Holistic approach to T2DM updates

Update in T2DM:
Holistic Approach
Chaicharn Deerochanawong M.D.
Professor of Medicine
Endocrinology Unit, Dept. of Medicine
Rangsit Medical school,
Rajavithi Hospital, Ministry of Public Health

Objectives in the Treatment of
Diabetes Mellitus
• Correct symptoms of hyperglycemia
• Prevent acute complications of
diabetes
• Prevent and delay progression of
chronic complications of diabetes
• Obtain good quality of life

Chronic complications of Diabetes
Retinopathy
Nephropathy
Neuropathy
MICROVASCULAR MACROVASCULAR
Cerebrovascular
disease
CHD
Peripheral
vascular
disease
World Health Organization/International Diabetes Federation, 1999. Diabetes Care 2001; 24 (Suppl 1): S5–20.

Heart Disease
Stroke
Others
Infection
Malignant
Neoplasms
Diabetes
Thailand Diabetes Registry 2006
Causes of Mortality in Patients
With Diabetes in Thailand
17%
22% 7%
14%
20% 20%
J Med Assoc Thai 2010; 93 (Suppl. 3): S12-20

Prevention of Chronic
Vascular Complications in Diabetes
• Holistic approach
• Individualized therapy

Prevention of CVD in Diabetes
Sattar N. Diabetologia 2013;56:686-95

Sattar N. Diabetologia 2013;56:686-95

Prevention and Management of
Diabetic Retinopathy and Nephropathy
• Blood Glucose Control
• BP control
• RAAS blockade
• Other drugs therapy: SGLT2-I,….

0
10
20
30
40
50
60
70
80
G Hb
< 6.5%
Cholesterol <175
mg/dl
Triglycerides <150
mg/dl
Systolic BP <130
mmHg
Diastolic BP <80
mmHg
intensive therapy Conventional therapy
Patients
%
P=0.06
P <0.001
P =0.19
P =0.001
P =0.21
STENO-2: Targeting Multiple CV Risk Factors
in Type 2 Diabetes Improves Outcome
53% reduction in combined
CVD events with intensive
multi-risk factor intervention
Gaede et al. NEJM 2008;358:580–91

Steno-2: 13-year follow-up
160 T2DM patients – patterns at 6 years and after
All-cause mortality (%) CV mortality, MI, CVA, CV procedure (%)
80
70
60
50
40
30
20
10
0
80
70
60
50
40
30
20
10
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Cumulative incidence
of death (%)
Cumulative incidence of
any cardiovascular event (%)
Years of follow-up
Years of follow-up
N at risk
80 78 75 72 65 62 57 39
80 80 77 69 63 51 43 30
N at risk
80 72 65 61 56 50 47 31
80 70 60 46 38 29 25 14
p = 0.02
p < 0.001
Gaede et al. NEJM 2008;358:580–91
Intensive therapy – 2.3% / year
Conventional therapy – 3.8% / year

ABCDES of Diabetes Care2019
A • A1C – optimal glycemic control (usually ≤7%)
B • BP – optimal blood pressure control (<130/80)
C • Cholesterol – LDL < 100 mgl/dL or >30% reduction
D • Drugs to protect the heart
A – ACEi or ARB │ S – Statin │ A – ASA if indicated in very high risk??
E • Exercise / Healthy Eating
S • Smoking cessation
S • Screening for complications
S • Self-management, stress and other barriers

Impact of Intensive Therapy for Diabetes:
Summary of Major Clinical Trials
Study Microvasc CVD Mortality
UKPDS      
DCCT /
EDIC*      
ACCORD     ?
ADVANCE     
VADT     
Long Term Follow-up
Initial Trial
* in T1DM

Major CV events
Stroke
Myocardial infarction
Favours more
intensive
Favours less
intensive
Meta-analysis of glucose-lowering trials
9% reduction
15% reduction
Turnbull et al. Diabetologia. 2009;52:2288-98.

