Management of
Diabetes Mellitus during
Ramadan
By
Professor
Megahid M, Abuelmagd
Diabetes and Endocrinology Unit
Mansoura University
DIABETES
&
RAMADAN
Pathophysiology of Fasting in normal
individuals
Peripheral tissues
(muscle)
Gluconeogenesis
Counteregulat
ory hormones Increased glucose uptake
Glucose
FFA,
Ketones
Liver
Glycogen stores
depleted
Pancreas
insulin secretion
decreased
Adipose
Pathophysiology of Fasting in Diabetes
Hyperglycaemia &Ketoacidosis
Gluconeogenesis & Peripheral tissues
(muscle)
ketogenesis
Counteregulat
ory hormones Increased glucose uptake
Glucagon
Glucose
FFA,
Ketones
Liver
Glycogen stores
depleted
Excessive
breakdown
Pancreas
insulin secretion
decreased or
absent
Adipose
THE NEED
FOR
BALANCE
HYPERGLYCEMIA
Diabetes-associated risks
Adjusted incidence per 1000
person years (%)
70
Microvascular
endpoint
60
50
Myocardial
infarction
40
30
20
10
0
5
6
7
8
9
10
11
Mean HbA1c (%)
UKPDS 35. BMJ 2000; 321: 405-12
10
Pathophysiology
Hyperglycemia
 Oxidative Stress
Atheroma
Formation
Endothelial
Dysfunction
Thrombus
Formation
Vascular Complications
11
Vascular Complications
3 years incidence (%)
50
vascular complications among diabetics
45
40
CONTROL n= 35620
35
DM n=8905
30
25
20
15
10
5
0
MI
HTN
Ramsey, pharmacoeconomics, 1999
FOOT ULCER
END STAGE
RENAL DISEASE
STROCK
DM RELATED EYE
DISEASE
12
Cost of vascular complications
Micro vascular
complications
X 1.7
Macro vascular
complications
X 3.0
Macro &
Micro
X 3.5
13
Causes of death in diabetes
% of deaths in diabetes
mainly due to vascular complications
45
40
35
30
25
20
15
10
5
0
IHD
OTHER HD
DM
CANCER
STROKE
INFECTIONS
OTHERS
14
Main risk associated with
fasting in diabetic patients is:
Hypoglycemia
Hypoglycemia
Decreased food intake is a well-known risk factor for the
development of hypoglycemia.
Results of the Diabetes Control and Complications Trial
(DCCT) showed a threefold increase in the risk of
severe hypoglycemia in patients who were in the
intensively treated group and had an average HbA1c
(A1C) value of 7.0%
Hypoglycemia
The incidence of severe hypoglycemia was probably
underestimated in this study, since events requiring
assistance from a third party without the need for
hospitalization were not included.
Sever hypoglycemia was more frequent in
patients:
•
•
in whom the dosage of oral hypoglycemic agents
or insulin were changed.
in those who reported a significant change in
their lifestyle
Hypoglycemia and clinical implications
• The ultimate goal of the glycemic management of diabetes is a
lifetime of euglycemia without hypoglycemia (1)
• Hypoglycemia is recognized to be a major limitation in
achieving good control (2)
1. American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care. 2005;28(5):1245-1249
2. Cryer PE. Diabetologia. 2002;45:937–948
Physiological defenses against falling plasma
glucose concentrations
Adapted from: Cryer PE. J Clin Invest. 2006;116:1470–1473
Hypoglycemia impairs defenses against recurrent
hypoglycemia (Hypoglycemia-Associated Autonomic Failure)
Antecedent
hypoglycemia
Sleep
Antecedent
exercise
Reduced sympathoadrenal
responses to hypoglycemia
Reduced
sympathetic
neural responses
Reduced epinephrine
responses
Defective glucose
counter regulation
Hypoglycemia
unawareness
Recurrent
hypoglucemia
Cryer PE. J Clin Invest. 2006;116:1470–1473
Mechanisms by which hypoglycemia may affect
cardiovascular events
Desouza CV, et al. Diabetes Care. 2010; 33:1389–394
Classification of hypoglycemia according to severity: European
Committee for Medicinal Products for Human Use (CHMP)
Episodes suggestive of
hypoglycemia
where blood glucose measurement were
not available.
