Transcript 2.Dr.Nancy-Ngugi-Recent-Advances_in_Diabetes_Mellitusx

Recent advances in
Diabetes Mellitus
Dr. Nancy Ngugi
Consultant Physician/Endocrinologist
Diabetes is an increasing healthcare epidemic
throughout the world
Africa
56.3
68.9
+22%
36.7
50.4
+37%
Eastern Mediterranean
and Middle East
Europe
34.6
67.9
+96%
North America
South and Central America
South-East Asia
Western Pacific
IDF. Diabetes Atlas 6th Edition – 2013
24.1
38.5
+60%
19.8
41.4
+109
%
138.2
201.8
+46%
72.1
123
+71%
Worldwide:
382million people in 2013
592 million projected for 2035
55% increase
2
2012 ADA and EASD : Patient-centered approach to managing
hyperglycemia in type 2 DM
Glycemic targets
-
HbA1c < 7.0% (mean PG 150-160 mg/dl [8.3-8.9 mmol/l])
-
Pre-prandial PG <130 mg/dl (7.2 mmol/l)
-
Post-prandial PG <180 mg/dl (10.0 mmol/l)
Individualization is key:
 Tighter targets (6.0 - 6.5%) - younger, healthier
 Looser targets (7.5 - 8.0%+) - older, comorbidities,
hypoglycemia prone, etc.
-
Avoidance of hypoglycemia
Inzucchi SE, et al. Diabetes Care 2012 (published ahead of print April 19 2012; doi 10.2337/dc12-0413).
2012 ADA and EASD position statement:
Patient-centered approach to managing hyperglycemia in type 2 DM
Patient-centered care is defined as an
approach to ‘providing care that is respectful of and responsive to
individual patient preferences, needs, and values and ensuring
that patient values guide all clinical decisions’1
o Glycemic targets and glucose-lowering therapies must be individualized
o Diet, exercise and education remain the foundation of any type 2 DM treatment
program
o All treatment decisions, where possible, should be made in conjunction with the
patient, focusing on his/her preferences, needs and values
o Comprehensive CV risk reduction must be a major focus of therapy
o Engaging patients in healthcare decisions may enhance adherence to therapy
ADA, American Diabetes Association; CV, cardiovascular; DM, diabetes mellitus; EASD, European Association for the Study of Diabetes.
1. Committee on Quality of Health Care in America: Institute of Medicine, 2001. The National Academies Press,
Washington. 2. Inzucchi SE, et al. Diabetes Care 2012 (published ahead of print April 19 2012; doi
10.2337/dc12-0413).
Figure 1. Summary of 2006 ADA-EASD consensus algorithm for the management of hyperglycaemia in type 2 diabetes. If HbA1c < 7 %
maintain therapy. If HbA1c ≥7% move promptly to next level.1,4
Lifestyle + metformin
If HbA1c ≥ 7%
Add SU
Add basal insulin
Add TZD
If HvA1c ≥ 7%
Add TZD
Add
basal
Insulin
Intensify
insulin
Add basal
insulin
If HbA1c ≥ 7%
Key: Su = sulphonylurea; TZD; thiazolidinedione
*TZD with insulin is off-label in the UK
Reoroduced with permission from Bailey et al. Br
J Diabete Vasc
Dis 2006;6:147-8.
Further intensify insulin or add basal insulin
* Metformin ± TZD*
Add SU
ADA/EASD 2012 :
Algorithm for the Management of Type 2 DM
Inzucchi SE, et al. Diabetes Care 2012 (published ahead of print April 19 2012; doi 10.2337/dc12-0413).
The main classes of glucose-lowering medications
-glucosidase inhibitors1
(delays digestion and
absorption of intestinal
carbohydrate)
Intestinal lipase
inhibitors2
(blocks free fatty acid
absorption from
the intestine)
Metformin1
(reduces hepatic
glucose production and
increases peripheral
glucose uptake)
Thiazolidinediones1
(reduces insulin resistance
in target tissues)
Sulphonylureas
and rapid-acting
secretagogues1
(stimulates insulin
secretion)
DPP-4 inhibitors3
(stimulates glucose dependant
insulin secretion from
b-cells and lowers glucagon
secretion from -cells)
