1. Speaker: Dr. Suman Karmakar Preceptor: Dr. Neetu Jain

2. Background

3. Problems with existing drugs
Why new drugs ?
Problems with existing drugs
Safety
Weight gain
Hypoglycemia
GI intolerance (Metformin, Acarbose)
↑ in cardiovascular mortality (Rosiglitazone)
Efficacy
Reduce HbA1C by 0.5-2%
Effect is not sustained as monotherapy in great majority of patients
except Metformin

4. Emerging Therapies of Diabetes
Changing Insulin : Newer insulin / Needle less delivery system
Glucagon-like peptide 1 (GLP) agonists: Exenatide, Liraglutide, Taspoglutide….
Dipeptidyl peptidase IV (DPP IV) inhibitors: Sitagliptin, Vildagliptin
Amylin analogue: Pramlintide
Selective Sodium Glucose Co transporter 2 (SGLT2) Inhibitor: Sergliflozin, Dapagliflozin
Glucokinase activators
Sirtuin activators: Resveratrol
Glucagon receptor antagonists
Tahrani AA, et al. Glycaemic control in type 2 diabetes: targets and new therapies. Pharmacol Ther, 2010

5. Diabetes Care, January 2009

8. SGLT 2 Inhibitors
Inhibit up to a 50% of filtered glucose from being reabsorbed by kidney
Dose-dependent ↑ in urinary glucose excretion
Nearly 3000-fold selectivity for SGLT2 vs. SGLT1  little effect on function of SGLT1 in small intestine  ↓ gastrointestinal adverse events
A prolonged pharmacokinetic half-life  single daily dosing

9. SGLT 2 Inhibitors Sergliflozin Remogliflozin Canagliflozin
Dapagliflozin
GlaxoSmithKline
Johnson & Johnson
Bristol-Myers Squibb & AstraZeneca

10. Double-blind, placebo-controlled, randomized, parallel-group, phase IIa study
47 subjects with established T2DM (A1C 6-10%) & unimpaired renal function
Assigned to one of four treatment arms: 5, 25, or 100 mg dapaglifozin or placebo (± Metformin)
Duration of follow up: 14 days
Significant reductions in FPG in dapaglifozin groups
AE:
Two episodes of hypoglycemia
Similar incidence of UTI
Greater incidence of genital infections

11. Randomized, double-blind, three-arm parallel-group, placebo-controlled study
71 patients with T2DM (A1C %)
Assigned 1:1:1 to placebo, 10 mg, 20 mg dapagliflozin plus OAD(s) & 50% of daily insulin dose
Primary outcome: change from baseline in A1C at week 12
Dapagliflozin ↓ed A1C, produced better FPG, PPG levels & ↓ed weight more than placebo
More genital infections in 20 mg dapagliflozin group

12. Double-blinded, placebo-controlled, randomized clinical trial
151 early-stage & 58 late-stage patients with T2DM (A1C %)
Efficacy of dapagliflozin at 12 weeks
Significant improvement in glycaemic control & body weight reduction in both early & late stage patients
Side effects were not assessed

13. Phase 3, multicentre, double-blind, parallel-group, placebo-controlled trial
546 adults with T2DM on metformin (≥1500 mg/day) without control (A1C 7-10%)
Assigned to dapagliflozin 2·5 mg, 5 mg , 10 mg or placebo
Primary outcome: change from baseline in A1C at 24 weeks
Statistically significant reduction in A1C
AEs:
Similar incidence of hypoglycemia
More frequent genital infections

14. Objectives Phase III trial Efficacy Safety Primary efficacy endpoint:
Change from baseline at 24 weeks in A1C
Secondary efficacy measures:
Change from baseline at 24weeks in
Fasting plasma glucose (FPG)
Body weight
Safety

15. Study design & methods Randomized Parallel-group Double-blind
Placebo-controlled
Phase 3 trial
? Method of randomization
The study
? Nature of placebo
Enrollment done between September, 2007 & July, 2008
Duration of study 2½ yrs
Multicentre study- at 85 sites in USA, Canada, Mexico & Russia
Study was funded by Bristol-Myers Squibb and AstraZeneca

16. Study design & methods Inclusion criteria :
Treatment-naïve patients with type 2 diabetes mellitus (DM) inadequately controlled with diet & exercise
Age18-77 years
Body mass index (BMI) ≤ 45 kg/m2
Fasting C-peptide ≥ 1.0 ng/ml

17. Study design & methods Exclusion criteria : History of type 1 DM
Serum creatinine ≥ 133 μmol/L (1.5 mg/dL) for men
≥ 124 μmol/L (1.4 mg/dL) for women
Urine albumin / creatinine >200 mg/mmol
AST and/or ALT >3 × ULN
Creatine kinase ≥ 3 × ULN
Symptoms of severely uncontrolled DM (including marked polyuria and polydipsia with >10% weight loss during last 3 months)
Significant renal, hepatic, hematological, oncological, endocrine, psychiatric or rheumatic diseases
Cardiovascular event (NYHA class III/IV CHF ) within 6 months
Severe uncontrolled BP(SBP ≥ 180 mm of Hg and/or DBP ≥ 110 mm of Hg)

18. Study design & methods Patients A1C 7-10% A1C 10.1-12% Placebo
OD in morning
Dapagliflozin OD
Dapagliflozin
OD in morning
In morning
In evening
5 mg
10 mg
2.5 mg
5 mg
10 mg
2.5 mg
5 mg
10 mg
Main cohort
Exploratory cohort

