SGLTI2 Inhibitors in Managing DM by Dr Shahjada Selim

1. SGLT-2 inhibitors in the
Management of DM
Dr Shahjada Selim
Associate Professor
Department of Endocrinology
Bangabandhu Sheikh Mujib Medical University, Dhaka
Email: selimshahjada@gmail.com, info@shahjadaselim.com

2. peripheral
glucose
uptake
hepatic
glucose
production
pancreatic
insulin
secretion
pancreatic
glucagon
secretion
gut
carbohydrate
delivery &
absorption
incretin
effect
HYPERGLYCEMIA
?
Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011
Multiple, Complex Pathophysiological Abnormalities in T2DM
(Ominous octet)
_
_
+
renal
glucose
excretion
DA
agonists
T Z D sMetformin
S U sGlinides
DPP-4
inhibitors
GLP-1R
agonists
A G I s
Amylin
mimetics
Insulin
Bile acid
sequestrants
SGLT2
inhibitor
Development a new molecule
• Effective BG lowering action
• Low risk of Hypo
• No weight Gain
• Complimentary or synergistic mechanism of action
• Durability
• Well tolerated
• Long term safety
• Add value B-cell preserve, CV benefits

3. Glucose handling by Kidney in Diabetes Mellitus
Glucose release
Glucose reabsorption
Fasting state release increased
Liver → mainly by increased gluconeogenesis 30%
Kidney→ Gluconeogenesis increased by 300%
Post meal state
Glucose release is more
40% increased release due to renal release by
gluconeogenesis
Renal glucose uptake
increased in both fasting and post meal state
3 folds higher in DM in fasting state
Maximum glucose reabsorption capacity
increased
Renal thresh hold 240mg/dl (13mmol/L )
Maximum capacity increased from
350mg/min to 420mg/min

4. SGLT2i (Empagliflozin) Lowers Renal Threshold
for Glucose Excretion
Adapted with permission from Abdul-Ghani MA, DeFronzo RA.
RTG = renal threshold for glucose excretion.
1. Cowart SL, Stachura ME. In: Walker HK et al, eds. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Boston, MA:
Butterworths; 1990:653-657. 2. Abdul-Ghani MA, DeFronzo RA. Endocr Pract. 2008;14(6):782-790. 3. Nair S, Wilding JP. J Clin Endocrinol Metab.
2010;95(1):34-42. 4. INVOKANA® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2013. 5. Rave K et al. Nephrol Dial Transplant.
2006;21(8):2166-2171. 6. Oku A et al. Diabetes. 1999;48(9):1794-1800.
Type 2 diabetes
(240 mg/dL)
RTG
30025020015010050
25
50
75
100
125
UrinaryGlucose
Excretion(g/d)
Plasma Glucose (mg/dL)
EMPA-gliflozin
Type 2 diabetes
+ Empagliflozin
(70-90 mg/dL)
RTG
Non-diabetic
(180 mg/dL)
RTG

5. Renal Glucose reabsorption

6. Sodium-Glucose Cotransporters

7. Glucose Metabolism in Diabetes
SGLT2
~90%
Glucose
SGLT1
~10%
Urinary
glucose
excretion
Adapted from Bays H. Curr Med Res Opin. 2009;25(3):671-681.
Tm 420mg/min with blood threshold 13mmol/L

8. Empagliflozin - SGLT2 Inhibition Reduces Renal Glucose
Reabsorption and Increases Urinary Glucose Excretion
Decreased glucose reabsorption into
systemic circulation
Glucose SGLT1SGLT2 SGLT2 inhibitor
Glomerulus Proximal Convoluted Tubule
Early Distal
Glucose in urine

9. Metabolic Adaptations following SGLT2-i Therapy
Improved Glycaemia, Insulin sensitivity, β-cell function
Peripheral Tissues Liver
Hyperglycaemia
SGLT2 inhibition
Lowered
Plasma Glucose Renal glucose
excretion
Kidney
Pancreas
Kalra S, Ved J, Baruah M. IJEM. 2017;21(3):482-3.
Del Prato S. Diabet Medicine. 2009;26:1185–1192.
Ferrannini E, et al. J Clin Invest. 2014;124:499–508
Metabolic Switch
Weight Loss Enhanced Insulin
Sensitivity
Improved
Hyperinsulinemia
Weight Loss

10. Empagliflozin - Metformin in Treatment Naïve Patients
Change in HbA1C from Baseline
 Hadjadj S et al. Diabetes Care. 2016 Oct;39(10):1718-28.

