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Dapagliflozin in Clinical Trial212.pptx

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Dapagliflozin in Clinical Trial212.pptx

  1. 1. Josef von Mering (1849-1908) Josef von Mering discovered the glucosuric effect of phlorizin in 1888. History Phlorizin came from the root bark of the apple tree in 1995, NIDDK-funded researchers found that phlorizin inhibited both SGLT1 and SGLT2
  2. 2. The role of Kidney in Glucose Homeostasis This Photo by Unknown Author is licensed under CC BY-SA-NC gluconeogenesis glucose filtration glucose consumption glucose reabsorption responsible for up to 20% of all glucose production via gluconeogenesis
  3. 3. Renal Actions of SGLT2 inhibitors. De Fronzo et al 2009
  4. 4. Current SGLT2 inhibitors Approved by FDA • Canagliflozin • Empagliflozin • Dapagliflozin • Ertugliflozin
  5. 5. SGLT2 inhibitors play a role in the following settings ( Type 2 DM): • Overt atherosclerotic (CVD) not reaching glycaemic goals with metformin and lifestyle modifications (empagliflozin, canagliflozin, and dapagliflozin, but not ertugliflozin). • Heart failure not reaching glycaemic goals with metformin and lifestyle modifications (empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin). • As a third-line agent in patients not meeting glycemic goals on two oral agents. • As a second agent in patients with inadequate glycemic control on metformin who are unwilling or unable to consider injection therapy and in whom weight gain and risk of hypoglycemia are a significant issue
  6. 6. Heart Failure in non diabetic: As a Secondary pharmacologic therapy • Heart failure with reduced ejection fraction (HFrEF) ejection fraction ≤ 40% • NYHA classes II–IV • Elevated NT-proBNP • All ejection fractions • Dapagliflozin is 10 mg once daily. • Empagliflozin is 10 mg once daily
  7. 7. CKD (with or without diabetes) As an Additional therapies in proteinuric patients • Diabetic kidney disease: T2DM • Aetiology of kidney disease: ischemic nephropathy, IgA nephropathy, FSGS, chronic pyelonephritis, chronic interstitial nephritis • No immunosuppression in the prior 6 months • ONLY Dapagliflozin 10 mg for diabetic and non-diabetic ( DAPA CKD) • Canagliflozin for Diabetic kidney disease only (CREDENCE Study) • Empagliflozin not yet approved (EMPA-KIDNEY result is pending)
  8. 8. SGLT2 inhibitors and eGFR Glycaemic control • eGFR ≥60 ml/min per 1.73 m2 anticipated HbA1c ↓: 0.6%–0.9% • eGFR 45–59 ml/min per 1.73 m2 anticipated HbA1c ↓: 0.3%–0.5% • eGFR < 45 ml/min per 1.73m2 Anticipated HbA1c ↓: minimal SGLT2 inhibitors have less glycaemic benefit in patients with more severe kidney disease at initiation, and for the specific treatment of hyperglycemia, SGLT2 inhibitors are not recommended for initiation in patients with eGFR <30 mL/min/1.73 m2 (empagliflozin, canagliflozin), <45 mL/min/1.73 m2 (dapagliflozin, ertugliflozin)
  9. 9. SGLT2 inhibitors and eGFR • Diabetic kidney disease & Nondiabetic kidney disease • eGFR ≥ 25 ml/min per 1.73 m2 • UACR 200–5000 mg/g • Congestive heart failure • eGFR >20 ml/min per 1.73 m2
  10. 10. Practical Point: Accepting the Acute “Dip” in eGFR • SGLT2 inhibitors are well recognized to result in an acute transient reduction in GFR • larger magnitude of dip in eGFR correlates with greater long-term benefit and therefore should be viewed as evidence of a positive hemodynamic effect • Monitor kidney function 1 month after initiation in higher risk patients, including those with a history of prior acute kidney injury, advanced CKD, or in those in whom there is increased concern regarding volume depletion increase in serum creatinine level by up to 30% from baseline is considered acceptable.
