T1D Exchange , average A1C levels have not improved .How can adjunctive therapies ( added to insulin ) can help? The Removal Trial.Three main clinical trials : DEPICT with dapagliflozin , EASE with empagliflozin , and inTANDEM with sotagliflozin.

1. Magdy El-Masry
Prof. of Cardiology
Tanta University

3. Hyperglycemia-Related
Microvascular & Macrovascular Diseases
 Microvascular (e.g. diabetic retinopathy, nephropathy and neuropathy) and macrovascular (e.g.
stroke , coronary artery disease and peripheral vascular disease) complications
 Glycemic variability (GV) is involved in the pathogenesis of diabetic microvascular and
macrovascular complications
The Link Between Diabetes and CVD
Diacylglycerol (DAG)
Advanced glycation end products (AGEs)
Reactive Oxygen Species (ROS)

4. Potential mechanisms of glycemic variability in
diabetic macrovascular and microvascular complications

5. Tight glycaemic control in people with T1DM has
been shown to reduce the risk of
microvascular and macrovascular complications
Insulin therapy is the mainstay for T1DM

6. According to data from T1D Exchange , average A1C levels have not improved in the last
decade , and adolescents continue to be a difficult group for glycemic management ,
despite increased use of continuous subcutaneous insulin infusion (CSII) and continuous
glucose monitoring (CGM) systems

7. The current challenges and risks of insulin therapy :
hypoglycemia , weight gain,
glucose variability , and diabetic ketoacidosis
Unmet need in Type 1 diabetes

8. How can adjunctive therapies ( added to insulin ) can help?
Adjunctive
therapy
does not
replace
insulin

9. Various add-on drug options to insulin
Metformin GLP-1 RAs SGLT-2is
 The first-line drug to manage hyperglycemia in type 1 DM is insulin.
Several therapies given in conjunction with insulin have been investigated in clinical
trials, including metformin , glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and
sodium-glucose co-transporter-2 inhibitors (SGLT-2is)

10. Metformin’s Role in Type 1 Diabetes : The Removal Trial*
Small reductions in BW and LDL-C levels
but did not improve A1C
( That’s disappointing !!!!! )
*REMOVAL Trial is the largest and longest double-blind placebo-controlled RCT to evaluate
cardiovascular effect of metformin in adults with type 1 DM with a median follow up duration of 5 years
in patients with high CV risk (have ≥ 3 of 10 specified cardiovascular risk factors)
Interpretation :Trial data do not support use of metformin to improve glycaemic control in adults with
long-standing type 1 diabetes as suggested by current guidelines, but suggest that it might have a
wider role in cardiovascular risk management (modest improvements in LDL-c & weight).
Lancet Diabetes Endocrinol 2017; 5(8): 597-609.

11. Addition of liraglutide and exenatide to insulin therapy caused
small ( 0.2 % ) reductions in A1C compared with insulin alone and
also reduce body weight by ≈ 3 kg
Glucagon-like Peptide-1 Receptor Agonists (GLP-1 RAs )
 Liraglutide → ADJUNCT ONE trial
 Exenatide → MAG1C trial

12. Interpretation
Short-acting exenatide does not seem to have a future
as a standard add-on treatment to insulin therapy in T1D diabetes.

13. Conclusions:
Liraglutide added to insulin therapy reduced HbA1c levels, total
insulin dose, and body weight, accompanied by increased rates of
symptomatic hypoglycemia and hyperglycemia with ketosis,
thereby limiting clinical use in this group.