11. Empagliflozin vs. Glimepiride as Add-on to Metformin
89% Lower Risk of Hypoglycemic Events
Hypoglycemia requiring assistance:
• 5 (0.6%) patients on glimepiride.
• No patients on empagliflozin.
Cochran-Mantel-Haenszel test; treated set (patients who received ≥1 dose of study drug).
*Plasma glucose ≤70 mg/dL and/or requiring assistance. RR, risk ratio.
Adjusted RR 0.112
(95% CI 0.074, 0.169)
p<0.0001
Salsali A et al. American Diabetes Association 76th Scientific Sessions; 10-14 June 2016, New Orleans, Louisiana, USA

12. Renal threshold for glucose
• Plasma level at which the glucose first appears in
the urine in more than the normal minute
amounts.
• Actual renal threshold is about 200 mg/dl of
arterial plasma, which corresponds to a venous
level of about 180 mg/dl.

13. Renal SGLT2 levels are increased in T2DM

14. New Dimension: Targeting
Kidney in glucose control

15. SGLT2
inhibition
Glycosuria
1. Glucose lowering (FPG &
PPG)
2. Insulin independent
HbA1c reduction
3. Loss of calories with
weight loss
4. Reduction of BP
Kidney Int. 2011; 79 (Suppl. 120): S1–S6.
SGLT2 inhibition with potential benefits

16. SGLT-2 inhibitors

17. Points Canagliflozin Dapagliflozin Empagliflozin
FDA
approval
March 29, 2013 January 8, 2014 August 1, 2014
Dose range 100-300 mg/day 5 mg-10
mg/day
10-25 mg/day
Half-life (h) 12-15 17 10-19
Administrati
on
Before the first
meal of the day
At any time of
the day with or
without food
In the morning
with or without
food
SGLT2 inhibitors

18. SGLT2-i agents: Characteristics
Empagliflozin Dapagliflozin Canagliflozin
SGLT2 : SGLT1
selectivity@ >2,5001 >1,2001 >2501
Non-specific*
Tissue Distribution
Lowest2 Intermediate2 Highest2
Impaired Glycolysis
in Proximal tubular
epithelium
Not observed3 Not observed3 Observed
in In-vitro study3
Risk of
Hyperkalemia
No imbalance$4 No imbalance$5
Higher in patients
with moderate
renal impairment$6
Risk of Bone
fractures
No imbalance4,7 No imbalance5,8 Increased risk6,9
Risk of lower limb
amputations
No imbalance4,7,11 No imbalance5,8
≈2-fold increase in risk
with canagliflozin
(both doses)10
CV death /
All-cause death
benefit in RCT
Demonstrated12 Not Demonstrated13 Not Demonstrated14
This is Not a
Head-to-Head Comparison

19. FPG (mg/dL) reduction in pivotal trials - 24 week
2014;16:147–158 P: < 0.05
BL, baseline; MET, Metformin; PIO, pioglitazone; QD, once daily; RI, renal impairment; SE, standard error; SU, sulphonylurea. * All data are
Placebo-corrected and statistically significant unless otherwise marked. 1. Hach T, et al. Diabetes.
2013;62(suppl 1A);A21 (P69-LB); 2. Roden M, et al. Lancet Diabetes Endocrinol. 2013;1(3):208–219; 3. Häring H-U, et al. Diabetes Care.
2014 (in press); 4. Kovacs C, et al. Diabetes Obes Metab. 2014;16(2):147–158; 5. Häring H-U, et al. D1ia8betes
Care. 2013;36(11):3396–404; 6. Rosenstock J, et al. Diabetologia. 2013;56(suppl 1);S372 (P931); 7. Barnett A, et al, Lancet Diabetes
Endocrinol. 2014; doi:10.1016/S2213-8587(13)70208-0.
Add-on to
Basal
insulin
Add-on to
PIO
Add-on to
MET+SU
Add-on to
MET
Monotherapy
224 224 217 213 165 168 225 216 169 155
N value
Baseline FPG
152.79 152.61 154.59 149.37 151.92 151.74 150.84 156.42 138 146
0
Adjusted mean
(SE) difference
vs Placebo in
change from
baseline in FPG
(mg/dL)
-10
-20
-30
-29.50-28.65 -28.44* -23.4 -28.44-31.20-40 *
-36.20
*
**
Empagliflozin 10
mg QD
* **
Empagliflozin 25 mg QD
-23.40
-26.49 -28.20
Glycemic Efficacy-Fasting Plasma Glucose