  11. 11. Contraindications and precautions
  12. 12. • Type 1 diabetes • Presence of type 2 DM with prior DKA or a condition predisposing to DKA (including pancreatic insufficiency, drug or alcohol addiction) • Type 2 diabetes and eGFR <45 mL/min/1.73 m2 (dapagliflozin, ertugliflozin), or <30 mL/min/1.73 m2 (empagliflozin, canagliflozin) • For HF, eGFR <30 ml per minute per 1.73 m2 (except for empagliflozin, for which the threshold is <20 ml per minute per 1.73 m2), end-stage kidney disease, or rapidly declining renal function.
  13. 13. Avoid use of SGLT2 inhibitors in patients with • Frequent bacterial urinary tract infections or genitourinary yeast infections. • Low bone mineral density and high risk for fracture and falls • Foot ulceration (eg, neuropathy, foot deformity, vascular disease, and/or history of previous foot ulceration) • Ketogenic diet
  14. 14. Before Starting SGLT2 inhibitors Educate patients on the symptoms and risks of DKA and appropriate steps to take if symptoms or signs occur, including discontinuing SGLT2 inhibitor and seeking immediate medical attention. Temporary discontinuation of SGLT2 inhibitor and monitoring for ketoacidosis are recommended in situations known to predispose to ketoacidosis (such as prolonged fasting due to illness or perioperative state). SGLT2 inhibitors need to stop at least 3 days preoperatively
  15. 15. Cardiovascular Effects
  16. 16. Salvatore et al. An Overview of the Cardiorenal Protective Mechanisms of SGLT2 Inhibitors. Int. J. Mol. Sci. 2022, 23, 3651.
  17. 17. Atherosclerotic Cardiovascular Disease (CVD) Empagliflozin and canagliflozin have been shown to decrease atherosclerotic cardiovascular morbidity and mortality in patients with T2DM and overt CVD. (CANVAS and EMPA-REG trials) In the primary analysis, dapagliflozin did not appear to reduce atherosclerotic cardiovascular morbidity or cardiovascular mortality. however, it decreased cardiovascular outcomes in a subanalysis of the primary trial.
  18. 18. Heart Failure In patients with type 2 diabetes and heart failure, all SGLT2 inhibitors have shown salutary effects. Kanie T ETAL. Dipeptidyl peptidase‐4 inhibitors, glucagon‐like peptide 1 receptor agonists and sodium‐glucose co‐transporter‐2 inhibitors for people with cardiovascular disease: a network meta‐analysis. Cochrane Database of Systematic Reviews 2021, Issue 10. Art. No.: CD013650. DOI: 10.1002/14651858.CD013650.pub2. Accessed 18 September 2022.
  19. 19. Until large, prospective, randomized trials are conducted, it is unknown whether SGLT2 inhibitors will have similar CVD effects in the majority of persons with type 2 diabetes who do not have overt CVD
  20. 20. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes (DECLARE-TIMI 58 ) major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke 17,160 patients with type 2 diabetes (mean A1C approximately 8.3 percent) who had or were at risk for CVD
  21. 21. 3 wishes a Diabetologist met a genie and claimed his three wishes Genie : you can ask for anything other than love or money . Diabetologist : why ? Do you have specialties ? Genie : yes and my subspecialty is profession , for example my former master was karim Benzema ( with sneaky smile ) Diabetologist : ok then , my first wish is as follow “ I want an oral hypoglycemic agent that control blood glucose level but don’t cause hypoglecemia “ Genie: done
  22. 22. 2nd and third wishes Diabetologist : Second wish “ it can be used as a first line or added to the most widely used drugs or insulin “ Genie : done Diabetologist : third wish “ it must have a huge cardiovascular benefits and minimal side effects with ” Genie : done , may I present to you the SGLT2 inhibitor , dapagliflozin . Let me explain : 1st : it can be used alone
  23. 23. 2 Ferrannini E, Ramos SJJ, Salsali A, Tang W, List JF. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo- controlled, phase 3 trial. Diabetes Care,. 2010; 33 (10); 2217-24. • A 24-week parallel-group, double-blind, placebo-controlled phase 3 trial. • Patients with A1C 7.0–10 were randomly assigned to receive once-daily placebo or 2.5, 5, or 10 mg dapagliflozin once daily in the morning • The reductions in A1C were statistically significant with 5 and 10 mg dapagliflozin. Dapagliflozin monotherapy in treatment-naïve type 2 diabetic patients with inadequate glycemic control by diet and exercise