1. Krentz AJ, Bailey CJ. Drugs. 2005;65:385-411. 2. Cheng A, Fantus G. Can Med Assoc J. 2005;172:213-26.
3. Barnett A. Int J Clin Pract. 2006;60:1454-70. 4. Chao EC. Discov Med. 2011 Mar;11(58):255-63.
DPP-4 inhibitors enhance incretin activity
 Under physiological conditions, GLP-1 and GIP are rapidly inactivated
by DPP-4
 DPP-4 inhibitors prolong the effects of GLP-1 and GIP on -cells and b-cells
leading to increased insulin secretion and decreased glucagon secretion1-4*
Increases and prolongs GLP-1
and GIP effects on b-cells
DPP-4
inhibitor
Food intake
Glucose-dependant
insulin secretion
b-cells
Stomach
Pancreas
DPP-4
Incretins
(GLP-1, GIP)
GI tract
-cell
Net effect:
Blood glucose
Increases and prolongs
GLP-1 effect on -cells
Glucagon secretion
Intestine
* GIP does not inhibit glucagon secretion by alpha cells
1. Drucker DJ, Nauck MA. Nature. 2006;368:1696-705. 2. Idris I, Donnelly R. Diabetes Obes Metab. 2007;9:153-65. 3. Barnett A. Int J Clin Pract.
2006;60:1454-70. 4. Gallwitz B, Haring H-U. Diabetes Obes Metab. 2010;12:1-11.
DPP-4 inhibitors: Rationale
Mixed Meal
Intestinal
GLP-1
release
GLP-1 (7-36)
active
DPP-4
DPP-4 inhibitor
DPP-4=dipeptidyl peptidase 4
Adapted from Ahrén B Curr Diab Rep 2003;3:365–372.
GLP-1 (9-36)
inactive
Postprandial GLP-1 levels are decreased in patients
with type 2 diabetes
Meal
Normal Glucose Tolerance
Impaired Glucose Tolerance
Type 2 Diabetes
20
*
*
*
*
*
*
GLP-1 (pmol/L)
15
*
10
5
0
0
60
120
Time (min)
Mean ± SE; N = 102; *P <.05 between T2DM and NGT groups.
Toft-Nielsen M, et al. J Clin Endocrinol Metab. 2001;86:3717-3723.
180
240
GLP-1 Analogs (Incretin Mimetrics)
– Exenatide
– Liraglutide
• Resistant to DPP-4 degradation
• Given as s.c. injections.
- Exenatide – twice daily
- once weekly
- Liraglutide - once daily
• Cause nausea, vomiting and diarrhoea initially but
subside with continued use.
• ↓HbA1c 0.5 – 1.5%
• Induce weight loss.
DPP-IV Inhibitors
– DPP-IV is a pleiotropic enzyme
– Acts as a binding protein
– EU/ FDA Approved
• Sitagliptin
• Vildagliptin*
• Saxagliptin
• Linagliptin
–
–
–
–
Oral preparation
Sustained inhibition of DPP-IV
HbA1C reduction of 0.7%
No Weight loss or Nausea
* Not FDA Approved
In normal glucose homeostasis, the kidneys filter and
reabsorb ~180 g of glucose per day
Glucose uptake ~ 250 g/day:
Glucose input ~ 250 g/day:
Net balance ~ 0g/day
• Dietary intake ~ 180 g/day
• Glucose production ~70 g/day
g/day
• Gluconeogenesis*
• Glycogenolysis
• Brain ~125 g/day
• Rest of the body ~125 g/day
+
-
The kidney filters
circulating glucose
Glucose filtered
~180 g/day
The kidney reabsorbs
and recirculates glucose
Glucose reabsorbed
~180 g/day
(Renal threshold for glucose
reabsorption is ~200 mg/dL)
In Type 2 diabetes, continued glucose reabsorption leads
to sustained hyperglycaemia
Glucose input >280 g/day:
Glucose uptake >250 g/day:
• Dietary intake >180 g/day
• Glucose production ~100 g/day
• Gluconeogenesis*
• Glycogenolysis
• Brain ~125 g/day
• Rest of the body >125 g/day
-
+
Average blood glucose
concentration 150 mg/dL
Kidney filters all
circulating glucose
Glucose filtered
~270 g/day
Increased reabsorption and
recirculation of glucose
Glucose levels exceed the
glucose reabsorption
threshold, resulting
in glucosuria
*Elevated glucose production in patients with Type 2 diabetes attributed to hepatic and renal gluconeogenesis.2
In normal renal glucose handling, 90% of glucose is
reabsorbed by SGLT2
Majority of
glucose
is reabsorbed by
SGLT2 (90%)
Remaining
glucose is
reabsorbed by
SGLT1 (10%)
SGLT2
Glucose
SGLT, sodium-glucose co-transporter
Glucose
filtration
Minimal to
no glucose
excretion
SGLT2 Inhibitors inhibits SGLT2 and removes excess glucose
in the urine independently of insulin
Reduced glucose
reabsorption
Proximal
tubule
SGLT2
Glucose
SGLT2-I
Increased urinary
excretion of
excess
glucose (~70
g/day,
corresponding to
280 kcal/day*1
)
Glucose
filtration
Glucose
• By inhibiting SGLT2, SGLT2 removes glucose and associated calories
• SGLT2-I is >1400-times more selective for SGLT2 versus SGLT1
*Increases urinary volume by only ~1 additional void/day (~375 mL/day) in a 12-week study of healthy subjects and patients with Type 2 diabetes.
