Lipèmia/Glucèmia postprandrial i risc CV.CV, cardiovascular; CVD, cardiovascular disease; PPG,...
Transcript of Lipèmia/Glucèmia postprandrial i risc CV.CV, cardiovascular; CVD, cardiovascular disease; PPG,...
Lipemia/Glucemia postprandrial i risc CV.
Antonio Ceriello
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Barcelona, Spain and IRCCS MultiMedica, Milan, Italy
Agenda
PPG, postprandial plasma glucose
PPG
Assessment of PPG
Addressing PPG
Agenda
PPG, postprandial plasma glucose
PPG
Definition of PPG
PPG homeostasis
Pathophysiology of PPG regulation in diabetes
Overall glucose exposure is the sum of physiological, basal and postprandial exposures
Schematic representation. Adapted from Monnier & Colette. Diabetes Metab 2015;41:179–82
Breakfast Lunch Dinner
Glycaemia (mmol/L; mg/dL)
Basal hyperglycaemia
Prep
ran
dia
l g
lycaem
ia F
PG
Postprandial glycaemia
Diabetes
Normal
4 h 4 h 4 h
Prep
ran
dia
l g
lycaem
ia
Prep
ran
dia
l g
lycaem
ia
Physiological exposure
Additional overall glucose in people with diabetes • Basal hyperglycaemia • Postprandial
hyperglycaemia
Postprandial hyperglycaemia
PPG increment: PPG peak–preprandial glycaemia
Agenda
PPG, postprandial plasma glucose
PPG
Definition of PPG
PPG homeostasis
Pathophysiology of PPG regulation in diabetes
Complementary roles of insulin and glucagon
EGP, endogenous glucose production; PPG, postprandial plasma glucose
Adapted from Aronoff et al. Diabetes Spectr 2004;17:183–90
EGP is primarily derived from the liver under the direction of glucagon
Rate of glucose
appearance
Liver
Gut
Pancreas Rate of glucose
disappearance
Plasma glucose
Insulin
Glucagon
Preprandial state
Low-level insulin secretion controls glucose disposal and has a minimal role in suppressing EGP
Postprandial state
Rate of glucose
appearance
Glucose is primarily derived from the gut
Insulin suppresses glucagon secretion and hepatic EGP and promotes glucose disposal in the periphery
Liver
Gut
Pancreas Rate of glucose
disappearance
Plasma glucose
Insulin
Glucagon
Fat Muscle
+ -
-
+
+
-
-
+
Promoted signal
+
-
Stimulatory
Inhibitory
Suppressed signal
Tissues
Fat Muscle
Tissues
Agenda
PPG, postprandial plasma glucose
PPG
Definition of PPG
PPG homeostasis
Pathophysiology of PPG regulation in diabetes
In subjects with diabetes:
• Both preprandial and postprandial hyperglycaemia can occur1
• PPG excursions are greater and of longer duration2
• HGP suppression is suboptimal1
• Impaired HGP suppression occurs early in the evolution of diabetes3
• Time to post-meal peak insulin concentration: ~2 h (vs. ~45 min in individuals without diabetes)2
• Appropriately timed exposure of the liver to insulin has a great impact on PPG3
PPG and insulin profile in diabetes
HGP, hepatic glucose production; PPG, postprandial plasma glucose
1. Firth et al. J Clin Invest 1986;77:1525–32; 2. Basu et al. J Clin Invest 1996;97:2351–61; 3. Rizza. Diabetes 2010;59:2697–707
240
Insulin c
oncentr
ation (
pm
ol/
L)
300
Time (min)
200
100
0
400
500
0
Postprandial insulin profile
Meal
180 120 60
No diabetes Type 2 diabetes
Endogenous glucose production accounts for a significant part of postprandial hyperglycaemia in type 2 diabetes
PPG, postprandial plasma glucose
Woerle et al. Am J Physiol Endocrinol Metab 2006;290:E67–77
59 61
15
27 4
10
0
20
40
60
80
100
Healthy Type 2 diabetes
Glycogenolysis
Gluconeogenesis
Meal
PPG
rele
ase o
ver
6 h
(g)
(75%)
(20%)
(5%)
(62%)
(28%)
(10%)
p<0.001
p=0.007
Time after meal ingestions (min)
–60 0 60 120 180 240 300 360
Pla
sm
a g
lucose (
mM
)
4
20