20. EMPA-REG METTM in Type 2 Diabetes
Change in 2-h PPG* at Week 24
Empagliflozin
Comparison with PlaceboPlacebo
(n = 57)
6.0
10 mg QD
(n = 52)
25 mg QD
(n = 58)
20
10
0
-10
-20
-30
-40
-50
-60
-44.5
-46.0
Placebo EMPA 10 mg EMPA 25 mg
264.5 254.6 252.1
(mg/dL)
CI, confidence interval; EMPA, Empagliflozin; PPG, post-prandial glucose; QD, once daily; SE, standard error.
*2-h PPG was evaluated in a subset of 167 randomised patients who had a valid MTT (MTT set).
ANCOVA, MTT (LOCF).
Häring HU, et al. Diabetes Care. 2014;37:1650–1659.
EMPA-REGMET:study1245.23
Adjustedmean(SE)changefrom
baselinein2-hPPG(mg/dL)
Mean baseline 2-h PPG
-
-51.9
(95% CI:
-69.2, -34.6)
P<0.0001
-50.5
(95% CI:
-67.4, -33.5)
P<0.0001
Glycemic Efficacy-Post prandial Plasma Glucose

21. Glycemic Efficacy-HbA1c Reduction (>10%)

22. Empagliflozin vs. Glimepiride as Add-on to Metformin
Systolic BP Reduction Maintained Over 4 years
MMRM analysis in the FAS using observed cases (excluding values observed after initiation of rescue therapy and/or after
changes in antihypertensive therapy and off-treatment values). *Number with data at visit; number of patients at 4 and 8
weeks, n=737 and n=705, respectively; †Number with data at visit; number of patients at 4 and 8 weeks, n=732 and n=696,
respectively. SBP, systolic blood pressure.
490
537
394
475
327
427
224
336
191
314
165
289
146
266
739
735
554
579
438
510
358
446
238
361
207
331
177
302
161
284
612
618
4 15665 78 104 130 18291 117 143 169 19512 4028 528 16
650
649
677
669
Glimepiride*
Empagliflozin†
Difference: -6.2 mmHg
(95% CI -8.5 to -4.0)
p<0.0001
Week
Adjustedmean(SE)changefrom
baselineinSBP(mmHg)
Salsali A et al. American Diabetes Association 76th Scientific Sessions; 10-14 June 2016, New Orleans, Louisiana, USA

23. Empagliflozin vs. Glimepiride as Add-on to Metformin
Weight-loss Maintained Over 4 years
MMRM analysis in the FAS using observed cases (excluding values observed after initiation of rescue therapy and
off-treatment values).
743
737
610
642
524
590
458
551
331
443
301
420
269
395
248
368
745
739
15678 104 130 18212 28 52
703
706
Glimepiride
Empagliflozin
Difference: -4.9 kg
(95% CI -5.5 to -4.3)
p<0.0001
Week
Adjustedmean(SE)changefrom
baselineinweight(kg)
Salsali A et al. American Diabetes Association 76th Scientific Sessions; 10-14 June 2016, New Orleans, Louisiana, USA

24. Empagliflozin vs. Glimepiride as Add-on to Metformin
Systolic BP Reduction Maintained Over 4 years
MMRM analysis in the FAS using observed cases (excluding values observed after initiation of rescue therapy and/or after
changes in antihypertensive therapy and off-treatment values). *Number with data at visit; number of patients at 4 and 8
weeks, n=737 and n=705, respectively; †Number with data at visit; number of patients at 4 and 8 weeks, n=732 and n=696,
respectively. SBP, systolic blood pressure.
490
537
394
475
327
427
224
336
191
314
165
289
146
266
739
735
554
579
438
510
358
446
238
361
207
331
177
302
161
284
612
618
4 15665 78 104 130 18291 117 143 169 19512 4028 528 16
650
649
677
669
Glimepiride*
Empagliflozin†
Difference: -6.2 mmHg
(95% CI -8.5 to -4.0)
p<0.0001
Week
Adjustedmean(SE)changefrom
baselineinSBP(mmHg)
Salsali A et al. American Diabetes Association 76th Scientific Sessions; 10-14 June 2016, New Orleans, Louisiana, USA

