Real World Case Study of 12 Weeks to Assess Glycemic and Non-Glycemic Changes with SGLT2I from Database of Six Type 2 Diabetic Patients View PDF

Type 2 diabetes mellitus (T2DM) has recently become a global health issue by ranking 9th in the list of major death causes. Since the last three decades, individuals tested with T2DM have been on increasing trend.T2DM global epidemic is believed to rise from 2.8% (in 2000) to 4.4% (in 2030), taking into consideration all age groups.

Asia has been a hotspot for high incidence of T2DM as a worldwide epidemic, with countries like China and India taking the lead. There is large variation in state-specific diabetes prevalence in India. Dietary habits like consuming more red meat, refined grains and beverages with added sugar are considered to have a significant effect in T2DM epidemic causing overweight condition.

Health complications related to cardiovascular and renal systems leads to high rates of morbidity and mortality. Many therapeutic options are available to treat T2DM since few decades. However, the disadvantages of using insulin-dependent treatment options are still prevalent. The mechanism of action exhibits many side effects like hypoglycemia, weight gain and low renal functionality. Furthermore, weight gain as well as hypertension leads to the condition of obesity and cardiovascular morbidity. Many researchers are now focusing on new drug classes that would effectively lower the glucose level in blood independently of insulin, as they might result in improved acceptability and sustainability. In light of this, the sodium glucose cotransporter 2 (SGLT2I) has been developed as a treatment option for T2DM patients with chronic renal dysfunctionality and cardiovascular diseases [2].

SGLT2I plays a crucial role in lowering HbA1c levels, blood pressure and weight loss.This in turn lowers the risk of hospitalization due to heart ailments and renal complications in T2DM patients. With declining kidney function, SGLT2Is’ impacton blood glucose control is attenuated [3].

Inclusion criteria: Type 2 diabetics, HbA1c more than 6.5%

Estimated Glomerular Filtration Rate (as per CKD-EPI) >/=45 ml/ min/1.73 m2

Duration of diabetes is more than 2 years at least

Patients had no changes in their treatment during this study period Stable therapies for all diseases for at least 6 months prior to study Onset.

No prior history of any SGLT2I uses in last 6 months

Exclusion Criteria: Any history of Myocardial Infarction or Acute Coronary Syndrome, acute kidney injuryin last 3 months of study onset.

No history of smoking at baseline or during study

No travelling to high altitudes during the study

No history of any drug intake that might affect the body or blood Parameters

No concurrent illness or inflammation at baseline that might affect blood markers

The study population included four males and two females who had the history of T2DM for more than two years and HbA1C>6.5% initiated on either Empagliflozin 25 or Dapagliflozin 10. Baseline demographic and metabolic variables were collected at the time of SGLT2I initiation. The concomitant medications taken by the patients along with the study drug are summarized in (Table 1). Baseline characteristics of the patients and changes in their physical and hemodynamic parameters over 12 weeks of follow-up after SGLT2I initiation are summarized in (Table 2) (P value computed by Wilcoxon Signed Rank test). We observed that there has been a significant weight reduction accompanied with statistically significant decrease in Waist circumference (p=0.048) and significant increase in the PCV from 36.17

Table 1.Treatment received by the 6 Type 2 diabetic patients.

Table 2.Baseline characteristics evaluation during SGLT2I initiation and determination of change in mean hemodynamic and metabolic parameters over follow-up.

Baseline Parameters

Table 3.Mean changes in hemodynamic and metabolic parameters over follow-up.

Pair 3 WAIST:HIP--Baseline1.015.0190.925 WAIST:HIP--Follow-up1.016.014

± 2.05 (mean ± SEM) to 39.07 ± 1.81 (increase of 2.90 ± 2.07%; p=0.028) as well as significant rise in Hemoglobin percentage (p=0.027). (Table 3) summarizes the mean change in the hemodynamic and metabolic parameters over the follow-up period taking into consideration the statistical values.

T2DM is associated with multiple chronic complications. Since decades, research has been focused on developing novel treatment modules for T2DM. One of the major discoveries in this field is SGLT2I, which possess remarkable glycemic as well as non-glycemic clinical advantages in treating T2DM patients.

SGLT2 led to release of glucose in urine that led to weight loss and decrease in body fat. Adiposity possesses a great risk in development of cardiovascular disease. Hence, reduction in weight not only reduced this risk but also plays a crucial role in reduction of blood pressure and lipid when observed with SGLT2 inhibitor therapy. In addition to this,modest reduction in weight is observed in T2DM patients treated with empagliflozin drug groups during EMPA-REG OUTCOME (w2 kg), which further contributed to reduction in cardiovascular mortality rate [4,5].

Variation in weight of the subjects of current study (1.5 kg) was found to be highly significant when its baseline value (85.7 ± 17 kg) was compared with the follow-up period (6 months) value (84.2 ± 16.6 kg, P=0.0001). Similar findings were observed while comparing baseline weight in the Emirati population (85.7 ± 17.8 kg vs. 84 ± 17.2 kg, P=0.0001), which was found to be consistent in the previous study in which SGLT2I’s efficacy was studied in reduction of glycated hemoglobin and weight loss in these Emirati T2DM patients [6].