12
Type 2 diabetes (n=26) Healthy (n=15)
p<0.001
• Endogenous glucose in subjects with type 2 diabetes started out higher and did not decrease after meal ingestion
• Early changes in insulin and glucagon secretion are important determinants of overall PPG
Summary of PPG
PPG, postprandial plasma glucose
Meal size and content, pancreatic hormones and gastric emptying are the most important regulators of PPG
Postprandial hyperglycaemia occurs early in the development of diabetes
The delay in the insulin response to a meal cannot appropriately suppress the hepatic glucose production, and is responsible for postprandial hyperglycaemia
Agenda
PPG, postprandial plasma glucose
PPG
Assessment of PPG
Addressing PPG
Agenda
PPG, postprandial plasma glucose
Assessment of PPG
Self monitored blood glucose (SMBG)
1,5-AG, 1,5-anhydroglucitol; CGM, continuous glucose monitoring; FGM, flash glucose monitoring; IDF, International Diabetes Federation; PPG, postprandial plasma glucose; SMBG, self-monitored blood glucose
Heinemann & Freckmann. J Diabetes Sci Technol 2015;9:947–50; IDF. 2011 Guideline for Management of Postmeal Glucose in Diabetes. www.idf.org; IDF. Self-Monitoring of Blood Glucose in Non-Insulin Treated Type 2 Diabetes. 2009. www.idf.org; National Diabetes Information Clearinghouse. http://diabetes.niddk.nih.gov
SMBG
Pre- Post- Pre- Post- Pre- Post- Bedtime
5-point profile
7-point profile
IDF guidelines:
• SMBG – optimal method for assessing PPG
• Emerging technologies: CGM, FGM, 1,5-AG
• SMBG – integral part of diabetes management
• The timing and frequency of SMBG must be individualised
• Breakfast post-meal glucose excursions
• Larger AUC1–4h vs. lunch or dinner
• Smaller intra- and inter-variability of post-meal peaks vs. lunch or dinner
• Time to peak
• ~90 min for all meals
Post-meal peaks during CGM
CGM, continuous glucose monitoring Cichosz et al. Diabetes Technol Ther 2013;15:78–83
24-h glycaemic profile (mean and SD)
10
Glu
cose (
mm
ol/
L)
8
6
4
0 10 20
Time (h)
Retrospective study of CGM in 86 newly diagnosed insulin-naïve patients with type 2 diabetes
• Meals used for calculation: breakfast (5–11 am), lunch (11 am–3 pm) and dinner (5–9 pm)
Flash Glucose Monitoring (FGM)
*A finger-prick test using a blood glucose meter is required during times of rapidly changing glucose levels when interstitial fluid glucose levels may not accurately reflect blood glucose levels, or if hypoglycaemia or impending hypoglycaemia is reported or the symptoms do not match the system readings
CGM, continuous glucose monitoring; FGM, flash glucose monitoring; PPG, postprandial plasma glucose; SMBG, self-monitored blood glucose
1. Bailey et al. Diabetes Technol Ther 2015;17:787–94.; 2. Abbott. www.freestylelibre.co.uk; 3. Heinemann & Freckmann. J Diabetes Sci Technol 2015;9:947–50
• FGM measures interstitial glucose1
• Handheld device used to scan sensor for current blood glucose level2
• One scan also records glucose data for the last 8 h2
• One sensor last for up to 14 days and is factory-calibrated; no calibration with finger pricks is needed*2
• Lower cost than CGM, similar price to SMBG (if testing 6–8 times per day)3
Meal tests
*p<0.05 differences vs. NGT subjects. Dashed lines indicate glucose tolerance levels: normal (<140 mg/dL); impaired (140–199 mg/dL); and diabetic (≥200 mg/dL)
ADA, American Diabetes Assocation; IGT, impaired glucose tolerance; MTT, mixed meal tolerance test; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test; SMBG, self-monitored blood glucose; WHO, World Health Organization
