Transcript Slide 1

Modern Management Type 2
Diabetes - Oral Agents
Janie Thomason
Diabetes Lead GP Moray CHP
Clinical Assistant Diabetes Dr Grays
Managing Diabetes Mellitus Type 2
• From diagnosis, explode the myth!
• There is no such diagnosis as “mild diabetes” - only
well controlled and poorly controlled DM.
2
“Diabetes is a state of disordered metabolism which
may present with hyperglycaemia if the patient
doesn’t first succumb to cardiovascular mortality”
BDA Meeting, 1998
Two-hour plasma glucose levels are an
independent risk indicator for mortality*1
Hazard ratio
2.5
2.0
1.5
1.0
11.1
0.5
7.8–11.0
<7.8
0.0
<6.1
6.1–6.9
FPG (mmol/L)
 7.0
Adjusted for age, centre, sex, cholesterol, BMI, SBP, smoking
Adapted from DECODE
* as measured by an OGTT
1. DECODE study group. Lancet 1999; 354: 617–621.
Lowering HbA1C Reduces Risk of Complications
In intensively-treated patients, HbA1C was 7.0% compared to 7.9% in
conventionally treated patients. This 0.9% decrease in HbA1c is
associated with a reduction in risk for diabetic complications
-16 P=0.052
MI
-21 P=0.015
-24
Retinopathy
Cataract extraction
P=0.046
Microvascular endpoint
-25 P=0.009
Albuminuria at 12 years
-34 P=0.00005
Any diabetes related endpoint
-12 P=0.029
0
-10
-20
-30
-40
-50
UK Prospective Diabetes Study (UKPDS) Group (33). Lancet 1998; 352 (Sept. 12): 837–853.
Glycaemic control and primary
prevention of cardiovascular
disease
• UKPDS demonstrated a 14% reduction in
MI with a 1% fall in HbA1C
• Metformin reduced HbA1C
by 0.6%, but
2
reduced MI by 39%
• Benefits of Metformin may relate to
improved insulin sensitivity and reduced
pro-thrombotic factors
Causes of hyperglycaemia in type 2 diabetes
Receptor +
post-receptor defect
Peripheral tissues
(muscle)
Glucose
Liver
Increased glucose
production
Pancreas
Impaired insulin
secretion
Insulin
resistance
Extrapolation of the time of deterioration
of -cell dysfunction1
ß-cell dysfunction (%)
100
80
60
40
20
0
–12
–10
Adapted from UKPDS 16.
1. UKPDS 16. Diabetes 1995; 44: 1249–1258.
–8
–6
–4
–2
Years from diagnosis
0
2
4
6
Loss of early-phase insulin release in type 2
diabetes mellitus1
Pattern of insulin release is altered early in type 2 diabetes
120
100
20g
glucose
80
60
40
20
0
–30 0 30 60 90 120
Time (minutes)
1. Ward W, et al. Diabetes Care 1984; 7: 491–502.
Type 2 diabetes
Plasma insulin (µU / ml)
Plasma insulin (µU/ml)
Normal
120
20g glucose
100
80
60
40
20
0
–30 0 30 60 90 120
Time (minutes)
Gaining control of hyperglycaemia1-3
GLUCOSE TOXICITY
-cell
dysfunction
Insulin signalling
defect
Loss of early phase
insulin release
Insulin resistance
Postprandial
glucose spikes
Increased basal
glucose levels
The development of
type 2 diabetes is the
result of a combination of
-cell dysfunction and
insulin resistance
FPG
Hyperglycaemia
HbA1c
1. Lebovitz HE. Diabetes Rev 1999; 7: 139–53. 2. Ward W, et al. Diabetes Care 1984; 7: 491–502. 3. Yki-Järvinen H.
Endocr Rev 1992; 13: 415–31.
