PATIENT-CENTERED D

M CONTROL
Dr. Frances Yu
OUTLNE
1. HbA1c: What level is normal? Risk in IGT & elevated GV
2. HbA1c target in DM
3. First line treatment: Lifestyle modification
A. Diet: Carb counting, Mediterranean diet
B. Exercise:
4. Medical treatment:
A. ADA Guideline
B. Treatment by individual age, BMI & comorbidities
5. SGLT2 Comparisons: CV & renal outcomes, side effects
6. Prescribing SGLT2
A. Indications: ADA, RAMP & HA Guideline
B. Precautions on initiation
C. Monitoring: potential side effects & complications
D. Patient education: sick day rule, side effects, DKA, Fournier’s gangrene
HBA1C
What level is normal?
HBA1C CONVERSION

HbA1c 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9
Glucose 3.8 3.9 4.1 4.2 4.4 4.6 4.7 4.9 5.0 5.2
HbA1c 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9
Glucose 5.4 5.5 5.7 5.8 6.0 6.2 6.3 6.5 6.6 6.8
HbA1c 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 6.9
Glucose 6.9 7.1 7.3 7.4 7.6 7.7 7.9 8.1 8.2 8.4
HbA1c 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9
Glucose 8.5 8.7 8.9 9.0 9.2 9.3 9.5 9.7 9.8 10.0
HbA1c 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 8.9
Glucose 10.1 10.3 10.4 10.6 10.8 10.9 11.1 11.2 11.4 11.6
HbA1c 9.0 9.1 9.2 9.3 9.4 9.5 9.6 9.7 9.8 9.9
Glucose 11.7 11.9 12.0 12.2 12.4 12.5 12.7 12.8 13.0 13.2
HbA1c 10.0 10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 10.9
Glucose 13.3 13.5 13.6 13.8 13.9 14.1 14.3 14.4 14.6 14.7
HbA1c 11.0 11.1 11.2 11.3 11.4 11.5 11.6 11.7 11.8 11.9
Glucose 14.9 15.1 15.2 15.4 15.5 15.7 15.9 16.0 16.2 16.3
HbA1c 12.0 12.1 12.2 12.3 12.4 12.5 12.6 12.7 12.8 12.9
Glucose 16.5 16.6 16.8 17.0 17.1 17.3 17.4 17.6 17.8 17.9
HbA1c 13.0 13.1 13.2 13.3 13.4 13.5 13.6 13.7 13.8 13.9
Glucose 18.1 18.2 18.4 18.6 18.7 18.9 19.0 19.2 19.4 19.5
HBA1C & MEAN GLUCOSE VALUES

Table 1
Correlation between A1C and estimated mean glucose values
A1C, glycated hemoglobin.
A1C 5.5–6.5 6.5–6.9 7.0–7.4 7.5–7.9 8.0–8.5
values (%)
Estimated 6.2–7.7 7.8–8.5 8.6–9.3 9.4–10.1 10.2–10.9
mean
glucose
(mmol/L)

 continuous glucose monitoring (CGM) demonstrated that a 2-hour P

PG <8.0 mmol/L correlates best with an A1C <7.0% 
 strong correlation between HbA1c and MPG (r ≈ 0.81–0.95), with ea
ch 1% change in HbA1c corresponding to a change in MPG of ∼35
mg/dl (1.9mmol/L). 

Diabetes Canada Clinical Practice Guidelines 2018

FG / PPG IN NORMAL HK POPULATION

Gary TC Ko, Hendena PS Wai, Joyce SF Tang et al.