Meier et al. Diabetes Obes Metab 2009;11:213–22
Glu
cose (
mg/d
L)
300
Time (min)
200
150
0
350
–30
Test meal
240 90 60
250
100
50
30 0 120 150 210 180
Mixed test meal (820 kcal)
* * *
* *
* *
* *
*
*
* * *
Glu
cose (
mg/d
L)
300
Time (min)
200
150
0
350
–30
75g oral glucose
240 90 60
250
100
50
30 0 120 150 210 180
NGT IGT Type 2 diabetes
Oral glucose (75 g)
* *
*
*
*
*
*
*
*
*
* *
*
*
*
*
• WHO, ADA: OGTT – recommended test for diagnosis of diabetes or IGT
• Unicentric study, n=60 type 2 diabetes, IGT or NGT
• OGTT vs. MTT (continental breakfast) vs. SMBG
Close correlation, OGTT and MTT
2-h PPG (r2=0.78, p<0.0001)
Summary of PPG assessment
SMBG is the recommended method for assessing PPG. The timing and frequency of SMBG must be individualised
CGM is recommended as adjunct to SMBG and FGM alone or as complement to SMBG, for treatment decision.
There is a close correlation between the OGTT and the meal tolerance test
Agenda
PPG, postprandial plasma glucose
PPG
Assessment of PPG
Addressing PPG
Agenda
PPG, postprandial plasma glucose
Addressing PPG
Contribution to overall glucose control (HbA1c)
Short-term effects of postprandial hyperglycaemia
Long-term diabetes-related complications
Targeting PPG
Relative contribution of PPG to HbA1c
BF, breakfast; FPG, fasting plasma glucose; L, lunch; PPG, postprandial plasma glucose
Monnier et al. Diabetes Care 2003;26:881–5
6.1 mmol/L 110 mg/dL
6.1
PPG
8 11 2 5
am pm
BF L
FPG
• 290 non-insulin-treated patients with type 2 diabetes
• 4-point profile: FPG (8 am) vs. PPG (11 am, 2 pm, 5 pm)
• Relative contribution to the average diurnal hyperglycaemia
70%
50% 45% 40% 30%
0%
20%
40%
60%
80%
100%
<7.3% 7.3–8.4% 8.5–9.2% 9.3–10.2% >10.2%
PPG
FPG
Rela
tive c
ontr
ibution (
%)
HbA1c
100
80
60
40
20
0
Relative contribution of PPG in relatively ‘well-controlled’ patients
FPG, fasting plasma glucose; NPH, neutral protamine Hagedorn; PPG, postprandial plasma glucose; RCT, randomised controlled trial
Riddle et al. Diabetes Care 2011;34:2508–14
300
08:00
250
200
150
100
50
0
10:00 12:30 14:30 18:00 20:00 23:00 Day 2 08:00
Self-m
onitore
d
glu
cose (
mg/d
L)
• Pooled analysis
• Six RCTs
• 1261 patients with type 2 diabetes receiving basal insulin (insulin glargine or NPH insulin)
• 7-point profiles
• FPG: AUCFPG-100 mg/dL 24 h
• PPG: AUCPPG-FPG 24 h
21%
66%
0%
20%
40%
60%
80%
100%
Before basal insulin (HbA1c
8.7%)
After basal insulin (HbA1c
7%)
PPG
FPG
Before basal insulin (HbA1c 8.7%)
After basal insulin (HbA1c 7.0%)
Relative contribution of PPG
100
80
60
40
20
0
Summary of PPG contribution to HbA1c
SMBG profiles and CGM allow estimation of the relative contribution of PPG (as AUC) to HbA1c
The relative contribution of PPG to overall hyperglycaemia (HbA1c) is significant in relatively well-controlled patients with diabetes
Glycaemic control is still suboptimal. Achieving the HbA1c targets requires correcting both the FPG and PPG values
Agenda
PPG, postprandial plasma glucose
Addressing PPG
Contribution to overall glucose control (HbA1c)
Short-term effects of postprandial hyperglycaemia
Long-term diabetes-related complications
Targeting PPG
Hyperglycaemia
Ceriello A. Annual Meeting Italian Society of Diabetology, 1998
Ceriello A. Diabetologia 2003; 46 Suppl 1:M9-16
LDL oxidation
Antioxidant consumption
F VIIa
Endothelium
Endothelial dysfunction
Atherosclerosis
Hypertriglyceridemia
Oxidative stress
Study Start Location No. of
patients Duration (years)
Chicago Peoples Gas Company Study 1992 US 873 19
Oslo Study 1995 US 873 19