  24. 24. 3 Ferrannini E, Ramos SJJ, Salsali A, Tang W, List JF. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care,. 2010; 33 (10); 2217-24. Reductions in FPG were apparent as early as week 1. Throughout the study, FPG reductions were more marked in 5 and 10 mg dapagliflozin arms and were statistically significant at week 24 Dapagliflozin monotherapy in treatment-naïve type 2 diabetic patients with inadequate glycemic control by diet and exercise
  25. 25. 4 Ferrannini E, Ramos SJJ, Salsali A, Tang W, List JF. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care,. 2010; 33 (10); 2217-24. Body weight decreases were greater with all dapagliflozin doses than with placebo Dapagliflozin monotherapy in treatment-naïve type 2 diabetic patients with inadequate glycemic control by diet and exercise
  26. 26. 5 Ji L, Ma J, Li H, Mansfield TA, T'joen CL, Iqbal N. Dapagliflozin as Monotherapy in Drug Naïve Asian Patients With Type2 Diabetes Mellitus: A Randomized, Blinded, Prospective Phase III Study . Clinical Therapeutics. 2014; 36 (1); 84-100 • Phase III, multicenter, parallel group, double-blind study • Drug-naive patients with HbA1c levels 7.0%-10.5% were randomized to receive placebo, dapagliflozin (DAPA) 5 mg, or dapagliflozin 10 mg • Compared with placebo, dapagliflozin 5 and 10 mg demonstrated clinically and statistically significant improvements in HbA1c levels after 24 weeks of treatment Dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes whose disease was inadequately controlled with diet and exercise.
  27. 27. 6 Ji L, Ma J, Li H, Mansfield TA, T'joen CL, Iqbal N. Dapagliflozin as Monotherapy in Drug Naïve Asian Patients With Type2 Diabetes Mellitus: A Randomized, Blinded, Prospective Phase III Study . Clinical Therapeutics. 2014; 36 (1); 84-100 Dose-dependent, statistically significant reductions in fasting plasma glucose were observed for both doses (5 mg and 10 mg) compared with placebo Dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes whose disease was inadequately controlled with diet and exercise.
  28. 28. 7 Ji L, Ma J, Li H, Mansfield TA, T'joen CL, Iqbal N. Dapagliflozin as Monotherapy in Drug Naïve Asian Patients With Type2 Diabetes Mellitus: A Randomized, Blinded, Prospective Phase III Study . Clinical Therapeutics. 2014; 36 (1); 84-100 Dapagliflozin also resulted in significant reductions from baseline in total weight compared with placebo Dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes whose disease was inadequately controlled with diet and exercise.
  29. 29. Genie : it can be used with insulin or other drugs . First : insulin
  30. 30. 8 Wilding JP, Woo V, Rohwedder K, Sugg J, Parikh S. Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: efficacy and safety over 2 years. Diabetes Obes Metab. 2014 • A 24‐week, randomized, placebo‐controlled, double‐blinded, multicenter trial • Patients, whose T2DM was inadequately controlled on insulin ≥30 IU/day, with or without up to two oral antidiabetic drugs, were randomly assigned to receive placebo or 2.5, 5 or 1 0 mg/day of dapagliflozin for 104weeks • Dapagliflozin stabilized glycemic control to a mean level close to 7.5% in a difficult‐to‐treat population of older patients (mean age 59.3) with T2DM of long duration (mean age 13.6) and substantial diabetes‐related and cardiovascular comorbidity Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin
  31. 31. 9 Wilding JP, Woo V, Rohwedder K, Sugg J, Parikh S. Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: efficacy and safety over 2 years. Diabetes Obes Metab. 2014 Glycaemic control was achieved without an increase in mean daily insulin requirement for the dapagliflozin‐treated patients over a 104‐week period. Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin
  32. 32. 10 Wilding JP, Woo V, Rohwedder K, Sugg J, Parikh S. Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: efficacy and safety over 2 years. Diabetes Obes Metab. 2014 Reductions in total body weight in the dapagliflozin groups by 4 8 weeks were maintained over 104weeks Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin
  33. 33. Genie: It can be combined with other drugs
  34. 34. 11 Nauck MA, Del Prato S, Meier JJ, Durán-García S, Rohwedder K, Elze M. Dapaglif lozin Versus Glipizide as Add-on Therapy in Patients With Type 2 Diabetes Who Have Inadequate Glycemic Control With Metformin. Diabetes Care. 2011; 34 (9): 2015-2022 • 52-week, double-blind, multicenter, active- controlled, noninferiority trial randomized patients with type 2 diabetes (baseline mean HbA1c, 7.7%), who were receiving metformin monotherapy, to add-on dapagliflozin or glipizide • Although the initial drop in HbA1c during the titration period with glipizide was greater than that observed with dapagliflozin, efficacy for glipizide declined during the maintenance period but remained stable for dapagliflozin. This resulted in equivalent efficacy at week 52 Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin
  35. 35. 12 Nauck MA, Del Prato S, Meier JJ, Durán-García S, Rohwedder K, Elze M. Dapaglif lozin Versus Glipizide as Add-on Therapy in Patients With Type 2 Diabetes Who Have Inadequate Glycemic Control With Metformin. Diabetes Care. 2011; 34 (9): 2015-2022 Whereas glipizide treatment led to weight gain and more hypoglycemic episodes, dapagliflozin produced significant weight loss and significantly fewer hypoglycemic episodes Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin
  36. 36. 13 Matthaei S, Bowering K, Rohwedder K, Grohl A, Parikh S. Dapagliflozin Improves Glycemic Control and Reduces Body Weight as Add-on Therapy to Metformin Plus Sulfonylurea: A 24-Week Randomized, Double-Blind Clinical Trial. Diabetes Care. 2015; 38(3):365–372 • A 24-Week Randomized, Double-Blind Clinical Trial. Patients with HbA1c of 7.0% to 10.5% receiving sulfonylurea and metformin were randomized to receive dapagliflozin 10 mg/day or placebo • HbA1c levels were significantly reduced from baseline over 24 weeks in patients treated with dapagliflozin compared with placebo Dapagliflozin as add-on therapy to Metformin Plus Sulfonylurea  Dapagliflozin in triple therapy in combination with metformin plus sulfonylurea is not recommended according to NICE guidelines.  Please refer to the local SPC for licensed indications
  37. 37. 14 Matthaei S, Bowering K, Rohwedder K, Grohl A, Parikh S. Dapagliflozin Improves Glycemic Control and Reduces Body Weight as Add-on Therapy to Metformin Plus Sulfonylurea: A 24-Week Randomized, Double-Blind Clinical Trial. Diabetes Care. 2015; 38(3):365–372 Greater reductions from baseline to week 24 in FPG were observed with dapagliflozin compared with placebo Dapagliflozin as add-on therapy to Metformin Plus Sulfonylurea
  38. 38. 15 Matthaei S, Bowering K, Rohwedder K, Grohl A, Parikh S. Dapagliflozin Improves Glycemic Control and Reduces Body Weight as Add-on Therapy to Metformin Plus Sulfonylurea: A 24-Week Randomized, Double-Blind Clinical Trial. Diabetes Care. 2015; 38(3):365–372 Significantly greater reductions from baseline to week 24 in body weight were observed with dapagliflozin compared with placebo. Dapagliflozin as add-on therapy to Metformin Plus Sulfonylurea
  39. 39. 16 Rosenstock J, Hansen L, Zee P, Li Y, Cook W, Hirshberg B. Dual Add-on Therapy in Type 2 Diabetes Poorly Controlled With Metformin Monotherapy: A Randomized Double-Blind Trial of Saxagliptin Plus Dapagliflozin Addition Versus Single Addition of Saxagliptin or Dapaglif lozin to Metformin. Diabetes Care. 2015; 38(3):376-83 • A double-blind trial in adults with HbA1c ≥8.0% and ≤12.0%, randomized to saxagliptin (SAXA) (5 mg/day) plus dapagliflozin (DAPA) (10 mg/day), or SAXA (5 mg/day) and placebo, or DAPA (10 mg/day) and placebo on background metformin extended release (MET) ≥1,500 mg/day • The addition of SAXA+DAPA to MET therapy resulted in significantly greater reductions from baseline in HbA1c at 24 weeks than did therapy with SAXA+MET or DAPA+MET Saxagliptin plus dapagliflozin versus saxagliptin and dapagliflozin added on alone in patients with type 2 diabetes poorly controlled with metformin
  40. 40. Genie : lastly , cardiovascular and other beneficial effects and minimal side effects