Effects of Age on Plasma Glucose Levels in Non-diabetic Hong Kong Chinese. Croat Med J. 2006 Oct; 47(5): 709–
HBA1C & CV RISK
HBA1C AND IGT
 GLUCOSE VARIABILITY & CV RISK
 In individuals with diabetes and in those with impaired glucose tolera
nce (IGT), blood glucose two hours after oral glucose loading has a hi
gher predictive value for CV events than fasting plasma glucose (FP
G)
 Several studies reported that long-term GV was related to micro- and
macro-angiopathies in patients with type 2 diabetes mellitus (T2DM).
 However, there are still unknown aspects regarding the relationships
of various durations of GV with prognosis.
 Minimizing GV could improve insulin resistance and reduced IMT (c
arotid intima-media thickness), consistent with a lowering in risk of C
VD

Shuang Liang, Hang Yin, Chunxiang Wei, Linjun Xie et al. Glucose variability for cardiovascular risk factors in type 2 diabetes: a meta-
analysis. J Diabetes Metab Disord. 2017; 16: 45.
Masaya Sakamoto et al. Type 2 Diabetes and Glycemic Variability: Various Parameters in Clinical Practice. J Clin Med Res. 2018 Oct;
10(10): 737–742.
OGTT RESULT & RISK OF DM

 Previous studies have suggested that the 1-hour glucose level above 155
mg/dL (8.5mmol/L) is a better predictor of progression to diabetes tha
n the 2-hour level.
 Individuals at high risk for developing diabetes could be identified earli
er by measuring the 1-hour postload glucose level.
 Patients with a 2-hour glucose level less than 140 mg/dL (7.7mmol/L) b
ut an elevated 1-hour glucose had a 28% increased mortality risk vs. pati
ents with non-elevated 1- and 2-hour glucose levels
 It was previously found that beta-cell function appears to be better pres
erved in those with a 1-hour level below 155 mg/dL, and declines when
the 1-hour value exceeds this value and deteriorates incrementally with I
GT and [type 2 diabetes].

One-hour post-load plasma glucose level during the OGTT predicts mortality: observations from the
Israel Study of Glucose Intolerance, Obesity and Hypertension.  Diabet Med. 2016 Mar 21.
HBA1C TARGET
< 7.0
 Diabetes Canada Clinical Practice Guidelines 2018
HBA1C TARGET
FRUCTOSAMINE

 for patient with high RBC turnover eg HbH disease

 HbA1c underestimate the glycemic level
1 ST
LINE: LIFESTYLE
Individualized treatment
 EFFICACY OF LIFESTYLE CONTROL

Xiao-Li Huang, Jian-Hua Pan, Dan Chen et al.

Efficacy of lifestyle interventions in patients with type 2 diabetes: A systematic review and meta-analysis European Journal of Internal
ADA 2018: PATIENT-CENTERED
PATIENT EMPOWERMENT PROGRAM
CARBS REQUIREMENT /MEAL
 Moderate carbohydrate diet advised

The National Diabetes Services Scheme (NDSS) is an initiative of the Australian

Government that commenced in 1987 and is administered with the assistance of
Diabetes Australia.
https://static.diabetesaustralia.com.au/s/fileassets/diabetes-australia/22271a4e-3b97-4
511-9ef0-e2e187519a88.pdf
1 SERVING CARB = 10G,
1BOWL RICE = 50G

50 g

40 g

30 g

20 g

10 g
CARB COUNTING: 10G
INDIVIDUALIZED & COLLABORATION
APPS FOR DM
APPS
FRUIT
LOW GLYCEMIC INDEX <= 55
EFFECT OF LC, MC, HC DIET ON NO
RMAL AND IGT

Low-carbohydrate (CHO) diet :“CHO≤45%,” medium-CHO diet :

45%<CHO≤65%,” and high-CHO diet : “CHO>65%.”
EFFECT ON BLOOD SUGAR OF 1G GL
UCOSE
HIGH PROTEIN DIET?