Diabetes Intervention Study 1996 Germany 1139 11
Chicago Heart Association Detection Project 1997 US 12220 22
Paris Prospective and Helsinki Policemen Studies 1998 – 7260 20
Rancho Bernardo Study 1998 US 1858 7
Funagata Diabetes Study 1999 Japan 2534 6
Honolulu Heart Program 1999 Hawaii 8006 23
Hoorn Study 1999 The Netherlands 2363 8
Mauritius-Fiji-Nauru Study 1999 – 9179 8–12
Epidemiological data correlating PPG with CVD 1/2
CV, cardiovascular; CVD, cardiovascular disease; PPG, postprandial plasma glucose
Standl et al. Diabetes Care 2011;34(Suppl. 2):120–7; Bergman et al. Diabet Med 2016;33:1060–6
Epidemiological data correlating PPG with CVD 2/2
CV, cardiovascular; CVD, cardiovascular disease; PPG, postprandial plasma glucose
Standl et al. Diabetes Care 2011;34(Suppl. 2):120–7; Bergman et al. Diabet Med 2016;33:1060–6
Study Start Location No. of
patients Duration (years)
DECODE 1999 EU 22514 8.8
Saydah, Diabetes Care 2001 US 3092 16
Framingham Offspring Study 2002 US 3370 4
Cardiovascular Health Study 2002 US 4014 8.5
Qiao, Eur Heart J 2002 Finland 6766 7–10
DECODA 2004 Asia 6817 5
San Luigi Gonzaga Study 2006 Italy 529 5
Whitehall Study 2006 UK 17869 33
AusDiab Study 2009 Australia 10026 7
Israel Study of Glucose Intolerance, Obesity and Hypertension
2016 Israel 2138 33
Consistent observation Significant correlation between postprandial hyperglycaemia and CV mortality or CV events
Study (publication year)
Intervention, sample, follow-up
Results on CV endpoints
Observations
STOP-NIDDM (2003)1
• Acarbose vs. placebo • IGT, n=1429
• 3.3 years
• Major CV events • HR: 0.51
(95% CI 0.28–0.95)
• Secondary endpoint (hypothesis-generating)
• Very small difference in PPG
HEART2D (2009)2
• Prandial vs. basal insulin • Type 2 diabetes and
AMI, n=1115 • 2.6 years
• Major CV events • HR: 0.98
(95% CI 0.80–1.21)
• 47% achieved PPG target (<7.5 mmol/L)
• PPG difference: 0.8 mmol/L
NAVIGATOR (2010)3
• Nateglinide vs. placebo • IGT, n=9518
• 6.4 years
• Extended CV outcomes • HR: 0.93
(95% CI 0.83–1.03)
PPG is not lower in nateglinide arm
Less supportive evidence from RCTs
AMI, acute myocardial infarction; CV, cardiovascular; HR, hazard ratio; IGT, impaired glucose tolerance; MACE, major adverse cardiovascular events; PPG, postprandial plasma glucose; RCT, randomised controlled trial
1. Chiasson et al. JAMA 2003;290:486–94; 2. Raz et al. Diabetes Care 2009;32:381–6; 3. NAVIGATOR study group. N Engl J Med 2010;362:1463–76
Five-point Primary Outcome (ITT analysis)
Acarbose: 14.4% (470), 3·33 per 100 person-years Placebo: 14.7% (479), 3·41 per 100 person-years
Acarbose Placebo
Mean Two-hour Plasma Glucose Levels Over Six Years
Overall least-squares mean difference −0.24 mmol/L 95% CI −0.16 to −0.32 p<0.0001
0.0
2 H
r P
lasm
a G
luco
se (
mm
ol/
L)
Acarbose Placebo
Pathophysiology of postprandial state due to excessive hyperglycaemia
Ceriello. Nutr Metab Cardiovasc Dis 2008;18:S17–33
Excessive postprandial hyperglycaemia
High density lipoprotein Cholesterol catabolism
Triglycerides rich lipoprotein and low density lipoprotein
removal
Glucose auto-oxidation
Fibrinolysis
Free fatty acids Insulin resistance Early phase insulin
secretion
Endothelial function disturbed (nitric oxide
release )
Plaque stability
Blood coagulation
Agenda
PPG, postprandial plasma glucose
Addressing PPG
Contribution to overall glucose control (HbA1c)
Short-term effects of postprandial hyperglycaemia
Long-term diabetes-related complications
Targeting PPG
PPG
Is it time for a paradigm switch in diabetes
management?