  41. 41. 17 Sonesson C, Johanasson PA, Johnsson E, Gause-Nilsson I. Cardiovascular effects of dapagliflozin in patients with type 2 diabetesand different risk categories: a meta-analysis. Cardivasc Diabetol. 2016 A pre-specified meta-analysis of cardiovascular (CV) events from 21 phase 2b/3 dapagliflozin clinical trials was undertaken to characterize the CV profile of dapagliflozin Patients with type 2 diabetes, both overall and with different levels of CV risk, including CV disease (CVD) history, age and other CV risk factors, were analyzed The results suggest the potential for a beneficial CV effect by dapagliflozin which is consistent with the multifactorial benefits on CV risk factors associated with SGLT2 inhibitors. Cardiovascular effects of dapagliflozin in patients with type 2 diabetes and different risk categories
  42. 42. 18
  43. 43. 19 Objective: To compare dapagliflozin with DPP-4 inhibitors with regard to risk associations with major adverse cardiovascular (CV) events (MACE; non- fatal myocardial infarction, non-fatal stroke or cardiovascular mortality), hospitalization for heart failure (HHF), atrial fibrillation and severe hypoglycaemia in patients with type 2 diabetes (T2D) in a real-world setting.
  44. 44. A total of 40 908 patients with T2D were identified 10,227 new users of dapagliflozin 30,681 DPP-4 inhibitor Hikma Pharmaceuticals PLC 20 Methods: All patients with T2D prescribed glucose-lowering drugs during 2012 to 2015 were identified in nationwide registries in Denmark, Norway and Sweden. Patients were divided into two groups: new users of dapagliflozin and new users of DPP-4 inhibitors
  45. 45. 21
  46. 46. 22 Dapagliflozin was associated with a lower risk of MACE, HHF and all-cause mortality compared with DPP-4 inhibitors. Dapagliflozin was associated with lower risks of CV events and all-cause mortality compared with DPP-4 inhibitors in a real-world clinical setting and a broad T2D population. Results
  47. 47. 23 Observational effectiveness studies cannot replace randomized clinical trials, but might prove to be an important complement to a broader and more generalized patient population in a real-world setting. While awaiting more complete evidence, observational comparative effectiveness studies may increase the understanding of the SGLT-2 inhibitor treatment outcome effects; however, confounding, particularly by indication, cannot be fully excluded in observational studies, and the large ongoing prospective trial DECLARE-TIMI 58, including >17 000 patients with both low and high CV risk, will further elucidate dapagliflozin-specific findings.
  48. 48. Triple antihyperglycemic therapy using a combination of a DPP-4 inhibitor and an SGLT2 inhibitor as dual add-on to metformin is an effective and well tolerated novel intervention that has not been previously reported in uncontrolled type 2 diabetes Hikma Pharmaceuticals PLC Insert > Header & Footer to change this text 24 Dapagliflozin lowered hyperglycemia in treatment-naive patients with newly diagnosed type 2 diabetes . Dapagliflozin as monotherapy in drug-naiveAsian patients significantly improved glycemic control with the additional benefit of weight loss with low rates of hypoglycemia and no increase in renal events. Genital infections and UTIs were more common with dapagliflozin. Dapagliflozin improved glycemic control, stabilized insulin dosing and reduced weight without increasing major hypoglycemic episodes in patients whose T2DM was inadequately controlled on insulin. However, rates of genital infection and of UTI were elevated with dapagliflozin therapy. Despite similar glycemic efficacy at the end of the maintenance period, dapagliflozin reduced weight and produced less hypoglycemia than glipizide in T2DM inadequately controlled with metformin. Dapagliflozin was well tolerated and effective as add-on to metformin plus sulfonylurea.Adverse effects included hypoglycemia and genital infections Conclusion
  49. 49. Thank you

Notas do Editor

  • The urge to discontinue the SGLT2 inhibitor because of a rise in serum creatinine should be resisted in most patients and efforts should be made to maintain patients on SGLT2 inhibitors given their cardiorenal benefits

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