Executive Summary
Introduction
Methodology
Evidence level | Semantic descriptor (reference methodology) | Grades | Recommendation |
---|---|---|---|
1 | Meta-analysis of randomised controlled trials, Randomised controlled trials | A | Strong |
2 | Meta-analysis of non-randomised prospective or case–controlled trials, non-randomised controlled trial, prospective cohort study, retrospective case–control study | B | Intermediate |
3 | Cross-sectional study, surveillance study (registries, surveys, epidemiologic study, retrospective chart review, mathematical modelling of database), consecutive case series, single case reports | C | Weak |
4 | No evidence (theory, opinion, consensus, review, or preclinical study) | D | No evidence |
Compliance with Ethics Guidelines
SGLT2I and Diabetes
SGLT2I
Canagliflozin | Dapagliflozin | Empagliflozin | |
---|---|---|---|
US-FDA approval | March, 2013 | January, 2014 | August, 2014 |
DCGI approval | November 2014 | February 2015 | August 2015 |
Dosage (range) | 100–300 mg daily | 5–10 mg daily | 10–25 mg daily |
Absorption | Time to peak in plasma: 1 to 2 h | Time to peak in plasma: 2 h | Time to peak in plasma: 1.5 h |
Vd (L) | 83.5 | 118 | 73.8 |
Protein binding (%) | 99 mainly to albumin | 91 | 86.2 |
Metabolism | O-glucuronidation by UGT1A9 and UGT2B4 | O-glucuronidation by UGT1A9; CYP-mediated metabolism (minor) | O-glucuronidation by UGT2B7, UGT1A3, UGT1A8, and UGT1A9 |
Excretion | Faeces > urine | Urine > faeces | Urine > faeces |
Bioavailability (%) | 65 | 78 | 78 |
Half-life (h) | 10.6–13.1 | 12.9 (10 mg dose) | 12.4 |
Onset of action (h) | Within 24 h (dose-dependent) | ||
Duration of action (h) | 24 | ||
Drug–drug interaction | ↑Efficacy: alpha lipoic acid, heparin guanethidine, MAO inhibitors, salicylates ↓ Efficacy: carbamazepine, efavirenz, phenytoin, rifampicin, ritonavir | ↑Efficacy: alpha lipoic acid, MAO inhibitors, salicylates, quinolone antibiotics, SSRIs ↓ Efficacy: rifampicin, diuretics, NSAIDs | ↑Efficacy: alpha lipoic acid, MAO inhibitors, salicylates, quinolone antibiotics, SSRIs ↓ Efficacy: rifampicin, diuretics, NSAIDs |
Contraindications | History of serious hypersensitivity, severe renal impairment (eGFR < 30 mL/min/1.73 m2), ESRD | ||
Dose adjustment in hepatic impairment | Mild-to-moderate (Child–Pugh class A, B): no dosage adjustment Severe (Child–Pugh class C): use not recommended | No dosage adjustment necessary; use caution if initiating in severe impairment | No dosage adjustment |
Dose adjustment in renal impairment | eGFR ≥ 60 mL/min/1.73 m2: no dosage adjustment eGFR 45–60 mL/min/1.73 m2: 100 mg once daily (maximum) | eGFR ≥ 45 mL/min/1.73 m2: no dosage adjustment eGFR < 45 mL/min/1.73 m2: not recommended | eGFR ≥ 45 mL/min/1.73 m2: no dosage adjustment eGFR < 45 mL/min/1.73 m2: not recommended |
Mechanism of Action
SGLT family | Gene | Substrate | Distribution in tissue | Function | Expression |
---|---|---|---|---|---|
SGLT1 |
SLC5A1
| Glucose, galactose | Small intestine, kidney (S3 segment of PCT), trachea, heart, brain, testis, prostate | Transportation of glucose/galactose | Intestine > kidney |
SGLT2 |
SLC5A2
| Glucose | Kidney (S1 and S2 segment of PCT), brain, liver, thyroid, muscle, heart | Transportation of glucose and sodium | Mainly found in kidney |
SGLT3 |
SLC5A4
| Glucose | Intestine, testis, uterus, lung, brain, thyroid | Glucose sensor | – |
SGLT4 |
SLC5A9
