modern management type 2 diabetes - oral agents janie thomason diabetes lead gp moray chp clinical...
TRANSCRIPT
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.
“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
2
Adjusted for age, centre, sex, cholesterol, BMI, SBP, smoking
<6.1 6.1–6.9 7.0
11.1
7.8–11.0
<7.8
FPG (mmol/L)
Two-
hour
pla
sma
gluc
ose*
(mm
ol/L
)
2.5
2.0
1.5
1.0
0.5
0.0
Haz
ard
rat
ioTwo-hour plasma glucose levels are an independent risk indicator for mortality*1
1. DECODE study group. Lancet 1999; 354: 617–621.
Adapted from DECODE * as measured by an OGTT
UK Prospective Diabetes Study (UKPDS) Group (33). Lancet 1998; 352 (Sept. 12): 837–853.
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
MI
Retinopathy
Cataract extraction
Microvascular endpoint
Albuminuria at 12 years
Any diabetes related endpointP=0.029
P=0.009
P=0.052
P=0.046
P=0.015
P=0.00005
-12-12
-25-25
-16-16
-21-21
-34-34
-24-24
0 -10 -20 -30 -40 -50% Reduction in Risk
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 reduced MI by 39%
• Benefits of Metformin may relate to improved insulin sensitivity and reduced pro-thrombotic factors
2
Peripheral tissues(muscle)
Glucose
Liver
Impaired insulin secretion
Increased glucose production
Receptor +post-receptor defect
Insulinresistance
Pancreas
Causes of hyperglycaemia in type 2 diabetes
1. UKPDS 16. Diabetes 1995; 44: 1249–1258.
0
20
40
60
80
100
Years from diagnosis
ß-c
ell
dys
fun
ctio
n (
%)
–10 –8 –6 –4 –2 0 2 4 6–12
Extrapolation of the time of deterioration of -cell dysfunction1
Adapted from UKPDS 16.
1. Ward W, et al. Diabetes Care 1984; 7: 491–502.
Normal Type 2 diabetes120
100
80
60
40
20
0–30 0 30 60 90 120
Time (minutes)–30 0 30 60 90 120
Time (minutes)
Pla
sma
insu
lin
(µ
U/m
l)
120
100
80
60
40
20
0
20g glucose20g
glucose
Pla
sma
insu
lin
(µ
U /
ml)
Pattern of insulin release is altered early in type 2 diabetes
Loss of early-phase insulin release in type 2 diabetes mellitus1
Gaining control of hyperglycaemia1-3
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.
GL
UC
OS
E T
OX
ICIT
Y
-celldysfunction
Loss of early phaseinsulin release
Postprandialglucose spikes
Insulin signalling defect
Insulin resistance
Increased basalglucose levels
Hyperglycaemia
FPG
HbA1c
The development of The development of type 2 diabetes is the type 2 diabetes is the
result of a combination of result of a combination of -cell dysfunction and -cell dysfunction and
insulin resistanceinsulin resistance
Historic therapeutic options for Type 2 diabetes
Year introduced Drug Main mode of action
1922 Insulin Increased peripheralglucose disposalDecreased hepatic glucoseproduction
1957 Sulphonylurea Increased insulin secretion
1957 Metformin Decreased hepatic glucoseproduction
1990 Acarbose Decreased intestinal CHOdigestion 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
12-2.5
-2
-1.5
-1
-0.5
0
Hb
AH
bA
1c1c (
%)
(%
)
Glipizide-GITS
Metformin
AcarboseTroglita-zone
Repaglinide
HbA1c in Diet Treated Patients: Effects of Various Medications
(Difference From Placebo. Different studies)
‘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 (NB, likewise generic Gliclazide!)
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)
Diastolic BP
Systolic BP
Trig (mmol/l)
HDL (mmol/l)
Chol (mmol/l)
Weight (kg)
HbA1C (%)
79 (+/- 11)
141 (+/- 18)
7.7 (+/- 17.2)
1.1 (+/- 0.4)
6.2 (+/- 3.6)
85.9 (+/- 24.0)
10.0 (+/- 1.7)
Baseline
75 (+/- 21)
140 (+/- 22)
7.2 (+/- 15.1)
1.2 (+/- 0.4)
6.4 (+/- 2.8)
87.5 (+/- 22.9)
8.4 (+/- 2.0)
6 months
ns
ns
ns
ns
ns
ns
P <0.01
P value
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 post-prandial 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, April 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)
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