Minor hypoglycemic episodes
defined as either a symptomatic episode
with blood glucose level below 3 mmol/L
[54mg/dl] and no need for external
assistance, or an asymptomatic blood
glucose measurement below 3 mmol/L,
Major hypoglycemic episodes
defined as symptomatic episodes
requiring external assistance due to
severe impairment in consciousness or
behaviour, with blood glucose level
below 3 mmol/L and prompt recovery
after glucose or glucagon administration,
Guideline on clinical investigation of medicinal products in the treatment of diabetes mellitus . CPMP/EWP/1080/00 Rev. 1 . Committee for
Medicinal Products for Human Use (CHMP) . 20 January 2010 .
Risk Difference of Hypoglycemia with Different
Glucose-lowering Agents for T2DM
Drug 1 less harmful
Drug 1 more harmful
Pooled effect
(95% CI)
Studies
(participated)
Met vs Met + TZD
0.00 (-0.01 to 0.01)
3 (1557)
SU vs repag
0.02 (-0.02 to 0.05)
5 (1495)
Glyb vs other SU
0.03 (0.00 to 0.05)
6 (2238)
SU vs Met
0.04 (0.0 to 0.09)
8 (2026)
SU + TZD vs SU
0.08 (0.00 to 0.16)
3 (1028)
SU vs TZD
0.09 (0.03 to 0.15)
5 (1921)
SU + Met vs SU
0.11 (0.07 to 0.14)
8 (1948)
SU + Met vs Met
0.14 (0.07 to 0.21)
9 (1987)
0
0.5
0.15
0.15
0.2
Weighted absolute risk difference
CI=confidence interval; Glyb=glyburide; Met=metformin; repag=repaglinide; SU=sulfonylurea; TZD=thiazolidinediones.
Bolen S, et al. Ann Intern Med. 2007;147:386–399
Relative Risk of Hypoglycemia with Different Glucoselowering Agents when added to Metformin
HbA1c Goal Achieved
Group vs. Placebo
No. of
Trials
RR (95% CI)
Hypoglycemia
No. of
Trials
RR (95% CI)
All drugs
10
2.56 (1.99 to 3.28)b
19
1.43 (0.89 to 2.30)
Sulfonylureas
1
3.38 (2.02 to 5.83)a
3
2.63 (0.76 to 9.13)a
Glinides
1
3.20 (1.47 to 7.58)
2
7.92 (1.45 to 43.21)
Thiazolidinedione
s
1
1.69 (1.24 to 2.33)
2
2.04 (0.50 to 8.23)
AGIs
0
2
0.60 (0.08 to 4.55)
DPP-4 inhibitors
6
2.44 (1.78 to 3.33)b
8
0.67 (0.30 to 1.50)
GLP-1 analogs
1
3.96 (2.37 to 6.79)
2
0.94 (0.42 to 2.12)
NA
Adapted from: Phung, et al. JAMA. 2010;303(14):1410–1418
Abbrevations: AGIs, α-glucosidase inhibitors; CI, confidence interval; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1;
HbA1c, glycated hemoglobin A1c; NA, not applicable; RR, relative risk; WMD, weighted mean difference.
a ≥ 75%
b = 50%-75%
UKPDS – Treating to Targets Elevates the Risk of
Hypoglycemia and Incidence can be High with SUs
Cumulative Incidence of Hypoglycemia in T2DM over 6 Years
76
80
Sulfonylurea (n=922)
70
Insulin (n=689)
Patients (%)
60
50
45
40
30
20
11.2
10
3.3
0
Sulfonylurea
Insulin
Any hypoglycema
Sulfonylurea
Insulin
Major hypoglycemia*
HbA1c = 7.1% in all groups
SUs=sulfonylureas; T2DM=type 2 diabetes melllitus; *Requiring medical assistance or hospital admission
UK Prospective Diabetes Study Group. Diabetes.1995;44:1249–1258.
Relative Risk (%)
Risk of Hypoglycemia with Different Sulfonylureas
Severe hypoglycemia*
n/1000 person years =
Gliclazide
0.85
Glipizide
8.70
*<50 mg/dL.