25. Empagliflozin vs Glimepiride as Add-on to Metformin
Renal Function (eGFR) Preserved Over 4 years
Baseline: mean (SE) in the treated set; weeks 12–208: adjusted mean (SE) from MMRM in the treated set; LVOT and FU:
adjusted mean (SE) from ANCOVA in patients from the FAS who had a measurement at follow-up. *FU was 4 weeks after
termination of study medication. FU, follow up; LVOT, last value on treatment.
15678 104 130 18212 28 52
503
537
492
525
588
579
751
740
677
679
657
651
478
520
459
510
573
570
707
690
726
713
Glimepiride 757
Empagliflozin 742
LVOT FU*
Difference 5.1;
(95% CI 3.5 to 6.8)
p<0.0001
Week
Mean(SE)eGFR(mL/min/1.73m2)
Salsali A et al. American Diabetes Association 76th Scientific Sessions; 10-14 June 2016, New Orleans, Louisiana, USA

26. Empagliflozin Improves UACR Outcomes
in Patients with Albuminuria
Wanner C et al. FR-PO805, American Society of Nephrology Kidney Week, 15–20 November 2016, Chicago, IL, USA.
Empagliflozin
33% Lower Odds of Deterioration
in UACR Status
Empagliflozin
61% Higher Odds of Improvement
in UACR Status

27. Empagliflozin Consistently Reduces
Serum Uric Acid Level
Zinman B et al. N Engl J Med 2015;doi:10.1056/NEJMoa1504720. Inzucchi SE et al. Diabetes Care. 2018 Feb;41(2):356-63.

28. Empagliflozin Mediates Sustained
↓se in Plasma Volume
7-8% ↓se in Plasma Volume, Independent of Baseline eGFR
(p <0.0001 at Week 12 and Week 206)
Schou M. M2031; American Heart Association Scientific Sessions 2017, 11–15 November, Anaheim, California, USA

29. Hallow KM et al. Diabetes Obes Metab. 2017 Oct 12. doi: 10.1111/dom.13126.
• SGLT2-i agent ↓ses IF volume by 2-fold greater than blood volume
• Loop diuretic ↓ses IF volume by only 78% of reduction in blood volume
SGLT2-i agent Effect Loop Diuretic Effect
Day
Day
Day
Day

30. Empagliflozin and Cardiac Diastolic Function
Proof of Mechanism
• Diastolic Dysfunction affects at-least 1 of 2 patients with T2DM1-4
• Empagliflozin therapy and Effect on Diastolic Dysfunction5:
Functional Improvement (Early Lateral Annular Tissue Doppler Velocity)
At Baseline: 8.5 (SD 1.6) cm/s
After Empagliflozin therapy: 9.6 (1.3) cm/s
P = 0.002
Structural Improvement (Left Ventricular Mass Index)
At Baseline: 88 (SD 21) g/m2
After Empagliflozin therapy: 75 (SD 19) g/m2
P = 0.01
1. Patil MB et al. J Assoc Physicians India. 2012 May;60:23-6.
2. Patil VC et al. J Cardiovasc Dis Res. 2011 Oct-Dec; 2(4): 213-22.
3. Kumar M et al. J Assoc Physicians India. 2016 Jan;64(1):40.
4. Saichandar P et al. J Assoc Physicians India. 2016 Jan;64(1):33.
5. Verma S et al. Diabetes Care. 2016 Dec;39(12):e212-e213.