14. SGLT-2 inhibitors – moving on with the evidence.
What the evidence says
Several SGLT2 inhibitors have completed phase 3 clinical
trials to evaluate the efficacy and safety of their use as
adjunctive therapy in T1DM
Three main clinical trials :
DEPICT with dapagliflozin ,
EASE with empagliflozin , and
inTANDEM with sotagliflozin

15. Phase 3 dapagliflozin clinical trials in T1DM
DEPICT2
DEPICT2
DEPICT1
a DEPICT1 24-week data

16. Phase 3 empagliflozin clinical trials in T1DM
EASE2
EASE3
b Pooled EASE2 and EASE3 data

17. Phase 3 sotagliflozin clinical trials in T1DM
inTANDEM1
inTANDEM2
inTANDEM3

18. Glycemic Benefits
A1c levels reduction was seen in all RCTs
Non-glycemic Benefits
Insulin dose reduction & Body weight reduction
Safety Profile : The risk of DKA from using SGLT inhibitors
A small but significant increased risk of DKA was observed with SGLT
inhibition in the DEPICT, inTANDEM and EASE trials with
dapagfliflozin, sotagliflozin and empagliflozin respectively.
The absolute risk of DKA in those taking SGLT-inhibitors varied
between 0 and 4.3% of participants depending on the trial.
Efficacy and safety of SGLT2 inhibitor in type 1 diabetes : analysis of RCTs
Three main trials : DEPICT with dapagliflozin , EASE with empagliflozin , and inTANDEM with sotagliflozin

19. Of greatest concern however was the increased risk of DKA, a
potentially life-threatening complication, associated with SGLT
inhibitors use and this is discussed in a recent consensus report
Diabetes Care 2019; 42(6):1147-54.

20. Two-hit hypothesis for the effect of SGLT2 inhibitors to promote euDKA (euglycemic ketoacidosis) via both
predisposing to volume depletion and lowering plasma insulin concentrations. When insulin dosage is lowered too
much, SGLT2 inhibitors can enhance ketogenesis to the extent that the risk of DKA increases.
A distinguishing feature of the DKA induced by SGLT-2 inhibitors was that it could occur at relatively low plasma
glucose levels (< 14 mmol/L ”250 mg/dL” ), so-called euglycaemic DKA
euDKA

21. Checklist for appropriate prescribing of dapagliflozin in T1DM.

22. An understanding of sick day rules and
when to discontinue SGLT inhibitors is important.

23. *Glycemic control
↓A1C & ↑TIR
(Time in range)
*Weight loss &
Reduce insulin dose
*The most common side-effect is
that of genital fungal infection.
*The most serious problem,
though rare, is that of DKA.
*Low risk of hypoglycemia
Goal ! Two : Cardiovascular Protection
Treating Diabetes Beyond A1C :
The Accomplishment of Two Goals at Once?
Benefit-risk profile of SGLT2 inhibitors ( Gliflozins )
Beyond safety and efficacy , the issue of CV protection

24. Cardiovascular Outcomes Trials in Diabetes
CVOTs
in
T1D
• More and more T2D
CVOTs , have been
completed in recent
years.
Explore the
CVOT study for
SGLT2i

25. Need for Joint Approach : Cardiology, Diabetology and Nephrology
SGLT2
Inhibitors,
Developed for
T2D, Now
'Belong to
Cardiologists
and
Nephrologists'
It will be the
responsibility of the
diabetes specialist
(not cardiologist or
nephrologist) to identify
individuals with T1DM
who are suitable for
SGLT-inhibitor use.
Pathway : RCTs → Choosing the right drug → Choosing the right patient

26. Experts debate CV benefit of type 2
diabetes drugs for adults with type 1
Cardiorenal protection with SGLT2i ( Lessons from the CVOTs )
Of major significance are cardiovascular benefits in those with established
CVD, renoprotection in diabetic nephropathy ,and the benefits in heart failure.
Agents labeled to reduce CVD for people with type 2 diabetes should NOT be
extended to those with type 1 diabetes.
Should type 2 diabetes medications with proven CV benefits be used in type 1
diabetes to prevent [atherosclerotic] CVD?
The answer to that is, seriously? No “The risks far outweigh the demonstrated
benefits.”

27. Europe embraces , FDA rejects
use of SGLT inhibitors for type
1 diabetes :
Sotagliflozin and Dapagliflozin approved
in Europe for T1D
(not approved by FDA in the US due to
increased risk for diabetic ketoacidosis).
NICE recommendations
NICE have recently published technology
appraisals for both dapagliflozin
and sotagliflozin recommending them as
options for add-on therapies to insulin for
treating type 1 diabetes in adults.