Tayek J. Diabetes Obes Metab. 2008;10:1128–1130.
Glimepiride
0.86
Tolbutamide
3.50
Chlorpropamide
16.00
Glyburide
16.00
Health and economical consequences of
hypoglycemia
Hospitalization costs1
CV complications2
Weight gain by defensive eating3
Dizzy turn unconsciousness2
Hypoglycemia
Seizures2
Car accident4
Increased risk of dementia5
Death6
Coma2
Quality of Life7
1. Jönsson L, et al. Cost of Hypoglycemia in Patients with Type 2 Diabetes in Sweden. Value In Health. 2006;9:193–198
2. Barnett AH. CMRO. 2010;26:1333–1342
3. Foley J & Jordan. J. Vasc Health Risk Manag. 2010;6:541–548
4. Canadian Diabetes Association’s Clinical Practice Guidelines for Diabetes and Private and Commercial Driving. CanJ Diabetes. 2003;27(2):128 –140.
5. Whitmer RA, et al. JAMA. 2009;301:15655–1572
6. Zammitt NN, et al. Diabetes Care. 2005;28:2948–2961
7. McEwan P, et al. Diabetes Obes Metab. 2010;12:431–436
Hypoglycemia and Weight Gain are intertwined
Foley J, et al. Vasc Health Risk Manag. 2010:6 541–548
Impact of changes in weight and rates of hypoglycaemia events
on Quality-Adjusted Life Year (QALY)
McEwan, et al. Diabetes Obes Metab. 2010;12:431–436
Vildagliptin improves Alpha and Beta
Cell selectivity for both
Hyper and Hypoglycemia
Vildagliptin improves β-cell sensitivity to
glucose
Glucose Sensitivity
(pmol/min/m2/mM)
75
70
65
60
55
50
45
−4 0 4 8 12 16 20 24 28 32 36 40 44 48 52
Time (weeks)
Basal Secretory Tone
Secretion at 7 mM glucose
(pmol/min/m2)
Glucose Sensitivity
260
240
220
200
180
−4 0 4 8 12 162024283236 40444852
Time (weeks)
Vildagliptin 50 mg once daily
Placebo
Mari A, et al. J Clin Endocrinol Metab. 2008; 93: 103–109.
Effects of vildagliptin treatment on the
sensitivity of the α-cell to glucose
During the hypoglycemic steps, glucagon levels increased from a significantly lower
baseline to a slightly higher level with vildagliptin compared with placebo.
170
Meal
7.5 mM 5.0 mM 2.5 mM
Dose
Glucagon (mg/L)
150
130
110
90
−30
0
30
60
Ahrén B, et al. J Clin Endocrinol Metab. 2009;94(4):1236–1243.
Vildagliptin 100 mg once daily is NOT an approved dose.
90
120
165
Time (min)
210
255
285
Vildagliptin 100 mg once daily
Placebo
Comparing with commonly used SUs
In patients uncontrolled with metformin monotherapy vildagliptin is as
effective as glimepiride over 1 year with low incidence of hypoglycaemia
and no weight gain
Duration: 52 weeks, add-on to metformin: vildagliptin vs glimepiride
Mean HbA1c reduction a
Incidence of hypoglycaemia
Number of
hypoglycaemic events
Patients with
1 hypos (%)
7.5
n = 1389
1383
1389
1383
Number of severe
hypoglycaemic
events c
1389
1383
554
−0.4%
6.7
−0.5%
6.5
No. of events
6.9
16.2
No. of events
NI: 97.5%
CI (0.02, 0.16)
Incidence (%)
7.1
0.0
-8 -4
0
4
8
12 16 20 24 28 32 36 40 44 48 52 56
1.7
39
Time (weeks)
Change in body weight a
Vildagliptin 50 mg twice daily + metformin
Glimepiride up to 6 mg once daily + metformin
(BL mean ~88.8kg)
Adjusted mean change in
body weight (kg) from BL
Mean HbA1c (%)
7.3
b
BL=baseline; CI=confidence interval
NI=non-inferiority; aPer protocol population ; bSafety population.
cGrade 2 or suspected grade 2 events.