S H Holt J C Miller P Petocz. An insulin index of f

oods: the insulin demand generated by 1000-kJ p
ortions of common foods. The American Journal of
Clinical Nutrition, Volume 66, Issue 5, 1 November
1997, Pages 1264-1276,  
https://doi.org/10.1093/ajcn/66.5.1264
BEST DIET FOR DM CONTROL

UK DM Guideline
MEDITERRANEAN DIET
PLANT-BASED DIET
 Plant-based diets can significantly improve psychological hea
lth, quality of life, HbA1c levels and weight and therefore the
management of diabetes.
 Average (HbA1c) and fasting blood glucose levels fell more s
harply in those who cut out or ate very few animal products
 The low-GI legume diet (1cup/d) reduced HbA1c values by -
0.5% (95% CI, -0.6% to -0.4%) and the high wheat fiber diet
reduced HbA1c values by -0.3% (95% CI, -0.4% to -0.2%).
 The relative reduction in HbA1c values after the low-GI legu
me diet was greater than after the high wheat fiber diet by -0.
2% (95% CI, -0.3% to -0.1%; P < .001). 

Toumpanakis A, Turnbull T, Alba-Barba I. Effectiveness of plant-based diets in

promoting well-being in the management of type 2 diabetes: a systematic
review. BMJ Open Diabetes Research and Care 2018;6:e000534. 
https://drc.bmj.com/content/6/1/e000534
PROTEIN
EXERCISE
EXERCISE EFFECT ON BG
Mean change in blood glucose levels (mg/dL) by exercise intensity and duration.

1.9 mmol/l

 The largest decrease in blood glucose followed ≥30 min of exercise u

ndertaken 1 h (−49.3 ± 53.1 mg/dL) = ~ 2.7mmol/l or 2 h (−46.4 ± 4
9.8 mg/dL) after eating (P < 0.001)

Sheri R. Colberg et al. Dia Care 2013;36:e177

http://care.diabetesjournals.org/content/36/10/e177
EXERCISE & HBA1C REDUCTION

Effect of regular exercise training on changes in HbA1c, BMI and VO 2

max among patients with type 2 diabetes mellitus: an 8-year trial
Farzad Najafipour, Majid Mobasseri, Abbas Yavari, Haidar Nadrian, Akbar Aliasgarzadeh, Naimeh Mashinchi
Abbasi, Mitra Niafar, Jalil Houshyar Gharamaleki, Vahideh Sadra
BMJ Open Diabetes Res Care. 2017; 5(1): e000414. Published online 2017 Nov 8.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687538/
 EXERCISE IS MEDICINE

Kristin I. Stanford and Laurie J. Goodyear. Exercise and type 2 diabetes: molecular mechanisms regulating
glucose uptake in skeletal muscle. Adv Physiol Educ. 2014 Dec; 38(4): 308–314.
doi: 10.1152/advan.00080.2014
MEDICAL RX
Individualized strategies
 INDIVIDUALIZED DRUG TREATMEN
T
Metformin
Young w/o Young w/ complications Elderly >=65
complications

Overweight or obese Normal weight

PIO DPP4I SGLT2-i

SU
Pros Pros Pros
Pros
• No hypo • No hypo • More potent
• Low cost
• Durability of control • Wt neutral • No hypo
Cons
• Fatty liver • Minimal SE • Reduce BP & Wt
• Hypo
improvement Cons
• Poor durablity Cons
Cons • Cost • Cost
• Wt gain
• Fluid retention/wt • Lower potency • Gential infection
CI:
gain CI: • DKA risk
• Controversial
• Peripheral fracture • Pancreatitis CI:
about CV risk
CI: CHF, risk of #, ca • Januvia: • Fracture
bladder, liver Dx hypersensitivity • T1DM, LADA
 INDIVIDUALIZED DRUG TREATMEN
T
Metformin

Young w/o Young w/ complications Elderly >=65

complications
Hx of ischaemic stroke CAD/heart failure DKD

PIO SGLT2i SGLT2i DPP4i PIO

IRIS Study (EMPA preferred) eGFR >=45 eGFR< 45 All eGFR ranges
PROACTIVE Secondary EMPA-REG EMPA-REG Dose Beware w/ fluid
Outcome & post-hoc CANVAS CANVAS reduction retention
analysis DECLARE DERIVE except LINA
-ongoing DELIGHT

Avoid SU if possibile
INDIVIDUALIZED DRUG TREATMEN
T
Metformin
Young w/o Young w/ complications Elderly >=65
complications