Possible explanations for the difficulty in
showing that aggressively treating
hyperglycaemia reduces CVD
• No benefits are seen when going below an HbA1c of 7.0%
• The benefits of tight glycaemic control take 5-10 years to
show
• The benefits of lowering blood glucose may be offset by:
– Hypoglycaemia
– Drug side-effects
• Benefits may only be seen in people with relatively early
disease
• Persisting with aggressive therapy in people who don’t
respond may cause harm

Microvascular
complications
Hypoglycemia
• Newly diagnosed
• Long life expectancy
• Young kids
• Very elderly
• Advanced complications
Benefit and Risk of
Tight Glycemic Control
GOAL A1C
< 6.5% or 7%
GOAL A1C
7.5%-9%

Mechanisms of Hyperglycemia in type
2 diabetes
Adapted from De Fronzo RA. Diabetes 2009;58:773–95.
Hyperglycaemia
Decreased
insulin
secretion
Increased
glucagon
secretion
Neurotransmitter
dysfunction
Decreased
incretin effect
Increased
HGP
Decreased
glucose uptake
Increased
glucose
reabsorption
Increased
lipolysis
Islet-a cell

Adapted from De Fronzo RA. Diabetes 2009;58:773–95.
Hyperglycaemia
Decreased
insulin
secretion
Increased
glucagon
secretion
Neurotransmitter
dysfunction
Decreased
incretin effect
Increased
HGP
Decreased
glucose uptake
Increased
glucose
reabsorption
Increased
lipolysis
Islet-a cell
Insulin,SU,
Glinide
Metformin TZD
TZD
DPP4-I,
GLP1R-A
DPP4-I,
GLP1R-A
SGLT2
inhibitor
GLP1R-A
Therapeutic Implications of
Hyperglycemia in type 2 diabetes

THE INFORMATION IN THESE SLIDES IS FOR INTERNAL USE ONLY. NOT TO BE SHARED OR DISTRIBUTED OUTSIDE OF BMS, AMYLIN, OR ASTRAZENECA.
Efficacy Hypo Wt. ASCVD CHF DKD Cost AE
Metfor
-min
High No Neutral
(loss)
Potential
benefit
Neutral Neutral Low GI, potential
B12 def
SGLT2i Interme
diate
No Loss Benefit
(secondary
prevention)
Benefit Benefit High GU inf, DKA,
vol dep,
amputation,
fracture
GLP1-
RA
High No Loss Benefit
(secondary
prevention)
Neutral Benefit High GI, risk of C
cell tumor,
pancreatitis?
DPP4i Interme
diate
No Neutral Neutral Potential
risk???? :
Saxa, Alo
Neutral High Pancreatitis?
Joint pain
TZD High No Gain Potential
benefit
Increase
Risk
Neutral Low Vol. retention,
fracture,
Bladder CA??
SU High Yes Gain Neutral Neutral Neutral Low
Insulin Highest Yes Gain Neutral Neutral Neutral Low

INDIVIDUALIZED THERAPY
FACTORS CONSIDERATIONS
• Age
• Weight
• Comorbidities
- Coronary artery disease
- Heart Failure
- Chronic kidney disease
- Liver dysfunction
- Hypoglycemia

Age: Older adults
- Reduced life expectancy
- Higher CVD burden
- Reduced GFR
- At risk for adverse events from polypharmacy
- More likely to be compromised from
hypoglycemia
Less ambitious targets
HbA1c <7.5–8.0% if tighter
targets not easily achieved
Focus on drug safety

Weight
- Majority of T2DM patients overweight / obese
- Intensive lifestyle program
- Metformin
- SGLT-2 inhibitors
- GLP-1 receptor agonists
- Bariatric surgery ( BMI > 35kg/m2)

Comorbidities
- Coronary Disease
- Heart Failure
- Renal disease
- Liver dysfunction
- Hypoglycemia
 Avoid hypoglycemia
 SGLT2-I : CVD benefit
 GLP-1 R agonist : CVD benfit
 Metformin: CVD benefit in
obese T2DM (UKPDS)
 ?? Pioglitazone &  CVD events
 DPP4-I : Safe

Comorbidities
- Coronary Disease
- Heart Failure
- Renal disease
- Liver dysfunction
- Hypoglycemia
 Metformin: May use unless
condition is unstable or severe
 SGLT2-I: Benefit
 Avoid TZDs
 DPP-4-I safe ( SAXA??)
 GLP1-RA safe