32. EMPA-REG OUTCOME Findings
Clinical Inferences for CVD Prevention
#Number Needed to Treat: Number of patients to be treated with empagliflozin for 3 years, to prevent 1 additional event.
32
Clinical
Outcome
Relative Risk Reduction
(Hazard ratio, p-value)
Absolute Risk Reduction
(Number Needed to Treat#)
3-point MACE
14%
(0.86, p = 0.04)
1.6%
(63 patients)
CV Mortality
38%
(0.62, p <0.001)
2.2%
(46 patients)
Hospitalizations for
Heart Failure
35%
(0.65, p = 0.002)
1.4%
(72 patients)
Hospitalizations for HF
or CV Mortality
34%
(0.66, p <0.001)
2.8%
(36 patients)
Incident or Worsening
Nephropathy
39%
(0.61, p <0.001)
6.1%
(17 patients)
≥40% sustained Decline
in eGFR
45%
(0.55, p <0.001)
1.4%
(72 patients)
All-cause Mortality
32%
(0.68, p <0.001)
2.6%
(39 patients)

33. Key Baseline Characteristics
• >50% patients had T2D of >10 years duration
• >25% patients had eGFR <60 ml/min/1.73 m2
• ≈39% patients had albuminuria (Micro- or Macro-albuminuria)
≈99% patients had pre-existing CVD
• >75% patients had Coronary artery disease (CAD)
• >46% patients had a history of MI
• ≈10% patients had Cardiac failure
Background ‘Standard of Care’ therapy:
• >48% patients were receiving insulin
• >80% were on ACE-i/ARB
• >76% were on statins
• ≈89% were receiving Anti-platelet agents
Zinman B et al. N Engl J Med 2015;doi:10.1056/NEJMoa1504720

34. All-cause Mortality
Empagliflozin vs. Placebo, On top of Standard of
Care
HR 0.68
(95% CI 0.57, 0.82)
p<0.0001
32% RRR
In Death due to
any cause
Zinman B et al. N Engl J Med 2015;doi:10.1056/NEJMoa1504720

35. CV Mortality
Empagliflozin vs. Placebo, On Top of Standard of
Care
HR 0.62
(95% CI 0.49, 0.77)
p<0.0001
38% RRR
In CV Death
Zinman B et al. N Engl J Med 2015;doi:10.1056/NEJMoa1504720

36. Empa-
gliflozin
Placebo
HR (95% CI)
n with event /
N analysed (%)
Main analysis 172/4687
(3.7)
137/2333
(5.9)
0.62
(0.49, 0.77)
Adjusted for control* of blood
pressure
172/4687
(3.7)
137/2333
(5.9)
0.61
(0.49, 0.76)
Adjusted for control* of LDL-
cholesterol
167/4615
(3.6)
136/2308
(5.9)
0.59
(0.47, 0.75)
Adjusted for control* of HbA1c 172/4685
(3.7)
137/2333
(5.9)
0.62
(0.49, 0.78)
Adjusted for control* of blood
pressure, LDL-c, and HbA1c
167/4614
(3.6)
136/2308
(5.9)
0.61
(0.48, 0.76)
CV Mortality Benefit with Empagliflozin is Consistent,
Regardless of Control of HbA1c, BP, LDL-c
*Adjusted for control at baseline and during the trial as time-dependent covariates.
Cox regression analysis in patients treated with ≥1 dose of study drug.
Fitchett D. ESC - 2017
HR (95% CI) for
CV Death
Favours empagliflozin Favours placebo

37. CI, confidence interval; QD, once daily; SE, standard error. ANCOVA (TS). Hach T, et al. Diabetes. 2013;62(suppl 1A):A21(P69-LB). Data on file.
Effect on Uric acid and Lipid profile

38. Participating countries
North America, Australia, New Zealand
Latin America
Asia
Africa
Europe
38
> 200 Indian
patients
590 cites from 42 countries

39. Adverse effects of SGLT-2 inhibitor

40. Genital and Urinary tract infections
Facts :
• Due to glycosuria caused by SGLT-2 inhibitors
• Genital mycotic infections
• Balanitis and balanoposthitis (M) and vulvovaginitis (F)
• Commonly by Candida, treated by local Anti-fungal
• UTIs, Urosepsis and Pyelonephritis
• More common in female, uncircumcised male
Advise to patients :
• Maintain good personal and genital area hygiene
• Washing genital area after each visit to toilet
• Retract the prepuce and wash (uncircumcised male)
• Avoid unusual sexual exposure
• Immediate medical attention if symptoms

41. Volume depletion
Facts :
• Due to glycosuria causing osmotic diuresis
• Increased frequency of urination
• Volume depletion-related effects such as Hypotension,
dehydration, postural dizziness, syncope
Advise to patients :
• Education about measures to avoid volume depletion
• Drink adequate amount of water during exercise, fasting,
starvation or hot weather