Young old (age >=65- Old old (age >= 75) or

75) w/ gd QOL & w/o any elderly
serious complications w/ signifcant
complications

DPP4i
Rx as young cohort
No hypog
CV safety (except saxagliptin
inc. HHH)
Virtual absence of serious AEs
Dose reduction except LINA

Avoid SU if possibile
PERSONALIZED SELECTION 2ND LIN
E RX
PIO SU DPP4I SGLT2-I
HT Neutral Neutral Neutral Slight 
advantage
Obesity Preferred  Avoid x Neutral Preferred 
CAD Preferred  Avoid x Neutral Preferred 
CVA Highly  Avoid x Neutral Neutral
Preferred
Heart failure Avoid x Neutral Neutral Highly 
(avoid Sax) x preferred

Mild to
moderate
Neutral Avoid x Neutral
(dose
Preferred 
renal reduction
impairment except LINA)
 SGLT2
Updates, considerations, initiation & patient education
MECHANISM
 DAPAGLIFLOZIN (Forxiga) CANAGLIFLOZIN (Invokana) EMPAGLIFLOZIN (Jardiance)

TRIAL DECLARE-TIMI58 CANVAS EMPA-REG

NUMBER 17,276 4,411 7,020
Mean FU (yr) 4.2 3.6 3.1
INCLUSION High CV risk or CVD (40.6%) >=2 risk factors orCVD Known CVD (100%)
A1c 6.5-12% (65.6%) A1c 7-10%
CrCl >= 60 (eGFR<60 in A1c 7-10.5% eGFR > 30 (<60 in 25.9%)
7.4%) eGFR > 30 (<60 in 20.1%)

Primary outcome - 3-point MACE: CV death, non-fatal MI, non-fatal CVA

Sig. in
MACE(RR) 7% (p = 0.17) post-MI  14% 14%
HHF 27% 33% 35%
HHF/CV Death 17% (predominant HHF)HFrEF 22% 34%
Composite 40% in eGFR to <60, ESRD (dialysis 90days, or sustained Doubling of serum Cr with
Renal outcome eGFR<15) or renal/CV death eGFR45, RRT, or renal death

RR 27% 40% 46%

Progress to N/A 27% 38%
macroalb
Serious side Lower limb amputation
effects Bone fracture
DKA, Fournier’s gangrene
Cost $5.1/ tab N/A $ 5.3 / tab
 BENEFIT: FIRST 3YR P
OST-MI
 The benefit in MACE reduction in patient
s with prior MI was greater in those who
were closer in time to their most recent MI
at enrollment in the study.
 Those who started on dapagliflozin within
12 months of their last MI had a 34% relat
ive risk reduction in MACE and those wh
o enrolled 12-24 months after their last MI
enjoyed an even more robust 58% relative
risk reduction on dapagliflozin.
 In contrast, patients who enrolled 24-36 m
onths post MI had only a 17% relative risk
reduction, and those who enrolled more th
an 36 months after their last MI had a subs
equent MACE rate no different from contr
ols.
DAPAGLIFLOZIN:
BENEFIT ON HHF/CVD DEATH

Patients with HFrEF Patients without HFrEF

HHF or CV death 38% relative risk reduction 12% relative risk reduction

HHF alone 36% relative risk reduction 24% relative risk reduction

CV death alone 45% relative risk reduction No benefit observed

All cause mortality 41% relative risk reduction No benefit observed

Only 30% of the more than 17,000 patients enrolled in DECLARE-TIMI 58 had documented ejection fraction at the
beginning of the study. Of those roughly 5,000 trial participants, 13% had heart failure with reduced ejection fraction.
DAPAGLIFLOZIN:
BENEFIT ON HHF/CVD DEATH