Sodium – Glucose – Cotransporter – 2 (SGLT2) - Inhibitors
•
•
•
•
Dapaglifozin
Canaglifozin
Empagliflozin
Reduces fasting and post prandial plasma
concentrations of glucose and HbA1c. 0.7 – 1.0%
Reduces weight
Low risk of hypoglycaemia
Can be used in combination with established glucose
lowering drugs including insulin.
Achieving optimal control of HbA1c requires daily control
of PPG and FPG – the glucose triad1-3
Both postprandial and fasting glucose contribute to HbA1c levels1-3
HbA1c
=
PPG
Influenced by:
• Pre-prandial glucose
• Glucose load from meal
• Incretin level
• Insulin secretion
• Insulin sensitivity in peripheral tissues
• Decrease in glucagon suppression
+
FPG
Influenced by:
• Hepatic glucose production
• Hepatic sensitivity to insulin
• Exercise during previous day
• Meal from the previous night
• Alcohol
• Nocturnal glycemic
1. IDF. International Diabetes Foundation. Guidelines for Postmeal Glucose. Available at: http://www.idf.org/webdata/docs/Guideline_PMG_final.pdf.
Accessed 26 Jan 2009. 2. Monnier L, et al. Diabetes Metab. 2006;32:2S11-16. 3. Woo V, et al. Int J Clin Pract. 2008;62:1935-42.
In patients with moderately uncontrolled glycemic,
postprandial glucose is the main contributor to HbA1c
levels1
At HbA1c levels between 7.3% and 9.2%, PPG and FPG contribute almost equally to HbA1c1
FPG
100
PPG
Contribution (%)
80
60
40
20
0
<7.3
(n=58)
7.3-8.4
(n=58)
8.5-9.2
(n=58)
9.3-10.2
(n=58)
>10.2
(n=58)
HbA1c (%)
Duration of diabetes in each subgroup (years)
8.4 ± 1.3
10.0 ± 1.1
13.8 ± 1.7
11.7 ± 1.2
1. Monnier L, et al. Diabetes Care. 2003;26:881-5.
8.3 ± 1.1
Guideline Comparisons of Goal BP and Initial Drug Therapy for Adult s with Hypertension
Guideline
Population
Goal Bp, mm Hg,
Initial Drug Treatment
2014 Hypertension
guideline
General ≥60 y
<150/90
Nonblack: thiazide-type diuretic, ACEI, ARB,
or CCB
General <60 y
<140/90
Black: thiazide-type diuretic or CCB
Diabetes
<140/90
Diabetes <140/90 Thiazide-type diuretic, ACEI, ARB, or CCB
CKD
<140/90
ACEI or ARB
General nonelderly
<140/90
β-Blocker, diuretic, CCB, ACEI, or ARB
General elderly <80y
<150/90
General ≥80 y
<150/90
Diabetes
<140/85
ACEI or ARB
CKD no proteinuria
<140/90
ACEI or ARB
CKD + proteinuria
<130/90
General <80 y
<140/90
General ≥80 y
<150/90
Diabetes
<130/80
ACEI or ARB with additional CVD risk
ACEI, ARB, thiazide, or DHPCCB without additional
CVD risk
CKD
<140/90
ACEI or ARB
ADA 201339
Diabetes
<140/90
ACEI or ARB
KDIGO 201240
CKD no proteinuria
<140/80
ACEI or ARB
CKD + Proteinuria
<130/80
General < 80 y
<140/90
<55 y: ACEI or ARB
General ≥80 y
<150/90
≥55 y or black: CCB
Black, lower risk
<135/85
Diuretic or CCB
Target organ damage
Or CVD risk
<130/80
ESH/ESC 201337
CHEP 201338
NICE
201141
ISHIB 201042
Thiazide, β-blocker (age <60y), ACEI (nonblack),
or ARB
Thank you