28. Br J Diabetes 2020;20:155-162
Key words: SGLT inhibitors , type 1 diabetes , ketoacidosis ,
position statement

29. What is new? / Key messages
• Dapagliflozin (SGLT-2 inhibitor) and sotagliflozin (SGLT1/2 inhibitor) have been
recommended by the National Institute for Health and Care Excellence (NICE) in people
with type 1 diabetes with BMI ≥27 kg/m2 when insulin alone is not sufficient for diabetes
control and the insulin requirement is at least 0.5 units/kg of body weight.
• Such combination therapy can continue if there is sustained reduction of Hb A1c of at
least 3mmol/mol (2.4%)after 6months.
- SGLT inhibitors should only be started under supervision of a consultant physician specialising in
endocrinology and diabetes after a structured educational programme for the person with type 1
diabetes including comprehensive information on diabetic ketoacidosis.
- Dapagliflozin is licensed in the UK for use in NHS while sotagliflozin may be available in future

30. Br J Diabetes 2021;21: ONLINE AHEAD OF PUBLICATION
Key words: CVOT, cardiovascular outcome trials,
cardiovascular disease , type 2 diabetes , position statement
Type 1 Diabetes → Not mentioned

31. The today take-home message is that
SGLTis for T1D :
a finely balanced matter?
“Proceed with extreme caution”
There is a need for larger
randomized controlled trials
(RCTs ) with SGLT2is in T1DM
and real-world evidence (RWE)
to clarify safety and
cardiovascular benefits

33. Some Backup/Appendix Slides

34. Dual SGLT1 and SGLT2 inhibitions with SOTAGLIFLOZIN (compared with selective SGLT2
inhibition) should result in lower postprandial glucose, and robust HbA1c reduction achieved
with less renal glucose excretion, that is, maintained with reduced kidney function.
SGLT1, sodium–glucose cotransporter type 1; SGLT2, sodium–glucose cotransporter type 2.

35. In the DEPICT trials the likelihood of DKA was to some extent mitigated by limiting insulin
reduction to 20% following initiation of dapagliflozin and then re-uptitrating insulin doses as
necessary (insulin reduction can release the brakes on lipolysis and ketogenesis).
The EASE trials also had a cautious approach to insulin reduction following initiation of
empagliflozin which again would potentially limit the occurrence of DKA.
A meta-analysis of RCTs of sotagliflozin in T1DM reported an increased relative risk of DKA of
3.93 versus placebo (higher than the DEPICT trials) but this did include people with low-
insulin need (a group at higher risk of DKA) and the inTANDEM trials instructed participants
to reduce prandial insulin doses by 30% with the first dose of sotagliflozin.
At increased risk of DKA were people suffering an acute illness.
A clinically important finding in the inTANDEM trials was that of a higher rate of DKA
amongst those using insulin pumps possibly due to disruption of the infusion.
Total Daily Dose of insulin
(TDD)

36. The potential mechanism of sodium–glucose co-transporter 2 (SGLT2) inhibitors on glycemia reduction, weight reduction, insulin resistance, β-cell function
improvement, and reduction of cardiovascular complications. SGLT2 inhibitors cause glycosuria and negative energy balance, thereby leading to body
weight loss. SGLT2 inhibitors improve insulin resistance and β-cell function by attenuating inflammation, affecting adipocyte-derived hormones, and
promoting β-cell-related factor expression. SGLT2 inhibitors improve energy utilization, cardiac efficiency, and contractility. These inhibitors reduce cardiac
load and blood pressure. The effects of SGLT2 inhibitors on cardiomyocytes and cardiac remodeling result in improved cardiac function. Moreover, their
ability to mitigate insulin resistance, glucose variability, visceral adiposity, oxidative stress, and inflammation and their improvement of kidney function
contribute to a reduction in the risk of cardiovascular disease.

38. The main benefits and risks of SGLT2 inhibitors plus insulin therapy.

39. NICE TA 597, February 2020. Dapagliflozin with insulin for treating type 1 diabetes.
NICE TA 622, February 2020. Sotagliflozin with insulin for treating type 1 diabetes.