Patients with HFrEF Patients without HFrEF

HHF or CV death 38% relative risk reduction 12% relative risk reduction

HHF alone 36% relative risk reduction 24% relative risk reduction

CV death alone 45% relative risk reduction No benefit observed

All cause mortality 41% relative risk reduction No benefit observed

Only 30% of the more than 17,000 patients enrolled in DECLARE-TIMI 58 had documented ejection fraction at the
beginning of the study. Of those roughly 5,000 trial participants, 13% had heart failure with reduced ejection fraction.
RENAL OUTCOME OF SGLT2-I
 A d j u s t e d m e a n (S E ) e G F R (m l/ m in / 1 . 7 3 m 2 )
EGFR (CKD-EPI) OVER 192 WEEKS

78 Placebo Empagliflozin 10 mg

76

74

72

70

68
2 5 6 8 9
Baseline 4 12 108 122 136 150 164 178 192
66 8 2 6 0 4
No. analyzed
Week
Placebo 2323 2295 2267 2205 2121 2064 1927 1981 1763 1479 1262 1123 977 731 448
Empagliflozin 10 mg 2322 2290 2264 2235 2162 2114 2012 2064 1839 1540 1314 1180 1024 785 513
Empagliflozin 25 mg 2322 2288 2269 2216 2156 2111 2006 2067 1871 1563 1340 1207 1063 838 524

No. in follow-up for

adverse/outcome events
Total 7020 7020 6996 6931 6864 6765 6696 6651 6068 5114 4443 3961 3488 2707 1703

Pre-specified mixed model repeated measures analysis in all patients treated with ≥1 dose of study drug who had a baseline and post-baseline measurement.
eGFR, estimated glomerular filtration rate; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration.
DIABETES CAUSES GLOMERULAR
HYPERTENSION
Na+/glucose co-transport
Afferent arteriole
SGLT2
SGLT2 GFR
SGLT2

PT Glucose
Efferent
PT: Proximal tubule
arteriole
GL: Glomerulus
MD: Macula densa

Adapted from Cherney D et al. Cir

Loop of Henle culation 2014;129:587

Renal hemodynamics under hyperglycemia

EMPAGLIFLOZIN LOWERS INTRA-
GLOMERULAR PRESSURE
Empagliflozin
blocks SGLT2
Afferent arteriole
SGLT2
SGLT2 GFR
SGLT2

PT Glucose
Efferent
PT: Proximal tubule
arteriole
GL: Glomerulus
MD: Macula densa

Adapted from Cherney D et al. Cir

Loop of Henle culation 2014;129:587

Renal hemodynamics with empagliflozin

 SGLT2-I: USE IN CKD

Dapagliflozin Canagliflozin Empagliflozin

eGFR ≥45-60 No dosage Maximum dose: 100 No dosage
adjustment mg once daily adjustment 

eGFR 30 to <45 mL not recommend use not recommend not recommend

initiation of therapy initiation of therapy
or continued use if or continued use if
persistent <45 persistent <45 
eGFR <30 contraindicated contraindicated contraindicated

• SGLT2 inhibitors promote the excretion of a large amount of glucose into urine, which
may lead to a lack of energy stores in elderly patients who are under dietary restrictions.
• Nutritional evaluation of elderly patients is recommended before treatment with SGLT2
inhibitors.
RENAL PRECAUTION IN USE OF SGL
T2