19. Study design & methods Each patent followed up for 24 weeks
Placebo lead-in in form of diet/exercise- 1 week for A1C %
2 weeks for others
All patients gave informed consent
Study protocol approved by respective institutional review board or independent ethics committee
Rescue medication: Metformin 500 mg, titrated as needed up to 2 g (open-label)
Given to- FPG >270 mg/dl at week 4
>240 mg/dl at week 8
>200 mg/dl at weeks 12-24
Patients with A1C >8% for 12 weeks despite max tolerated metformin dose were discontinued
All received diet / exercise counseling as per ADA recommendations throughout study period

20. Safety assessments Vital signs Laboratory measurements
System organ class
High level group term
High level term
Preferred term
Lowest level term
Vital signs
Laboratory measurements
Adverse events [coded using preferred terms of Medical Dictionary for Regulatory Activities (MedDRA version 11.1)]
UTI and genital infections- reported as adverse event of special interest
Daily self-monitoring of blood glucose- reporting any unusually high or low blood glucose event or any symptoms s/o hypoglycemia

21. Statistical analysis
Point estimates and 95% confidence interval were calculated for mean change from baseline
Analysis of covariance (ANCOVA) with treatment group as effect & baseline value as covariate (applying Dunnett’s adjustment)
Per study design, no p values were generated for endpoints in exploratory cohorts

22. Results
???
???
Rescue Rx
Excluded
???
Patient disposition

23. Results
Demographics and baseline characteristics

24. Proportion of patients reaching target A1C < 7%
Results
Proportion of patients reaching target A1C < 7%
-0.16 (±2.50)%
32%
-1.23 (± 0.98)%
41%
Baseline A1C ≥9%
-1.98 (± 0.90)%
44%
-1.90 (± 0.79)%
51%
p=0.0005
p<0.0001

25. Statistically significant
Results
Statistically significant

26. Not statistically significant
Results
Not statistically significant

27. Results
a p<0.001; b p< Data are mean ± SE unless noted otherwise.*Assessed in patients with non-missing baseline and week 24 values with last observation carried forward.† Mean value after adjusting for baseline value. ‡ Data are mean (SD).

28. Not statistically significant
Results
Changes from baseline at week 24
Not statistically significant
Data are mean ± SE unless noted otherwise; † Mean value after adjusting for baseline value; § Assessed in patients with non-missing baseline and week 24 values; ║Ratio from morning, fasting spot urine test; NA=not assessed

29. Results Decreases from baseline in:
hs-CRP [-1.53 (1.06) to (1.10) mg/L]
Uric acid
Increases from baseline in:
HDL cholesterol [0.02 (0.07) to 0.17 (0.08) mmol/L]
Greater renal glucose losses associated with larger ↓ in body weight (r=-0.13, p=0.008) & changes in A1C (p=0.11)

30. Not statistically significant
Results
Nocturia
Adverse events
Not statistically significant

31. Discussion
Persistently increased renal glucose excretion consistent with urinary loss of ~ Cal/day- a shift towards negative net energy balance
Confounding effect of diet / exercise on weight loss
Dapagliflozin is efficacious in higher A1C levels where filtered glucose load may exceed kidney’s absorption capacity
↓ BP is in keeping with diuretic effect
No major episode of hypoglycemia
↑ in UTI & genital infections is a concern

32. Merits First study comparing monotherapy with placebo
First study to test efficacy of evening dose
First study bold enough to enroll patients with A1C > 10%
No placebo for patients with A1C > 10%
Only 3rd phase III study with maximum no. of subjects & longest period of follow up
Extensive assessment of effect on relevant metabolic parameters
Extensive safety assessment

33. Limitations Method of randomization- not mentioned
Nature of placebo- not mentioned
Short duration of follow up
Long list of exclusion criteria
Why evening dose was tried- not mentioned
Time points when follow up done- not clear
Why p value not generated for exploratory cohort- not clear
Use of last observation carried forward (LOCF)
Adverse events could be elaborated for better understanding

34. Critical appraisal

35. Validity assessment
The study drug has been compared with placebo which serves as control
It was a randomized study but method of it is not clear
The groups were comparable at baseline
Equal care was given to both the groups
The follow up period seems to be of short duration
It was a double blinded study
It was not Intention to treat analysis

36. Results assessment Favorable effects on A1C, FPG & body weight
The ↓ in A1C & FPG were statistically significant
Confidence interval used 95%

37. Applicability assessment
The study population is mainly Caucasian
Its applicability in Indian population might be questionable
Internists are the first contacts to diabetics
Several new drugs makes judgment difficult
In this study both favorable as well as adverse outcomes are considered
The drug has not yet been marketed- the cost remain an issue to look for

38. Conclusion Clinically meaningful ↓ in A1C & FPG
Favorable effects on weight, BP, hs-CRP, uric acid, HDL cholesterol
Efficacy documented in patients with A1C >10%
No major side effects including hypoglycemia
Though ↑ in UTI & genital infections- rarely led to discontinuation
The future studies may look into these effect in long term & head to head comparison with other groups of drugs
Insulin-independent mechanism of action make dapagliflozin a major break through in the treatment armamentarium for patients with diabetes