Comorbidities
- Coronary Disease
- Heart Failure
- Renal disease
- Liver dysfunction
- Hypoglycemia
 Increased risk of hypoglycemia
 Metformin & lactic acidosis
 half-dose @GFR < 45 &
stop @GFR < 30
 Caution with SUs (glibenclamide)
 DPP-4-i’s – dose adjust for most
 Avoid SGLT-2 inhibitors if GFR < 45
 Avoid GLP-1 R agonists if GFR < 30

Comorbidities
- Coronary Disease
- Heart Failure
- Renal disease
- Liver dysfunction
- Hypoglycemia
 Most drugs not tested in
advanced liver disease
 Pioglitazone may help steatosis
 Insulin best option if disease
severe

Comorbidities
- Coronary Disease
- Heart Failure
- Renal disease
- Liver dysfunction
- Hypoglycemia
 Emerging concerns regarding
association with increased
morbidity / mortality
 Proper drug selection is key
in the hypoglycemia prone
 Avoid SU, insulin (if possible)

Choosing Glucose lowering Drugs in T2DM
Metformin
Is cost is a major issue?
Yes No
SU TZD
insulin

After Metformin, Cost is not a major issue
1. SGLT2-I: CVD, HF, Renal protection
2. GLP1-RA : CVD protection, reduce albuminuria
Consider by hierachy….
1. SGLT2-I ( if GFR >45)
2. GLP1-RA ( if GFR>30)
Established ASCVD
Yes No

SGLT2-I should not be considered in:
1. GFR < 45 m/min/m2
2. High risk for DKA
3. High risk for hypovolemia
4. High risk for urinary tract infection
5. High risk for amputation

SGLT2-I should not be considered in:
1. GFR < 45 m/min/m2
2. High risk for DKA
- type 1 DM, lean T2DM on insulin Rx????,
- on low CHO diet or fasting
3. High risk for hypovolemia
- frail elderly, acute illness
4. High risk for urinary tract infection
- neurogenic bladder, Hx of recurrent UTI
4. High risk for amputation
- history or presence of amputation,
DM foot, symptomatic PVD????

If not candidate for SGLT2-I or GLP1-RA
Established ASCVD
Yes No
Consider: DPP4-I or TZD
: before SU or insulin

No Established ASCVD
Need to minimize
Hypoglycemia
Need to address
Weight loss
eGFR
< 30 ml/min
SGLT2-I*
DPP4-I
TZD
SGLT2-I*
GLP1-RA
DPP4-I
TZD
Glipizide?
Insulin
* Reduce renal progression and HHF

1. Start with metformin if no contraindication
and tolerable
2. Cost concern?
3. Established ASCVD?
4. Need to minimize hypoglycemia?
5. Need to address weight loss?
6. CKD stage 4-5?

in 1148 Type 2 diabetic patients
Effects of tight BP control (BP 144/82 mmHg) vs
less tight BP control (154/87 mmHg)
any diabetes-related endpt. 24% p=0.0046
diabetes-related deaths 32% p=0.019
stroke 44% p=0.013
microvascular disease 37% p=0.0092
heart failure 56% p=0.0043
retinopathy progression 34% p=0.0038
deterioration of vision 47% p=0.0036
UKPDS: Blood Pressure Control Study

Association of Systolic BP and
Cardiovascular Death in Type 2 DM
250
225
200
175
150
125
100
75
50
0
25
< 130 130–139 140–159 160–179 180–199 > 200
Systolic blood pressure (mm Hg)
Cardiovascular
mortality
rate/10,000
person-yr
Nondiabetic
Stamler J et al. Diabetes Care 1993;16:434-444.
Diabetic