*P
<0.001; adjusted mean change from BL to Week 52,
between-treatment difference and P value were from
an ANCOVA model containing terms for treatment,
baseline and pooled centre.
n=
1117
1071
Ferrannini E et al. Diab Obes Metab 2009; 11: 157–166.
Vildagliptin was as effective as glimepiride when added to metformin at
2 years with no weight gain and low incidence of hypoglycemia
Duration: 104 weeks, add-on to metformin:
vildagliptin vs glimepiride
Hypoglycaemia
Number of hypo events
N = 1553 1546
N=
15
No. of events
4
2
0
0
Vildagliptin 50 mg bid + met
Glimepiride up to 6 mg qd +met
Change from BL to EP
(BL Mean ~89kg)
Adjusted mean change
in body weight (kg)
Primary objective of non-inferiority was met:
97.5% CI= (-0.00, 0.17); upper limit 0.3%
16
14
12
10
8
6
4
2
0
13
0
Change in body weight 3
1
Adjusted mean change in HbA1c was comparable between
vildagliptin and glimepiride treatment: −0.1% (0.0%) for both
N = 1553 1546
12
10
8
6
59
Mean HbA1c
Discontinuations due to hypos
1553 1546
16
14
No. of events
N = 1553 1546
18.2
Incidence (%)
Number of severe events a
No. of events
Patients with > 1 hypo (%)
2
n = 1539
Between-treatment
Difference
1520
1.2
2.0
1.0
0.0
-1.0
-2.0
-0.3
-1.5
*
1) Per protocol population. 2) Safety population. 3) Intent-to-treat population. a) any episode requiring the assistance of another party *p <0.001. BL=baseline; EP = week 104 endpoint; Met=
metformin; hypo = hypoglycemia; HbA1c= glycosylated hemoglobin.
Matthews DR et al. Diab Obes Metab 2010; 12: 780–789.
Very elderly patients pooled analysis
Very elderly patients pooled analysis:
Vildagliptin add on metfrmin shows NO hypoglycemic event
Pooled analysis at 24 weeks; 50 mg bid
HbA1c Reduction: At 24 weeks treatment
n=
62
25
BL
8.3
8.5
*
*<0.05 vs baseline (within group)
Monotherapy
studies pool
Add on therapy
studies pool
n=
62
25
BL
74.9
82.8
Change in Body
Weight (kg) from
baseline
Add on therapy
studies pool
Change in HbA1c
(%) from baseline
Monotherapy
studies pool
Body Weight: At 24 weeks treatment
*
Mono > 75
*
Add on > 75
Hypoglycemic events Monotherapy studies pool Add on therapy studies pool
Any events
0.0
0.0
Severe events
0.0
0.0
 OR No hypoglycemic events, including severe events was reported in elderly
patients with monotherapy and add-on therapy
Schweizer A. et al, Diabetes, Obesity and Metabolism 13: 55–64, 2011.
Even When
Add-on to Insulin
Fewer hypoglycemic events in vildagliptin
add-on to insulin compared with insulin alone
Add-on Treatment to Insulin
Duration: 24 weeks
Add-on to insulin:
vilda vs PBO
No. of Events
No. of Severe Events
185
No. of Events
200
160
120
113
80
40
0
No. of Severe Events
*
10
**
8
6
6
4
2
0
0
Vilda 50 mg twice daily
+ insulin
PBO + insulin
PBO=placebo; vilda=vildagliptin; *P <0.001; **P <0.05 between groups.
Fonseca V, et al. Diabetologia. 2007; 50: 1148–1155.
The Question Now:
Is Vildagliptin A Safe Drug To Be Used
With Diabetic Patients During Rmadan
VECTOR: Aim and objectives
Vildagliptin Experience Compared To gliclazide Observed during Ramadan
Main aim
 To determine the incidence of hypoglycaemic events in Muslim patients with T2D
fasting during Ramadan, who are treated with dual therapy of metformin plus
vildagliptin or metformin plus sulphonylurea (SU)
Primary objectives
 The incidence of hypoglycaemic events defined as:

Any reported symptoms by the patient and/or any blood glucose measurement of less than
3.9 mmol/L (also defined as mild or Grade 1 hypoglycaemia)

The need for third party assistance (also defined as severe or Grade 2 hypoglycaemia);
Secondary objectives
 The change in weight;
 The change in HbA1c levels; and
 The treatment adherence during Ramadan.
