea and vomiting
• ? pancreatitis
Meta- analysis
• DPP-4 inhibitors
• A1c by mean 0.74%• Weight neutral• Risk of infection• Not inferior to other
oral hypoglycaemic agents
• GLP-1 Analogues
• A1c by mean 0.97%• Induce weight Loss• More GI side effects
JAMA 2007; 289: 194- 206
In Conclusion
• Several classes of drugs are available
• Metformin, SU’s and Acarbose … tried, tested and do not suit every patient
• Glitazones…
• DPP-4 inhibitors / GLP- 1…we need to get the feel for them
www.EndoDiabetes.com