RCT Intensive vs Standard BP HT Rx
Clinical Trials Intensive Standard Outcomes
ACCORD-BP SBP<120
(achieved119/64)
SBP 130-140
(achieved133/70)
-No benefit
-Stroke reduce 41%
-More AEs: AKI, high K+
ADVANCE-BP achieved 136/73 achieved 142/75 -reduced primary
composite endpoints
( micro and macro)
HOT DBP<80 DBP<90 -no benefit the whole
group, DM subgroup
reduced 51% CV
events
SPRINT
( no DM )
SBP<120
(achieved121.4)
SBP<140
(achieved136.2)
- Reduced 25%
composite CV events
- Reduced death 27%
- More AEs: AKI, high K+

• For patients with DM and HT, BP should be
individualized: CV risk, potential AE and
patient preference (C)
• DM with HT and 10 y ASCVD risk >15%, goal
of BP may be <130/80 if it can be safely
attained (C)
• DM with HT and 10 y ASCVD risk <15%, treat
to a BP target of < 140/90 (A)
Blood Pressure Goal in T2DM
ADA 2019 Recommedation

• Absolute benefit of BP reduction correlated
with absolute baseline CV risk in SPRINT and
in earlier trials with conducted with higher
baseline BP level
• This approach is consistent with guideline of
ACC/AHA, which advocate a BP target of
<130/80 for all patients with or without DM
Why target of BP < 130/80 in DM with ASCVD risk
>15%, if it can be safely achieved?

Relation Between the Proportional Reduction in
MAJOR VASCULAR EVENTS and Mean
Absolute LDL-C Reduction in 14 Statin Trials
Cholesterol Treatment Trialist Collaborators, Lancet 2005;366:1267

Groups
Events (%)
Treatment Control
0·5 1·0 1·5
Rate Ratio (CI)
Prior disease
Post MI
Other CHD
None
Age (years)
65
>65
Gender
Male
Female
Treated hypertension
Yes
No
History of diabetes
Yes
No
Diastolic blood pressure (mm Hg)
90
>90
Prior disease
3051 (21·2) 3860 (26·9)
1257 (19·3) 1581 (24·2)
None 2046 (8·5) 2553 (10·6)
≤ 3454 (12·5) 4448 (16·2)
2900 (16·6) 3546 (20·3)
Male 5097 (14·9) 6504 (19·0)
Female 1257 (11·7) 1490 (13·8)
Yes 3925 (15·8) 4783 (19·2)
2429 (12·0) 3211 (15·9)
1465 (15·6) 1782 (19·2)
No 4889 (13·7) 6212 (17·4)
90 5191 (14·9) 6493 (18·6)
1154 (11·4) 1496 (14·8)
≤
0·79 (0·75 – 0·83)
0·80 (0·73 – 0·87)
0·78 (0·72 – 0·84)
0·78 (0·74 – 0·82)
0·81 (0·77 – 0·86)
0·78 (0·75 – 0·81)
0·83 (0·76 – 0·91)
0·81 (0·77 – 0·85)
0·77 (0·73 – 0·82)
0·79 (0·72 – 0·86)
0·79 (0·76 – 0·82)
0·79 (0·76 – 0·83)
0·77 (0·80 – 0·84)
p<0.00001
Overall 6354 (14·1) 7994 (17·8) 0·79 (0·77 – 0·81)
RR (95% CI)
RR (99% CI)
Effects on MAJOR VASCULAR EVENTS Per Mmol/L LDL-C
Reduction, Subdivided by Baseline Prognostic Factors

Risk Reduction According to Baseline Risk
Cholesterol Treatment Trialists' (CTT) Collaborators, Lancet 2012

Figure 4
Cholesterol Treatment Trialists’ Collaboration, Lancet 2010;376:1670
Event Reduction Is Independent of Baseline LDL-C
All trials combined
<2 mmol/L 910 (4.1%) 1012 (4.6%)
≥2 to <2.5 mmol/L 1528 (3.6%) 1729 (4.2%)
≥2.5 to <3.0 mmol/L 1866 (3.3%) 2225 (4.0%)
≥3 to <3.5 mmol/L 2007 (3.2%) 2454 (4.0%)
≥3.5 mmol/L 4508 (3.0%) 5736 (3.9%)
Total 10973 (3.2%) 13350 (4.0%)
Events (% per annum) RR (CI) per 1 mmol/L reduction in LDL-C
Statin/more Control/less
0.78 (0.61–0.99)
0.77 (0.67–0.89)
0.77 (0.70 – 0.85) 2
1 =1.08
0.76 (0.70–0.82) (p=0.3)
0.80 (0.76–0.83)
0.78 (0.76–0.80)
Trend
test
99% or
95% CI
Statin/more Control/less