42. Hypoglycemia
• Insulin-independent mechanism of action
• Low risk when used as monotherapy
• Comparable to that of metformin or DPP4-inhibitor
• Increased risk with insulin and insulin secretagogues

43. Euglycemic DKA
Facts
• AACE/ACE reported that incidence of DKA in clinical trials of SGLT2i
in T2DM was low and majority of the reported cases were in TIDM
in whom SGLT2i use is not approved.
• SGLT2-inhibitor should be avoided in acute stressful situations
including acute illness, trauma/surgery, significant weight loss,
H/O DKA.
• Also avoided in severely insulinopenic patients and if used
concomitantly with insulin, the dose of insulin must be gradually
down-titrated, avoiding drastic reduction.
Advise to patients :
• Adequate food/carbohydrate intake and proper nutrition
• Maintenance of hydration, avoidance of binge-drinking of alcohol

44. Other rare adverse effects of SGLT-2 inhibitor
• Ischemic events/lower limb amputation (Cangliglozin)
• Bone fractures (Cangliglozin)
• Increased Low-Density Lipoprotein Cholesterol (LDL-C)
• Fournier gangrene

45. Drug interactions
Co-administration of SGLT2-inhibitor with :-
• Diuretics : Resulted in increased urine volume and frequency.
• Insulin or Insulin Secretagogues: Increases the risk for
hypoglycemia.

46. Place of SGLT-2 inhibitor in DM Management

47. ADA Standards of Care, 2020

50. ESC - EASD Guidelines on diabetes, prediabetes, and cardiovascular disease 2019 - Task Force. European Heart Journal. 2019:1-69. doi:10.1093/eurheartj/ehz486
Anti-hyperglycemic Recommendations for T2DM w/CVD

51. Robust indication for SGLT-2 inhibitor
• Overweight/obesity
• Hypertension
• ASCVD predominates
• Heart failure/CKD predominates
• Compelling need to minimize hypoglycemia
• Contraindication to other drugs
• Intolerance to other drugs

52. SGLT2-inhibitor in special populations
Renal impairment/CKD :
1. ADA has updated its diabetes standards of care to incorporate
results from the CREDENCE trial.
2. In the placebo-controlled trial, clinicians should consider using
SGLT2-inhibitor when the eGFR is at or above 30, especially with
albuminuria above 300 mg/g, to lower renal and CV risk.

53. During Ramadan :
1. No dose modification.
2. Dose should be taken with iftar.
3. Extra clear fluids should be ingested during non-fasting
periods.
4. Should not be used in the elderly, patients with renal
impairment, hypotensive individuals or those taking diuretics
SGLT2-inhibitor in special populations…

54. Characteristics Considerations
• Insulin-independent action
• Decrease FPG, PPG, A1c
• Weight loss
• Blood pressure lowering
• Low risk of hypoglycemia
• CV Mortality benefit in T2D with
ASCVD (Empagliflozin)
• MACE benefit in T2D with ASCVD
(Empagliflozin, Canagliflozin)
• Preservation of renal function
(slowing of decline in eGFR)
• Possible reduction in HF risk
• Uro-genital infections
• Ineffective in renal impairment
(eGFR <45mL/min/1.73m2)
• Monitoring of renal function,
volume and electrolyte status
• Volume-depletion related events
in predisposed individuals
• Bone fractures (Canagliflozin)
• Lower-limb amputations
(Canagliflozin)
• Euglycemic Diabetic Ketoacidosis
SGLT2-inhibitors
Considerations for Clinical Use

55. Take home message
• SGLT2 inhibitors are a new strategy for the treatment of T2DM.
• Their action is based on the blockage of SGLT2 of renal tubular cells
which as a result has glycosuria and excess calories' loss.
• The accompanying beneficial effects of this phenomenon are :
 Regulation of fasting and postprandial blood glucose levels
 HbA1c reduction
 Body weight loss
 Reduction of SBP and cardiovascular benefit
• However it is associated with genital and urinary tract infections.
• SGLT2 inhibitor can be combined with the existing treatments for
T2DM and can be an effective weapon for the management of
uncontrolled diabetes.