M. Hassanein et al Current Medical Research & Opinion Vol. 27, No. 7, 2011, 1367–1374
Study Design
Observational,
Non-interventional
Two-cohort study
Conducted in the UK.
HbA1c 8.5% up to 1 month prior to fasting
-----Data collection
Metformin 2000 + Vildagliptin 50 mg bid daily
Metformin 2000 +
6weeks pre Ramadan
Gliclazide 80 mg* per daily
Ramadan
n23
n 36
6 weeks post Ramadan
*Different formulations were used for gliclazide therefore the following conversion factor was used:
80 mg standard formulation 30 mg modified release formulation.
M. Hassanein et al Current Medical Research & Opinion Vol. 27, No. 7, 2011, 1367–1374
Vildagliptin: Significantly lowered HbA1c
compared to SU
Change in HbA1c (%)
from baseline
Duration: ≤16 week observational study
Add-on to metformin: vildagliptin vs gliclazide
BL=
0.1
7.6
7.2
+ 0.1
0.0
p= 0.02*
-0.2
Vildagliptin 50 mg twice daily (n=23)
Sulfonylurea (n=36)
-0.4
-0.4
Hypoglycaemic events
Vildagliptin
Sulfonylurea
Any events
0
34 (in 15 pts)
Severe events
0
1
*mean between-group difference 0.5%
BL=baseline; HbA1c=haemoglobin A1c
Hassanein M, et al. Curr Med Res Opin 2011; 27: 1367–1374
VECTOR Study: Results
No. of Hypos
P=0.0002
Hypoglycaemia
• Vildagliptin arm no Hypo
• SU arm
- 34 Hypo including
1 severe HE
M. Hassanein et al Current Medical Research & Opinion Vol. 27, No. 7, 2011, 1367–1374
VECTOR Study: Results
 Adherence
 Vildagliptin arm : 0.2 missed doses (p=0.0204)
 SU arm : 7.6 missed doses
 Weight
 Body weight remained unchanged in both groups
M. Hassanein et al Current Medical Research & Opinion Vol. 27, No. 7, 2011, 1367–1374
Consistency of Data
Devendra et al. Int J Clin Pract. 2009;63(10):1446–
1450
Devendra et al. Int J Clin Pract.
2009;63(10):1446–1450
Methods
HbA1c was > 8.5% despite
treatment with metformin 2 g daily
before Ramadan
All patients received education about how to identify and manage
hypoglycemia during Ramadan.
Vildagliptin 50 mg bid daily n26
N= 52
Metformin 2 g
StudyDesign
Design
Study
Gliclazide 160 mg bd n 26
2 weeks
Ramadan
10 days after Ramadan
Recording of hypoglycemia and weight gain
Devendra et al. Int J Clin Pract. 2009;63(10):1446–1450
Vildagliptin therapy and hypoglycaemia in
Muslim T2DM during Ramadan
Glycated haemoglobin (%)
Hypoglycemic events
n=
26
26
n=
26
26
BL
8.98
8.95
BL
0.42
0.27
0.6
0.42
-0.5
-1
-1.5
-1.26
*
-2
-2.5
-3
*P=0.8217; **P=0.0168
-1.23
LSM change in
hypoglycemic events
LSM change in HbA1c
0
0.4
0.2
0
-0.2
-0.24 **
-0.4
Vildagliptin
Gliclazide
Analysis of covariance models with treatment group, gender and ethnicity as factors. aAge, duration of diabetes, HbA1c, weight and prefasting value, bage, duration of
diabetes, weight and prefasting value, or cage, duration of diabetes, HbA1c and prefasting value as covariates. SD, standard deviation; SEM, standard error mean.
Devendra et al. Int J Clin Pract. 2009;63(10):1446–1450
Diabetes Care, Diabetologia.
19 April 2012 [Epub ahead of print]