Reduction in Cardiovascular Events Over 5 Years According
to Risk Category and Amount of LDL-C Reduction
LDL-C reduction
(mmol/L)
Cholesterol Treatment Trialists' (CTT) Collaborators, Lancet 2012

Use LDL-C
lowering drugs
to Treat Risk,
Not Cholesterol

High, Moderate and Low Intensity
Statin Therapy
High Intensity Moderate Intensity Low Intensity
LDL reduction
>50%
LDL reduction
30-50%
LDL reduction
<30%
Atorvastatin 40-80 mg
Rosuvastatin 20 mg
Atorvastatin 10-20 mg
Rosuvastatin 5-10 mg
Simvastatin 20-40 mg
Pravastatin 40-80 mg
Fluvastatin XL 80 mg
Pitavastatin 2-4 mg
Simvastatin 10 mg
Pravastatin 20 mg
Fluvastatin 40 mg
Pitavastatin 1 mg
Stone NJ. Ann Int Med 2014;160:339-43

Group 1
ACS or
CAD < 12 Months
Group 3
Ishcemic stroke
or TIA
Group 4
Cardiac embolic
stroke
or intracerebral
hemorrhage
Group 2
CAD > 12 Months
PAD
Atheroslerotic
aortic disease
Secondary ASCVD Prevention

Group 3
LDL >190
mg/dL
- primary
- FH
Group 1
Diabetes
mellitus
- Age > 40 years
- Age < 40yrs + >2 risks
Group 2
CKD
- Age > 50 y+GFR <60
- Renal transplant
Group 4
10 yr Thai CV
risk >10%
Primary ASCVD Prevention

1 ผู้ป่วยเบาหวานอายุตั้งแต่ 40 ปีขึ้นไปให้ ควรเริ่มยา statin
โดยมีเป้าหมายคือระดับ LDL-C < 100 มก/ดล.หรือ LDL-
C ลดลงจากค่าเริ่มแรกก่อนได้รับยาอย่างน้อยร้อยละ 30
ยกเว้นผู้ที่มีระดับ LDL-C ตั้งแต่ 190 มก./ดล. ขึ้นไปให้เริ่ม
statin ที่ทาให้ระดับ LDL-C < 100 มก/ดล.หรือ LDL-C
ลดลงจากค่าเริ่มแรกก่อนได้รับยาอย่างน้อยร้อยละ 50
หาก LDL-C ไม่ลดลงตามเป้าหมายภายในระยะเวลา 6
เดือน หรือมีอาการไม่พึงประสงค์จาก statin จึงพิจารณา
เพิ่มยากลุ่ม non-statin ได้แก่ ezetimibe
Thai RCPT Guideline 2016 for Rx dyslipidemia

2. ผู้ป่วยเบาหวานอายุน้อยกว่า 40 ปีที่มีปัจจัยเสี่ยงอื่น
ตั้งแต่ 2 ข้อขึ้นไป ควรได้รับคาแนะนาการปรับเปลี่ยน
พฤติกรรมชีวิต โดยมีระยะเวลาในการปรับเปลี่ยน
พฤติกรรมชีวิต 3 – 6 เดือน และถ้าหลังการปรับเปลี่ยน
พฤติกรรมชีวิตแล้ว ระดับ LDL-C ยัง >130 มก./ดล.
น่าจะพิจารณาให้ยากลุ่ม statinโดยมีเป้าหมายคือระดับ
LDL-C < 100 มก./ดล.
Thai RCPT Guideline 2016 for Rx dyslipidemia