Why should we target 1-hour post-meal glucose ?
?
Coronary heart disease and peak glucose levels
Honolulu heart study, N= 6394; p< 0.001 comparing quintiles 1 and 5, p<0.01 comparing quintiles 1 and 5. Donahue RP et al. Diabetes 1987; 36:689-92
0
10
20
30
40
50
60
40-114
mg/dL
115-133
mg/dL
134-156
mg/dL
157-189
mg/dL
190-532
mg/dL R
ate
* p
er 1
00
0
Fatal coronary heart disease
Total coronary heart disease
Glucose levels one hour after 50 gm glucose load
One hour PPG control
“Diabetes and mortality risk is associated with elevated 1-hour glucose
level. The risk was independent of traditional CV risk factors, and it was
accentuated when combined with BMI. The obvious need is to compare
1-hour glucose with fasting and 2-hour postload glucose levels as
well as Hb A1c in a similar setting and in various populations”.
One hour PPG control
This large longitudinal study provides evidence that 1-hour postload plasma glucose in the absence of clinical diabetes at
baseline apparently is an independent risk factor for fatal coronary heart disease and stroke in middle-aged and older nondiabetic men
and women, and also for CVD and for all cause mortality.
One hour PPG control
One hour PPG control
• Oxidative stress:
• higher at higher levels of glycaemia
• induces endothelial dysfunction
• Endothelial dysfunction
• is directly correlated to the level of glycaemia reached during OGTT and “glucose spike”
• is a stronger predictor of CIMT.
• is worse at 1h than at 2h (OGTT and meals).
• Inflammation and thrombosis activation, follow the same pattern of endothelial dysfunction as during acute hyperglycaemia.
Deleterious mechanisms of 1h hyperglycaemia OGTT/PP: possible mechanisms
1. Ceriello A et al, Nutr Metab Cardiovasc Dis 2016,26: 285-92; 2. Giacco F et al, Diabetes 2015; 64: 3273–84; 3. Ceriello A, et al. Diabetes Res Clin Pract 2008,82: 262–7; 4. Ceriello A et al. Diabetes 1995,44:924–8.
CIMT, carotid intima-media thickness, OGTT, oral glucose tolerance test
Endothelial Dysfunction and Oxidative Stress Worsen as Glycaemia Increases During an OGTT
* P<0.05 versus fasting, † P<0.01 versus one hour, ‡ P<0.01
1. Endothelial vasodilation in response to 75 g oral glucose load (N=58)
2. Assessed by plasma level of thiobarbituric acid reactive substances (TBARS), a marker of lipid peroxide
Kawano H et al. J Am Coll Cardiol 1999;34:146-154.
Arterial function1
12
10
8
6
4
2
0
-2
FMD of brachial artery (%)
400
Plasma glucose levels (mg/dL)
0 100 200 300
n=174
r=-0.61
P<0.01
8
6
4
2
0
FMD of brachial artery (%)
Fasting 1h 2h
‡
‡ ‡
* †
NGT
IGT
DM
Plasma TBARS levels (nmol/mL)
Oxidative stress2
Fasting 1h 2h 1
2
3
‡ ‡
‡
* †
NGT
IGT
DM
Changes of glycaemia, GLP-1, FMD, plasma nitrotyrosine, 8-iso-
PGF2a, and insulin during the meal and the OGTT in normal
healthy control patients and T2D patients.