40. Danne T, Garg S, Peters AL et al. International consensus on risk management of diabetic ketoacidosis in patients with type 1
diabetes treated with sodium-glucose cotransporter (SGLT) inhibitors. Diabetes Care 2019; 42(6):1147-54.

41. Cut points for ketosis/DKA and corresponding remedial actions
Blood ketone (BHB) level Urine ketone* Remedial actions
<0.6 mmol/L (normal) Negative No action needed
0.6–1.5 mmol/L (ketonemia) Trace or small
Treat as follows or per clinician instructions:
• Ingest 15–30 g rapidly absorbed
carbohydrate and maintain fluid consumption
(300–500 mL) hourly
• Administer rapid-acting insulin based on
carbohydrate intake (hourly)
• Check blood/urine ketones (every 3–4 h)
until resolution
• Check blood glucose frequently to avoid
hyperglycemia and hypoglycemia
Seek medical attention if levels persist and
symptoms present
1.6–3.0 mmol/L (impending DKA) Moderate
Follow treatment recommendations listed above
Consider seeking immediate medical attention
>3.0 mmol/L (probable DKA) Large to very large Seek immediate medical attention
BHB, β-hydroxybutyrate.
* Urine ketone concentrations are dependent on hydration and other factors;
these values do not closely correlate with blood BHB levels.

42. Risk factors for DKA associated with SGLT inhibitor therapy
Risk level for
DKA
Factor
Moderate/high
• Reduced basal insulin by more than 10–20%
• Insulin pump or infusion site failure
• Reduced or inconsistent carbohydrate intake
• Excessive alcohol use
• Use of illicit drugs
• Volume depletion/dehydration
• Acute illness of any sort (viral or bacterial)
• Vomiting
Low/
moderate
• Vigorous or prolonged exercise
• Reduced prandial insulin dose by more than 10–20%
• Travel with disruption in usual schedule/insulin regimen
• Insulin pump use
Minimal/
low
• Low BMI (<25 kg/m2)
• Inconsistent caloric intake
• Moderate alcohol use*
• Female sex
* If ketone levels increase from baseline.

43. Patient criteria for SGLT inhibitor therapy
• >18 years of age
• Adherent to prescribed diabetes regimen
• Willing/able to perform all prescribed diabetes self-management tasks
• Performs blood glucose monitoring or uses CGM as prescribed
• Willing/able to perform ketone testing as prescribed
• Has received education/training in ketone testing and interpreting/acting upon test
results
• Has access to ketone testing materials
• Has immediate access to a clinician if blood or urine ketone levels are elevated
• No or moderate use of alcohol; no use of illicit drugs
• Unimpaired cognition
• Not pregnant or wanting to become pregnant

44. Educational components of a risk mitigation strategy
when introducing SGLT inhibitors for type 1 diabetes
Patient
education
• All patients initiating SGLT inhibitor therapy should
receive through training/education in the following areas:
◦DKA causes and symptoms
◦Euglycemic ketoacidosis
◦Importance of ketone monitoring
◦Use of ketone monitoring—training in testing
procedure, proactive monitoring, situations when
monitoring is indicated
◦Treatment protocol for addressing ketosis
◦Guidance in when to seek medical attention

45. Clinician
education
• All prescribing clinicians should acquire full
understanding of the safe use and risks associated with
SGLT inhibitor therapy:
◦Criteria for patient selection—baseline ketone level,
demographic/behavioral considerations
◦Training/educational needs of patients—detection
(ketone levels, symptoms), prevention strategies,
treatment
◦Potential for missed DKA, euDKA
◦Treatment strategies—STICH protocol recommended:
▪ STop SGLT inhibitor treatment for a few days
▪ Insulin administration
▪ Carbohydrate consumption
▪ Hydration with a suitable drink (e.g., water or
noncaloric athletic drink with balanced electrolytes)

46. Risk
Communication
• Product labeling, website
• Health care professional education
• Medication guide, patient alert card*