Thai RCPT Guideline 2016 for Rx Dyslipidemia
3 ผู้ป่วยเบาหวานอายุน้อยกว่า 40 ปีที่ไม่มีปัจจัยเสี่ยง
อื่น อาจไม่จาเป็นต้องเริ่มยาลดระดับ LDL-C แต่ต้อง
เน้นการปรับเปลี่ยนพฤติกรรมชีวิต โดยมีระยะเวลาใน
การปรับเปลี่ยนพฤติกรรม 3 – 6 เดือน และถ้าหลังการ
ปรับเปลี่ยนพฤติกรรมชีวิตแล้ว ระดับ LDL-C > 130
มก./ดล. อาจพิจารณาให้ยากลุ่ม statinโดยมีเป้าหมาย
คือระดับ LDL-C < 100 มก./ดล

Thai RCPT Guideline 2016 for Rx Dyslipidemia
4 ผู้ป่วยเบาหวานที่ได้รับ statin แล้วแต่ระดับ non-
HDL-C ยังเกินเป้าหมาย ( < 130 มก./ดล.ในการ
ป้องกันแบบปฐมภูมิ, < 100 มก./ดล.ในการป้องกันแบบ
ทุติยภูมิ) น่าพิจารณาเพิ่ม intensity ของ statin ก่อน
หาก non-HDL-C ยังไม่ได้ตามเป้าหมาย จึงพิจารณา
เพิ่มยากลุ่ม fibrates

Adverse events of Statins
• Statins: myalgia
myositis, rhabdomyolysis
hepatitis
New onset diabetes

Summary of Statin Safety
Recommendations
• Baseline measurement of ALT should be
performed before initiating statin therapy
• Baseline measurement of CK is reasonable for
individuals believed to be an increased risk for
adverse muscle events eg. concomitant drug
Rx that may increase the risk for myopathy
• Do not routinely monitor ALT or CK unless
patient is symptomatic ( class I, level A )
Stone NJ. Circulation 2013

Summary of Statin Safety
Recommendations
•Decreasing the statin dose may be considered
when 2 consecutive values of LDL–C levels are
< 40 mg/dL
•Individuals receiving statin therapy should be
evaluated for new-onset diabetes mellitus ( 0.1 and
0.3 excess cases of diabetes per 100 statin-treated
individuals )
•Healthy lifestyle habits should be encouraged to
prevent progression to diabetes ( class I, level B )

If muscle symptoms develop during statin Rx
1. Discontinue the statin
2. Evaluating CK ( may consider Cr, myoglobinuria
in severe case )
3. Evaulate other conditions that might increase the
risk for muscle symptoms ( hypothyroid,
rheumatologic diseases, reduce hepatic or renal
function,… )
4. If the symptoms resolve, rechallenge with the
same dose of statin or lower
5. If the symptoms recur, discontinue statin and
rechallenge with progressively lower doses of
the same or a different statin

ACEI (ARB) Therapy in
Type 2 Diabetes
• Diabetic nephropathy
( Microalbuminuria, Clinical proteinuria )
• Coronary artery disease
• Hypertension with
- multiple risk factors
- diabetic nephropathy
- cardiovascular disease

ADA Recommendation 2019
Aspirin for Primary Prevention in DM
• May consider aspirin therapy ( 75-162 mg/day ) as
a primary prevention strategy in patients with
diabetes who increase CV risk after discussion
with the patients on benefit vs increased risk of
bleeding
• Not recommend aspirin for primary prevention in
patients < 50 yrs without other major risk factors.
For patients in these age-groups with multiple
other risk factors, need clinical judgement
Diabetes Care 2019;37(suppl 1):S113

Annual Screening for Complications
and early treatment is important
• Nephropathy : serum creatinine (eGFR) , spot morning
urine albumin or MAU
• Retinopathy : dilated retina exam every 1-2 year
• Neuropathy : comprehensive, monofilament
• Foot ulcer : identify high risk
• Coronary artery disease : symptoms, EKG???
• Cerebrovascular disease : symptoms, carotid bruit

Diabetic Self Management Education
• What is diabetes?
• Complications of diabetes
• Goals of therapy
• Hyperglycemia and Hypoglycemia
• Medical nutritional therapy
• Exercise
• How to use OAD, insulin?
• Sick day care
• Foot care

( Holistic and Individualized Approach )
S • Self-management, stress and other barriers

Holistic approach to T2DM updates

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