DM:Practical Point in Primary Care Setting · Diabetes Mellitus •Correct symptoms of hyperglycemia ... microvascular disease 37% p=0.0092 heart failure 56% p=0.0043 retinopathy

DM:Practical Point in

Primary Care Setting

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

InfectionMalignant

Neoplasms

Diabetes

Thailand Diabetes Registry 2006

Causes of Mortality in PatientsWith 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

Pa

tien

ts %

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-up160 T2DM patients – patterns at 6 years and after

All-cause mortality (%) CV mortality, MI, CVA, CV procedure (%)

8070605040302010

0

8070605040302010

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-upYears of follow-upN 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

Microvascularcomplications

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

Decreasedinsulin

secretion

Increasedglucagonsecretion

Neurotransmitterdysfunction

Decreasedincretin effect

IncreasedHGP

Decreasedglucose uptake

Increasedglucosereabsorption

Increasedlipolysis

Islet-a cell

Adapted from De Fronzo RA. Diabetes 2009;58:773–95.

Hyperglycaemia

Decreasedinsulin

secretion

Increasedglucagonsecretion

Neurotransmitterdysfunction

Decreasedincretin effect

IncreasedHGP

Decreasedglucose uptake

Increasedglucosereabsorption

Increasedlipolysis

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 Intermediate

No Loss Benefit (secondaryprevention)

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 Intermediate

No Neutral Neutral Potentialrisk???? : 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 protection2. GLP1-RA : CVD protection, reduce albuminuria

Consider by hierachy….1. SGLT2-I ( if GFR >45) ( may be < 30 in the future)

2. GLP1-RA ( if GFR>30)

Established ASCVD

Yes No

SGLT2-I should not be considered in:

1. GFR < 45 m/min/m2 ( may be 30 in the future )

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



If not candidate for SGLT2-I or GLP1-RA

Established ASCVD

Yes No

Consider: DPP4-I or TZD : before SU or insulin

Choosing Glucose lowering Drugs in T2DMAfter Metformin, Cost is not a major issue

No Established ASCVD

Need to minimize Hypoglycemia

Need to address Weight loss

eGFR< 30 ml/min

SGLT2-I*GLP1-RA DPP4-I

TZD

SGLT2-I* GLP1-RA

DPP4-ITZD?

Glipizide?Insulin* Reduce renal progression and HHF

1. Start with metformin if no contraindication and tolerable and consider SGLT2-I or GLP1-RA if indicated

2. Cost concern?

3. Established ASCVD?

4. Need to minimize hypoglycemia?

5. Need to address weight loss?

6. CKD stage 4-5?



Metformin

Is cost is a major issue?

Yes No

SU TZD

insulin



1. SGLT2-I: CVD, HF, Renal protection2. 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


1. GFR < 45 m/min/m2

2. High risk for DKA



5. High risk for amputation


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


- frail elderly, acute illness


- 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-ITZD

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 wholegroup, 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 T2DMADA 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?





1 ผู้ป่วยเบาหวานอายุตัง้แต ่ 40 ปีขึน้ไปให้ ควรเริม่ยา statin โดยมเีป้าหมายคอืระดบั LDL-C < 100 มก/ดล.

หรอื LDL-C ลดลงจากคา่เริม่แรกกอ่นไดร้บัยาอยา่งน้อย

ร้อยละ 30 ยกเว้นผู้ทีม่รีะดบั LDL-C ตัง้แต ่ 190

มก./ดล. ขึน้ไปให้เริม่ statin ทีท่ าให้ระดบั LDL-C <

100 มก/ดล.หรอื LDL-C ลดลงจากคา่เริม่แรกกอ่นไดร้บั

ยาอยา่งน้อยร้อยละ 50 หาก LDL-C ไมล่ดลงตาม

เป้าหมายภายในระยะเวลา 6 เดอืน หรอืมอีาการไมพ่งึประสงคจ์าก statin จงึพจิารณาเพิม่ยากลุม่ non-statin

ไดแ้ก ่ ezetimibe

Thai RCPT Guideline 2016 for Rx dyslipidemia

2. ผู้ป่วยเบาหวานอายุน้อยกวา่ 40 ปีทีม่ปีจัจยัเส่ียงอืน่

ตัง้แต ่ 2 ข้อขึน้ไป ควรไดร้บัค าแนะน าการปรบัเปลีย่น

พฤตกิรรมชวีติ โดยมรีะยะเวลาในการปรบัเปลีย่น

พฤตกิรรมชวีติ 3 – 6 เดอืน และถ้าหลงัการ

ปรบัเปลีย่นพฤตกิรรมชวีติแลว้ ระดบั LDL-C ยงั

>130 มก./ดล. น่าจะพจิารณาให้ยากลุม่ statinโดยมี

เป้าหมายคอืระดบั LDL-C < 100 มก./ดล.

Thai RCPT Guideline 2016 for Rx dyslipidemia

Thai RCPT Guideline 2016 for Rx Dyslipidemia

3 ผู้ป่วยเบาหวานอายุน้อยกวา่ 40 ปีทีไ่มม่ปีจัจยัเส่ียง

อืน่ อาจไมจ่ าเป็นต้องเริม่ยาลดระดบั LDL-C แตต้่อง

เน้นการปรบัเปลีย่นพฤตกิรรมชวีติ โดยมรีะยะเวลาใน

การปรบัเปลีย่นพฤตกิรรม 3 – 6 เดอืน และถ้าหลงั

การปรบัเปลีย่นพฤตกิรรมชวีติแลว้ ระดบั LDL-C >

130 มก./ดล. อาจพจิารณาให้ยากลุม่ statinโดยมี

เป้าหมายคอืระดบั LDL-C < 100 มก./ดล

Thai RCPT Guideline 2016 for Rx Dyslipidemia

4 ผู้ป่วยเบาหวานทีไ่ดร้บั statin แลว้แตร่ะดบั non-

HDL-C ยงัเกนิเป้าหมาย ( < 130 มก./ดล.ในการ

ป้องกนัแบบปฐมภมู,ิ < 100 มก./ดล.ในการป้องกนัแบบ

ทุตยิภูม)ิ น่าพจิารณาเพิม่ intensity ของ statin กอ่น

หาก non-HDL-C ยงัไมไ่ดต้ามเป้าหมาย จงึ

พจิารณาเพิม่ยากลุม่ fibrates







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

ABCDES of Diabetes Care2019( Holistic and Individualized Approach )










Thank you for your attention

Documents

DM:Practical Point in Primary Care Setting · Diabetes Mellitus •Correct symptoms of hyperglycemia ... microvascular disease 37% p=0.0092 heart failure 56% p=0.0043 retinopathy