| Glucose, mannose | Intestine, kidney, liver, brain, lung, trachea, uterus, pancreas | Transportation of glucose and mannose | – |
SGLT5 |
SLC5A10
| Glucose, galactose | Kidney | Unknown | – |
SGLT6 |
SLC5A11
| D-chiro-inositol | Spinal cord, kidney, brain | Absorption of glucose | – |
Place in Therapy
American College of Physicians (ACP) 2017 [33] | Recommends addition of either SU/TZD/SGLT2i/DPP4i to metformin to improve glycaemic control when a second oral therapy is considered Combinations of metformin and SGLT2i reduce weight more than metformin monotherapy SGLT2i, as monotherapy or with metformin, reduce SBP more than metformin monotherapy |
National Institute for Health and Care Excellence (NICE) 2017 [34] | As a first line agent, SGLT-2i instead of DPP4i should be preferred if an SU/TZD is not appropriate If A1C > 7.5%, DPP4i/SU/TZD/SGLT2i can be used as a second-line or third-line agent |
International Diabetes Federation (IDF) 2017 [35] | The preferred combinations may be metformin + SU, DPP4i or SGLT2i Recently SGLT2i have been considered as an option to add to metformin + SU or metformin + DPP4i combination |
American Diabetes Association (ADA) 2018 [1] | If A1C > 9%, consider dual therapy If A1C target not achieved in 3 months, proceed to triple therapy SGLT2i along with other antidiabetic drugs can be used as dual or triple therapy |
AACE 2017 [36] | If entryA1C < 7.5%, consider monotherapy If entry A1C ≥ 7.5%, consider dual and triple therapies SGLT2i placed before DPP4i, SU, and TZD in mono, dual, and triple therapies |
Diabetes Canada Clinical Practice Guidelines 2018 [37] | If A1C > 1.5% above target, incretins and/or SGLT2i should be considered if lower risk of hypoglycaemia and/or weight gain are priorities In adults with T2DM, on insulin, with inadequate glycaemic control, SGLT2i should be considered as an add-on therapy to improve glycaemic control with weight loss and lower hypoglycaemic risk compared to additional insulin |
Stable coronary artery disease (SCAD) management protocols in India 2016 [38] | All SCAD patients with diabetes should be treated with oral antidiabetics which have shown CV safety/benefits such as metformin, gliclazide, gliptins, SGLT2i |
Research Society for the Study of Diabetes in India (RSSDI) 2017 [39] | SGLT2i can be considered as a second-line agent when glucose targets are not being achieved SGLT2i can be considered as a third-line agent along with AGIs, DPP4i, or TZD |
Responders to SGLT2i
Clinical Efficacy
Author et al. | Study | Patients (n) | Intervention | Glycaemic efficacy | Change in Weight | Change in BP | Adverse effects (AE) | Outcome/conclusion |
---|---|---|---|---|---|---|---|---|
Canagliflozin
| ||||||||
Inagaki et al. [57] | RCT | 272 | A: CANA 100 mg or 200 mg B: Placebo 24 weeks | Change in A1C (A vs B): − 0.74 or − 0.76 vs +0.29% Change in FPG: − 31.6 or − 31.9 vs +3.7 mg/dl Change in PPG: − 84.9 or − 79.0 vs − 0.5 mg/dl (all, P < 0.05) | % Change: − 3.76 or − 4.02 vs − 0.76 (P < 0.05) | % Change: − 7.88 or − 6.24 vs − 2.72 mmHg (P < 0.05) | % Genital infections: 6.5 or 6.3 vs 0 % Symptomatic hypoglycaemia: 2.2 or 1.1 vs 1.1 | CANA significantly improved glycaemic control and was well tolerated |