Historic therapeutic options for Type 2
diabetes
Year introduced Drug
Main mode of action
1922
Insulin
Increased peripheral
glucose disposal
Decreased hepatic glucose
production
1957
Sulphonylurea Increased insulin secretion
1957
Metformin
Decreased hepatic glucose
production
1990
Acarbose
Decreased intestinal CHO
digestion rate
New drugs in the real World…
Opportunities in Type 2 Diabetes
to:
• To provide better glycaemic control with
less adverse side-effects
• To tailor both tablets and insulins
according to the patient’s lifestyle and
circumstances
• To (hopefully) reduce cardiovascular
disease and microvascular complications
HbA1c in Diet Treated Patients: Effects of Various
Medications
(Difference From Placebo. Different studies)
0
HbA1c (%)
-0.5
-1
Troglitazone
-1.5
-2
Acarbose
Glipizide
-GITS
Metformin
Repaglinide
-2.5
12
‘Achieving’ Glycaemic Targets in the
UKPDS (2): HbA1C <7.0%
3 years 6 years 9 years
Diet
25%
12%
9%
Sulphonylurea 50%
34%
24%
Metformin
44%
34%
13%
Insulin
47%
37%
28%
Glycaemic control with Diet,
Sulphonylurea, Metformin, or Insulin
in Patients with Type 2 Diabetes
Progressive requirement for
multiple therapies (UKPDS 49)
JAMA 1999; 281: 2005-2012
Selecting an oral hypoglycaemic agent
• Sulphonylurea first choice if BMI < 25 kg/m2
• Action - potentiates pancreatic beta cell insulin release
– Gliclazide
40-320mg / 24hr
• or as Gliclazide MR (Diamcron MR) 30-120mg
– Glimepiride
2-6mg (od advantage)
– Glipizide
2.5-20mg / 24hr
– (consider tolbutamide in renal impairment)
Remember - discuss risk of hypoglycaemia
- remind patient to inform DVLA of treatment
New Sulphonylureas: Glimepiride and
Gliclazide MR (2)
• Consider switching from Gliclazide if compliance
difficulties (i.e. 1 tablet daily, rather than 4)
• Although reduced hypoglycaemia, can still
cause severe hypoglycaemia
(NB, caution in the elderly, and patients
with renal impairment)
• Lack of long-term data
likewise generic Gliclazide!)
(NB,
Selecting an oral hypoglycaemic agent
• Metformin
• Action - reduces insulin resistance
– Primary drug of treatment if overweight; adjunct to insulin
– Dose 500mg - 3g / 24hrs
• commence 500mg od with/after food, increasing in 500mg
increments at 2 week intervals
• side effects often limit dose. (diarrhoea; lethargy; anorexia;
malabsorption of B12 and folate)
• CI in renal failure (creatinine > 150), liver disease and
alcoholism
The need for new therapy options in
Type 2 Diabetes
• Patients prefer tablets to injections
• Ideally, a tablet providing sustained
glycaemic control over years, rather than
months
• Such a tablet needs to address both
progressive beta cell loss (insulin
deficiency) and insulin resistance
New Oral Hypoglycaemic Agents
• The PPAR gamma agonists (TZDs):
Rosiglitazone (Avandia)
Pioglitazone (Actos)
• Newer Sulphonylurea agents:
Glimepiride (Amaryl)
Gliclazide MR (Diamicron
MR)
• Prandial glucose regulators:
Repaglinide (Novonorm)
Nateglinide (Starlix)
Selecting an oral hypoglycaemic agent
• Rosiglitazone(Avandia); Pioglitazone (Actos)
• Action: thiazolidindione acting at the level of the PPAR-gamma
receptor to improve insulin resistance
• Dose - 4 to 8mg /24 hrs Rosiglitazone
15 to 45mg/24 hrs Pioglitazone
– Licensed as add-on to either metformin or sulphonylurea or
recently as monotherapy; recently available as triple therapy
– CI if hepatic impairment (AAT x2 normal at baseline) or cardiac
failure
– Does require commitment to monitoring LFT’s – suggest
baseline and 6 monthly (current research looking at use in IGT
and reducing cardiovascular mortality)
Clinical Effectiveness of Rosiglitazone
after 9 months (n=23)
Baseline
9 months
P value
HbA1C (%)
9.5 (+/- 1.3)
8.5 (+/- 1.4)
P =0.03
Weight (kg)
88.2 (+/- 21.4)
95.3 (+/- 21.4)
ns
Chol (mmol/l)
5.3 (+/- 1.1)
5.5 (+/- 1.5)
ns
HDL (mmol/l)
1.0 (+/- 0.2)
1.1 (+/- 0.4)
ns
Trig (mmol/l)
3.0 (+/- 2.3)
2.5 (+/- 1.2)
ns
Systolic BP
144 (+/- 20)
153 (+/- 20)
ns
Diastolic BP
78 (+/- 11)
81 (+/- 14)
ns
Clinical Effectiveness of Pioglitazone
after 6 months (n=23)
Baseline
6 months
P value
HbA1C (%)
10.0 (+/- 1.7)
8.4 (+/- 2.0)
P <0.01
Weight (kg)
85.9 (+/- 24.0) 87.5 (+/- 22.9)
ns
Chol (mmol/l)
6.2 (+/- 3.6)
6.4 (+/- 2.8)
ns
HDL (mmol/l)
1.1 (+/- 0.4)
1.2 (+/- 0.4)
ns
Trig (mmol/l)
7.7 (+/- 17.2)
7.2 (+/- 15.1)
ns
Systolic BP
141 (+/- 18)
140 (+/- 22)
ns
Diastolic BP
79 (+/- 11)
75 (+/- 21)
ns
The Role of the TZDs, 2006
• Add-on therapy to Metformin in the overweight
and obese patient with Type 2 Diabetes
• Maybe a better choice than a sulphonylurea in
many patients (no problems with hypos /
improved cardiovascular surrogate markers)
• Sulphonylureas produce a more rapid
improvement in glycaemic control, and are the
best option in symptomatic patients but
increasing concerns with increased mortality
The Role of the TZDs, 2006
• An alternative to Metformin in the sulphonylurea
treated patient who is intolerant of Metformin, or
has renal impairment
• Sulphonylurea monotherapy is usually in normal
weight patients, and UKPDS demonstrated
excellent long-term control reducing
microvascular complications but not
macrovascular
• Combination with sulphonylurea should be the
rarer use of dual therapy with a glitazone
When not to use the TZDs?