Apply to all
three SGLT2

 45
GOPC RAMP (DM) MANUAL – APR2019
ADA UPDATES ABOUT DKD MX

 Urinary albumin (e.g., spot urinary albumin-to-creatinine ratio) and est

imated glomerular filtration rate (eGFR) should be assessed at least an
nually in all patients w/ T2DM.
 For patients with type 2 diabetes and diabetic kidney disease, clinician
s should consider using an SGLT2 inhibitor when the eGFR is at or ab
ove 30, especially with albuminuria above 300 mg/g, to lower renal an
d CV risk.
 For patients with CKD at elevated risk for CV events, a glucagon-like
peptide 1 receptor agonist may lower risk for albuminuria progression
and/or CV events.
 SGLT2 CLASS: OVERALL BENEFIT
 Consistent effects on reducing the risk of heart failure and adverse re
nal outcomes which do not appear to be dependent on baseline ather
osclerotic risk or prior heart failure.
 The benefit of SGLT2 inhibitors on 3-point MACE in patients with esta
blished atherosclerotic cardiovascular disease is more moderate tha
n the impact on heart failure
 SGLT2 seem to exert its CV benefits by improving cardiac homodynam
ics (simultaneous reduction in preload and afterload) and reduction in
heart failure
 None have shown a significant reduction in developing acute ischaemi
c events – myocardial infarction or stroke
ROBERT EJ RYDER,1 RALPH A DEFRONZO. Diabetes medications with cardiovascular protection after HARMONY
Outcomes and DECLARE-TIMI 58: could metformin, pioglitazone, SGLT2 inhibitors and long-acting GLP-1 receptor
agonists complement each other to save lives by different mechanisms? Br J Diabetes 2019;19:1-5
https://doi.org/10.15277/bjd.2019.207
PRESCRIBING SGLT2
Indications, Precuations, Side effects & Pt education
SGLT2 HA INDICATIONS:
(HA FORMULARY 13 APR 2019)

1.Type II DM, with established CVD with reasonable QOL, as ad

d on to 2 oral anti-diabetic drugs; discontinue if not achieve HbA
1c < 8% in 6-8 months
[Specialists: Card / FM / Geri / Renal / Endo]
2. Alternative to insulin after failure of optimal doses of SU and
metformin, or optimal doses of SU if metformin is intolerable /co
ntraindicated, discontinue if fail to achieve HbA1c<8% within 6-
8 months
[Specialists: Card / FM / Geri / Renal / Endo]
3. Type II DM, adjunctive to insulin to optimise control, disconti
nue if fail to achieve HbA1c<8% in 6-8 months
[Specialists: Card / Geri / Renal / Endo]
SGLT2-I INITIATION: RISK FACTORS TO CONSI
DER
MONITORING FOR POTENTIAL SE /
RISK
MONITORING FOR POTENTIAL COM
PLICATIONS
DKA PREVENTION
SGLT2 – I PATIENT EDUCATION : SE
 SGLT2-I : PREVENTING DKA

若您有下列情形，應於開始服用 SGLT2 抑制劑前告知您 的醫療人員：

 a. 將接受手術。
 b. 因疾病、手術、節食或任何其它因素減少進食。
 c. 併有或曾有胰臟的問題，包括胰臟炎或是進行胰臟 手術。
 d. 時常或是短時間內大量飲酒。
密切注意任何酮酸中毒相關症狀 :
 如噁心、嘔吐、腹痛、 不尋常的疲倦及呼吸困難。
 若出現上述症狀，應停藥並 立即就醫。
 如果可行的話，可先使用酮體試紙檢查尿液 中酮體含量。

https://www.drugoffice.gov.hk/eps/news/showNews/Taiwan%3A+Risk+communication+on+drug+safety+information+f
or+SGLT2+inhibitors/consumer/2015-06-29/tc/24906.html
 SGLT2-I: RISK OF FOURNIER’S GAN
GRENE
 陰部壞死性筋膜炎 (necrotizing fasciitis of the perineum)
，亦稱為弗尼爾氏壞疽 (Fournier’s gangrene):
 若於服用 SGLT2 抑制劑類藥品後，您的生殖器或生殖
器到直腸區域出現任何壓痛、發紅、腫脹，伴隨發燒超
過 38℃ 或感覺不適，請立即尋求醫療協助，因為這些
症狀可能迅速惡化。
 SGLT2 抑制劑類藥品亦可能會造成局部的生殖器黴菌
感染，亦稱為酵母菌感染。酵母菌感染不同於弗尼爾氏
壞疽，因其只會導致有限的局部性症狀，如陰道或陰莖
分泌物增多、搔癢或發紅，並不會伴隨發燒或全身不適
的感覺。

https://www.fda.gov.tw/TC/siteList.aspx?sid=1571&key=SGLT2
Q&A
Thanks!