Stenlöf et al. [55] | RCT | 584 | A: CANA 100 or 300 mg vs B: Placebo 26-weeks | Change in A1C (A vs B): (− 0.77 or − 1.03 vs 0.14% (P < 0.001) LS mean changes in FPG vs placebo: − 2.0 or − 2.4 mmol/l (all, P < 0.001) LS mean changes in PPG vs placebo: − 2.7 and − 3.6 mmol/l (all, P < 0.001) | LS mean changes vs placebo: − 2.2% (− 1.9 kg) and − 3.3% (− 2.9 kg) (P < 0.001) | LS mean changes vs placebo: − 3.7 and − 5.4 mmHg (P < 0.001) | Incidences of GTI, UTI and osmotic diuresis-related AEs were higher with CANA | CANA treatment improved glycaemic control, reduced body weight and was generally well tolerated |
Dapagliflozin
| ||||||||
Kaku et al. [58] | RCT | 261 | A: DAPA (5 or 10 mg) OD B: Placebo 24 weeks | Change in A1C (A vs B): − 0.41% or − 0.45% vs − 0.06% Change in FPG (A vs B): − 8.6 mg/dl or − 13.7 mg/dl vs +5.8 mg/dl | − 2.13 kg or − 2.22 kg vs − 0.84 kg | Two patients on DAPA 10 mg had hypoglycaemia; Events suggestive of GTI or UTI are each reported in four patients | DAPA as monotherapy was well tolerated and effective in reducing A1C, FPG and BW over 24 weeks | |
Ji et al. [59] | RCT | 393 | A: DAPA (5 or 10 mg) OD B: Placebo 24 weeks | Change in A1C (A vs B): − 1.04% or − 1.11% vs − 0.29% (P < 0.0001, both) Change in FPG (A vs B): − 25.1 mg/dl or − 31.6 mg/dl vs +2.5 mg/dl Change in PPG (A vs B): − 46.8 mg/dl or − 54.9 mg/dl vs +1.1 mg/dl | − 1.64 or − 2.25 kg vs − 0.27 kg | Hypoglycaemia was uncommon; GTI: 3.1% or 4.5% vs 0.8%; UTI: 3.9% or 5.3% vs 3.0% | DAPA as monotherapy in drug-naive Asian patients was well tolerated, significantly improving glycaemic control with the additional benefit of weight loss | |
Empagliflozin
| ||||||||
Gupta et al. [60] | RCT | 108 | A: EMPA10 mg (E10) or 25 mg (E25) B: Placebo 76 weeks | Adjusted mean change in A1C vs placebo: E10 (− 0.81%, P = 0.0029); E25 (− 1.11%, P < 0.0001) A1C < 7% vs placebo: E10 (20.8%, P < 0.0001); E25 (28.0%, P < 0.0001) Adjusted mean change in FPG vs placebo: E10 (− 35.7, P < 0.0001); E25 (− 32.9, P < 0.0001) | Adjusted mean change vs placebo: E10 (− 1,41, p = 0.0125); E25 (− 1.50, P = 0.0051) | Non-significant | AEs were similar except for GTI (E10, 20.8%); (E25, 3.4%); (placebo, 3.6%) | Treatment with EMPA was well tolerated and resulted in sustained glycaemic efficacy over long-term (76 weeks) in drug-naive Indian T2DM patients |
Roden et al. [54] | RCT | 899 | A: EMPA10 mg (E10) B: EMPA 25 mg (E25) C: SITA 100 mg (S100) D: Placebo 24 weeks | Adjusted mean change in A1C from baseline vs placebo: E10 (− 0.74%, P < 0.0001); E25 (− 0.85, P < 0.0001); S100 (− 0.73, P < 0.0001) | Reported AEs: A vs B vs C vs D: 55% vs 60% vs 53% vs 61% | EMPA provides a tolerable and efficacious strategy to reduce A1C in patients with T2DM who had not previously received drug treatment |
Positioning of SGLT2I in Treatment Continuum—Focus on After Metformin
Glycaemic Efficacy
SGLT2i vs Placebo
Author et al. | Patients (N) | Intervention | Comparator | Glycaemic efficacy |
---|---|---|---|---|
Lavalle-González et al. [64] | 918 | A: CANA 100 mg or 300 mg daily | B: Placebo 26 weeks | A1C: ↓from baseline (A vs B): − 0.79 or − 0.94% vs − 0.17% (P < 0.001) FPG: ↓from baseline (A vs B): − 1.5 or − 2.1 mmol/l vs +0.1 mmol/l (P < 0.001) PPG: ↓from baseline (A vs B): − 2.7 or − 3.2 mmol/l vs − 0.6 mmol/l (P < 0.001) Achievement of target A1C < 7% (A vs B): 45.5 or 57.8% vs 29.8% (P = 0.000) |
Qiu et al. [65] | 279 | A: CANA 50 mg or 150 mg BID | B: Placebo 18 weeks | A1C: ↓from baseline (A vs B): − 0.45 or − 0.61% vs − 0.01% (P < 0.001) FPG: ↓from baseline (A vs B): − 0.7 or − 1.2 mmol/l vs + 0.3 mmol/l Achievement of target A1C < 7% (A vs B): 47.8 or 57.1% vs 31.5% (P < 0.05 or P < 0.001 vs placebo) |