• As a substitute for insulin
(osmotic symptoms and weight loss
= lifelong insulin)
• Cardiac failure or fluid retention
• Significant liver disease
• Woman of child-bearing age planning
pregnancy
TZDs and the future...
• Long-term cardiovascular and mortality
end-point studies are ongoing. Evidence
gathering eg Proactive study
• A first-line role can only be justified when
‘hard end-point’ data is available
• They are most likely to be of benefit earlier
in the course of Type 2 Diabetes
Selecting an oral hypoglycaemic agent
• Acarbose
• Action : alpha-glucosidase inhibitor which slows digestion and
absorption of carbohydrates
– used as adjunct to other agents or insulin
– dose 50 - 300mg / 24 hrs as tolerated (increment slowly)
_ No effect on mortality and morbidity
– safety point - if patient also on insulin or SU, hypo must be
treated with dextrose/glucose
Selecting an oral hypoglycaemic agent
• Nateglinide (Starlix): Repaglinide (Novonorm)
• Action: improve beta cell insulin release in response to postprandial hyperglycaemia
• Novonorm licensed for monotherapy or with Metformin; Starlix
licensed for use as adjunct to Metformin alone
– Novonorm 500mcg initially before meals (max 16 mg/24 hrs);
Starlix 60mg-120mg before meals
– Glucose sensitive - apparently low risk of hypoglycaemia even if
meal omitted
– May be improved cardiovascular mortality - data not yet
available
– “Niche” drug – useful if sensitive to SU
Clinical Experience with Repaglinide
• Patients being troubled by hypoglycaemia
caused by sulphonylureas (e.g., the
elderly and patients with renal impairment)
• Patients with ‘flexible lifestyles’ or ‘erratic
eaters’ (CF, basal bolus insulin regimes
with rapid acting analogues)
• Patients who fast
Hospitalisation with Hypoglycaemia
• The Leicester Royal Infirmary,
1997 to March 1999
• 83 patients, the notes of 75 patients being
reviewed (90%)
• 38 patients (51%) had Type 2 Diabetes
• 50% male, and patients aged 51 to 92 years
(mean 76 years)
April
Hypoglycaemia in the elderly with
Type 2 Diabetes
• High risk, and sulphonylureas should be avoided
• Metformin is the safest choice, assuming no
contra-indication (i.e., renal impairment)
• TZD monotherapy will be an option in the near
future (need to ensure no overt cardiac failure)
• Repaglinide has been a useful option in
monotherapy during recent years
Indo-Asian people with Type 2
Diabetes
• One quarter of Indo-Asian people over 60
years have Type 2 Diabetes
• High prevalence of cardiovascular disease
and diabetic nephropathy
• Fasting seasons / days for both Muslim and
Hindu people, and problems with
sulphonylureas
• After Metformin monotherapy, TZDs and
prandial glucose regulators maybe the best
options
CONCLUSIONS
• TREATMENT improves outcomes SAVES
lives
• RANGE of treatments available
• EVIDENCE available to help chose the
most suitable option
• One Size Fits All - NOT AVAILABLE
• DIET & LIFESTYLE are at least as
important perhaps more so than the type
of OHA or insulin used