Protective role of glucagon-like peptide 1 on endothelium during the meal
Data are expressed as mean ± SE
Ceriello A et al. Diabetes Care 2011; 34: 697–702
△ meal test controls ▲OGTT controls ○ meal test T2D ● OGTT T2D
• 1h glucose might be more dangerous than that at 2h simply because glycaemia is higher at 1h, during an OGTT and post-meal – common sense, but
• There are data showing that the glycaemic peak usually appears 1h after the start of meal.1-3
Why 1h postmeal hyperglycaemia is more deleterious than that of 2h?
1. Polonsky KS et al. J Clin Invest 1988; 81: 442–448. 2. Mazze RS et al. Diabetes Technol Ther 2008; 10: 149–59. 3. Tsujino D et al. Diabetes Technol Ther 2009; 11: 457–60
Pathways of hyperglycaemia-induced vascular damage
NADPH, nicotinamide adenine dinucleotide phosphate hydrogen; GFAT, glutamine fructose phosphate amidotransferase Brownlee M. Nature 2001;414:813–20
2011 PPG guidelines from IDF
IDF, International Diabetes Federation; PPG, postprandial plasma glucose
IDF. 2011 Guideline for Management of Postmeal Glucose in Diabetes. www.idf.org
Treatment recommendations
• Post-meal hyperglycaemia is harmful and should be addressed
• Implement treatment strategies to lower PPG in people with post-meal hyperglycaemia
• A variety of both non-pharmacological and pharmacological therapies should be considered to target PPG
• PPG should be measured 1–2 h post-meal
• The target for PPG is 9.0 mmol/L (160 mg/dL) as long as hypoglycaemia is avoided
• Self-monitoring of blood glucose should be considered because it is currently the most practical method for monitoring PPG
Glycaemic control recommendations ADA/EASD, AACE and IDF guidelines
*No comorbidities, long life expectancy; †depending on disease duration, life expectancy, important comorbidities, patient attitudes and resource or support targets can be set more or less stringent
AACE, American Association of Clinical Endocrinologists; ADA, American Diabetes Association; EASD, European Association for the Study of Diabetes; IDF, International Diabetes Federation; PPG, postprandial plasma glucose
1. Chiang et al. Diabetes Care 2014;37:2034–54; 2. Inzucchi et al. Diabetologia 2015;58:429–42; 3. ADA. Diabetes Care 2015;38(S1):33–40; 4. Garber et al. Endocr Pract 2016;22;84–113; 5. IDF. 2011 Guideline for Management of Postmeal Glucose in Diabetes. www.idf.org
Age group Type 1
diabetes1
Type 2 diabetes2
Young (<18 years) <7.5% 7.0%
Adult <7.0% 7.0%
Older adults Healthy* Complex/intermediate Very complex/poor health
<7.5% <8.0% <8.5%
7.0%†
Association PPG target
(1–2 h postmeal)
ADA/EASD2,3 <10 mmol/L <180 mg/dL
AACE4 <7.8 mmol/L <140 mg/dL
IDF5 <9 mmol/L <160 mg/dL
HbA1c recommendations (ADA/EASD) PPG recommendations
Conclusions – already accepted
Glycaemic control is dependent on adequate regulation of FPG and PPG levels
Postprandial hyperglycaemia is associated with • Oxidative stress (e.g. atherosclerosis) • CVD • CV mortality
Reducing PPG levels may lower CV risk
Guidelines recognise the importance of addressing PPG at every stage of diabetes treatment
Conclusions – paradigm switch
Current ADA and the IDF guidelines suggest targeting PPG at 1h and between 1h and 1.5 h after the start of meals, respectively.
Paradigm switch in diabetes management
Introduce 1hOGTT for prediabetes and T2D diagnosis and 1hPPG for diabetes control
New ultra fast acting insulins and non-invasive technologies for blood
glucose monitoring