Ji et al. [66] | 676 | A: CANA 100 mg or 300 mg daily | B: Placebo 18 weeks | A1C: ↓from baseline (A vs B): − 0.97 or − 1.06% vs − 0.47% (P < 0.001) FPG: ↓from baseline (A relative to B): − 1.0 or − 1.4 mmol/l |
Schumm-Draeger et al. [67] | 400 | A: DAPA 2.5 mg or 5 mg BID | B: Placebo 16 weeks | A1C: ↓from baseline (A vs B): − 0.52 or − 0.65% vs − 0.30% (P = 0.0106 or P < 0.0001) FPG: Significantly greater improvements for DAPA vs placebo Achievement of target A1C < 7%: Significantly greater improvements for DAPA vs placebo |
Bailey et al. [68] | 546 | A: DAPA 2.5 mg or 5 mg or 10 mg daily | B: Placebo 102 weeks | A1C:↓from baseline (A vs B): − 0.48% (P = 0.0008) or − 0.58% (P < 0.0001), or − 0.78% (P < 0.0001) vs + 0.02% FPG: ↓from baseline (A vs B): − 1.07 or − 1.47 (P = 0.0003), or − 1.36 mmol/l (P = 0.0012) vs − 0.58 mmol/l Achievement of target A1C < 7% (A vs B): 20.7 or 26.4 ((P = 0.0202) or 31.5% (P = 0.0014) vs 15.4% |
Henry et al. [69] | – | A: DAPA 5 mg or 10 mg daily | B: Placebo 24 weeks | A1C: ↓from baseline (A vs B): − 2.05 vs − 1.35% (P < 0.0001); or − 1.98% vs − 1.44% (P < 0.0001) FPG: Combination therapy statistically superior to monotherapy (P < 0.0001) |
Häring et al. [70] | 637 | A: EMPA 10 mg or 25 mg daily | B: Placebo 24 weeks | A1C:↓from baseline (A vs B): − 0.70 or − 0.77% vs − 0.13% (P < 0.001) FPG: ↓from baseline (A vs B): − 1.11 or − 1.24 mmol/l vs + 0.35 mmol/l (P < 0.001) PPG: ↓from baseline (A vs B): − 2.55 or − 2.47 mmol/l vs + 0.33 mmol/l (P < 0.001) Achievement of target A1C < 7% (A vs B): 37.7 or 38.7% vs 12.5% (P < 0.001) |
Ross et al. [71] | 983 | A: EMPA 12.5 BID or 25 mg OD or 5 mg BID or 10 mg OD | B: Placebo 16 weeks | A1C:↓from baseline (E12.5 mg BID vs 25 mg daily), − 0.11%; and (E5 mg BID vs 10 mg daily), − 0.02% |
Merker et al. [72] | 463 | A: EMPA 10 mg or 25 mg daily | B: Placebo 76 weeks | A1C: ↓from baseline (vs B): − 0.6 or − 0.7% (P < 0.001) |
SGLT2i vs Active Comparator
Author et al. | Patients (N) | Intervention | Comparator | Glycaemic efficacy |
---|---|---|---|---|
Leiter et al. [75] | 1450 | A: CANA 100 mg or 300 mg daily | B: GLIM titrated up to 6 or 8 mg/daily 104 weeks | A1C: ↓from baseline (A vs B): − 0.65 or − 0.74% vs − 0.55% FPG: ↓from baseline (A vs B): − 1.1 or − 1.3 mmol/l vs − 0.6 mmol/l Achievement of target A1C < 7% (A vs B): 42.5 or 50.2% vs 43.9% |
Del Prato et al. [76] | 814 | A: DAPA 2.5, 5 or 10 mg | B: GLIP 5, 10 or 20 mg 208 weeks | A1C: ↓from baseline (A vs B): − 0.10 vs + 0.20% FPG:↓from baseline (A vs B): − 0.7 vs − 0.2 mmol/l A1C coefficient of failure (A vs B): 0.19 vs 0.61 (P = 0.0001) |
Ridderstråle et al. [77] | 1549 | A: EMPA 25 mg OD | B: GLIM 1-4 mg OD 104 weeks | A1C: ↓from baseline (A vs B): − 0.66 vs − 0.55% (P < 0.0001 for non-inferiority) FPG: ↓from baseline (A relative to B): − 0.85 or − 0.17 mmol/l (P < 0.0001) |
Lavalle-González et al. [64] | 1284 | A: CANA 100 mg or 300 mg daily | B: SITA 100 mg daily 52 weeks | A1C: ↓from baseline (A vs B): − 0.73 or − 0.88% vs − 0.73% FPG: ↓from baseline (A vs B): − 1.5 or − 2.0 vs − 1.0 mmol/l (P < 0.001) Achievement of target A1C < 7%(A vs B): 41.4 or 54.7% vs 50.6% |
Rosenstock et al. [78] | 355 | A: DAPA 10 mg daily | B: SAXA 5 mg daily 102 weeks | A1C: ↓from baseline (A vs B): − 1.20% vs − 0.88% FPG: ↓from baseline (A vs B): − 32 mg/dl vs − 14 mg/dl PPG: ↓from baseline (A vs B): − 70 mg/dl vs − 36 mg/dl Achievement of target A1C < 7% (A vs B): 22% vs 18% |
DeFronzo et al. [79] | 413 | A: EMPA 10 mg or 25 mg daily | B: LINA 5 mg daily 52 weeks | A1C: ↓from baseline (A vs B): − 0.66 or − 0.62% vs − 0.70% FPG: ↓from baseline (A vs B): − 18.8 mg/dl or − 20.8 vs − 13.1 mg/dl Achievement of target A1C < 7% (A vs B): 32.6 or 28.0% vs 36.1% |
Extra-Glycaemic Benefits
Body Weight Reduction
Author et al. | Patients (n) | Intervention | Comparator | Change in BW | Change in SBP |
---|---|---|---|---|---|
Lavalle-González et al. [64] | 918 | A: CANA 100 mg or 300 mg daily | B: Placebo 26 weeks | − 3.3 or − 3.6 kg vs − 1.1 kg (both P < 0.001) | − 3.8 or − 5.1 mmHg vs + 1.5 mmHg (both P < 0.001) |
Bailey et al. [68] | 546 | A: DAPA 2.5 mg or 5 mg or 10 mg daily | B: Placebo 102 weeks | − 1.10 or − 1.70 or − 1.74 vs + 1.36 kg (all P < 0.0001) | + 0.7 or − 1.1 or − 0.3 vs + 1.5 mmHg |
Haring et al. [70] | 637 | A: EMPA 10 mg or 25 mg daily | B: Placebo 24 weeks | − 2.08 or − 2.46 kg vs − 0.45 kg (both P < 0.001) | − 4.5 or − 5.2 mmHg vs − 0.4 mmHg (both P < 0.001) |
Leiter et al. [75] | 1450 | A: CANA 100 mg or 300 mg daily | B: GLIM titrated up to 6–8 mg/daily 104 weeks | − 3.6 or − 3.6 kg vs + 0.8 kg | − 2.0 or − 3.1 mmHg vs − 1.7 mmHg |
Del Prato et al. [76] | 814 | A: DAPA 2.5, 5 or 10 mg | B: GLIP 5, 10 or 20 mg 208 weeks | − 3.65 kg vs + 0.73 kg | − 3.69 mmHg vs − 0.02 mmHg |
Ridderstråle et al. [77] | 1449 | A: EMPA 25 mg daily | B: GLIM 1–4 mg daily 104 weeks | Difference – 4.5 kg (P < 0.0001) | − 3.1 mmHg vs + 2.5 mmHg (P < 0.0001) |
Lavalle-González et al. [64] | 1284 | A: CANA 100 mg or 300 mg daily | B: SITA 100 mg daily 52 weeks | − 3.3 or − 3.7 kg vs − 1.2 kg (both P < 0.001) | − 3.5 or − 4.7 mmHg vs − 0.7 mmHg (both P < 0.001) |
Rosenstock et al. [78] | 355 | A: DAPA 10 mg daily | B: SAXA 5 mg daily 102 weeks | − 2.4 kg vs 0.0 kg | − 3.5 mmHg vs 0.0 mmHg |
DeFronzo et al. [79] | 413 | A: EMPA 10 mg or 25 mg daily | B: LINA 5 mg daily 52 weeks | − 2.9 or − 2.8 kg vs − 0.3 kg | − 3.5 or − 2.8 mmHg vs + 0.3 mmHg |
The Indian Phenotype
-
higher insulin sensitivity index and lower acute insulin response to glucose [108];
-
early loss of β-cell function [102];
-
‘thin-fat Indian concept’ or ‘sarcopenic obesity’ (Asian Indians have thinner limbs [smaller muscle mass] with central obesity, with a higher waist-to-hip ratio and higher subscapular-to-triceps skin fold ratio than their British counterparts, which leads to higher insulin resistance) [109];
-
more people suffer from diabetes at a relatively lower BMI compared with those of European descent [110];
-
elevated mean A1C level (9.0%), which is 2.0% higher than the target suggested by international bodies [109].
Challenges with Indian patients | Relevant SGLT2i features |
---|---|
Higher abdominal adiposity and visceral fat at any given body mass index | ↓ Body weight (more visceral fat mass loss than subcutaneous fat loss) |
Higher waist circumference and waist to hip ratio | ↓ Waist circumference |
Low level of adipokine and high plasma leptin increases concentrations of triglycerides | ↓ Both triglycerides and leptin |
Low rate of glucose disposal | ↑ Rate of glucose disposal |
Impaired insulin secretion and increased insulin resistance | Improve β-cell function and ↓ insulin resistance |