Clar and colleagues carried out systematic meta-analysis of clinical trials with dapagliflozin and canagliflozin. The study outcome stated reduction in the levels of HbA1c by 0.54% when treated with dapagliflozin when compared with placebo. However, when treated with canagliflozin, comparatively more decrease in levels of HbA1c was observed when compared to sitagliptin (by 0.21%). Administration of both the drugs showed decrease in body weight in a consistent manner (Dapagliflozin=1.18 kg; canagliflozin=2.3 kg) [7].

Normally all SGLT2I show a decrease in CRP levels due to their decrease in insulin resistance (IR) level. In our study, there was a slightreduction in CRP; however it was not statistically significant. There was no follow-up and the reason for no reduction in CRP might be due to lifestyle changes as well as any concomitant infection for which they did not seek medical advice or report at the clinic.

Due to the increase in the diuretic effect of SGLTL2 inhibitors, use in clinical practice is greatly increased. On initiation of the SGLT2I therapy, there is immediate increase in urine output and sodium excretion. Also, there is increase in hematocrit after SGLT2I administration. A recent study has been published which indicates that the diuretic effect of SGLT2I are not the only factor of rise in the hematocrit values in a diabetic patient. Based on the results of randomized study Dapagliflozin may lead to increase in production of red blood cell production by suppressing plasma levels of hepcidin (a pro-inflammatory inhibitor of iron transport). This might be a new mechanism which possibly leads to increase in hematocrit levels with SGLT2 Inhibitor treatment.

The initial part of increase is due to the diuretic effect but the later part is attributed by the rise in erythropoietin levels.

With administration of SGLT2-dapagliflozin drug in T2DM patients, increased levels of hemoglobin and hematocrit are observed due to increased erythropoiesis. Increased Hematocrit level in EMPAREG outcome (Trial number NCT01131676) has been attributed to be a major CV benefit contributing factor [8]. Recently Sano et al. has proposed that the increase in EPO levels with SGLT2Is could be due to recruitment of neural-crest derived fibroblasts producing EPO which stops getting converted to myofibroblasts due to reduction in proximal tubular oxygen consumption [9]. Another proposed mechanism is hypoxia at the level of corticomedullary junction due to afferent arteriolar constriction by SGLT2Is.

The baseline HbA1c level was 7.45 ± 0.2, which dropped to 6.82 ±0.5 at 12 weeks (P=0.1). This particular effect was found to be independent of the age of the patients, their gender and duration of diabetes, other comorbid conditions and use of other drugs. This drop in HbA1c in 3 months has been seen in many studies and exhibits a novel mechanism of SGLT2Is, which do not need functioning beta islets cells [10]

Monotherapy treatment approach of T2DM using dapagliflozin drug only is used with inadequately controlled lifestyle. The subjectsexhibited a low level of HbA1c which was highly significant when compared to placebo group when treated with dapagliflozin (5mg and 10 mg; P

A recent review on clinical trials using dapagliflozin, canagliflozin, luseogliflozin, ipragliflozin and tofogliflozin was conducted [7]. The results of all the trials showed thatadministration of SGLT2Is in mono, dual or triple therapy seems to behighly efficient in gaining HbA1c value <7% [2,3]. As per a pooled data analyses from 2286 T2DM patients, five randomizedand placebo controlled, phase III clinical trials were considered for analysis of empagliflozin’s effect on HbA1c, blood pressure andweight. Also, the HbA1c reduction decreased with the decrease in the baseline estimatedglomerular filtration rate (eGFR) [3].

This study exhibited significant effects of SGLT2 on various clinical parameters. In addition to this, it was well tolerated across eGFR subgroups.

In real-life scenario, administration of SGLT2I resulted in statistically significant decrease in the weight and waist circumference and significant increase in hemoglobin and hematocrit within 12 weeks period irrespective of baseline HbA1c and any telephonic follow-up for lifestyle interventions.

Real-world practice differs a lot from a Randomized Control Trial setting where many things are not possible to be done but these drugs maintain their extra-glycemic benefits irrespective of any Randomized Trial setting.

1. Zheng Y, Ley SH, Hu FB (2018) Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nature Rev Endocrinol 14: 88-98. https://www.nature.com/articles/nrendo.2017.151
2. Chan GW, Tang SW (2018) SGLT2 Inhibitor empagliflozin: finally at the latter stage of understanding? Kidney Int 93: 22-24. https://www.sciencedirect.com/science/article/pii/S0085253817305380
3. Cherney DI, Cooper ME, Tikkanen I, Pfarr E, Johansen OE, et al. (2018) Pooled analysis of Phase III trials indicate contrasting influences of renal function on blood pressure, body weight, and HbA1c reductions with empagliflozin. Kidney Int 93: 231- 244. https://www.sciencedirect.com/science/article/pii/S0085253817304775
4. Zou H, Zhou B, Xu G (2017) SGLT2 inhibitors: a novel choice forthe combination therapy in diabetic kidney disease. Cardiovascular Diabetol 16: 65. https://cardiab.biomedcentral.com/articles/10.1186/s12933-017-0547-1
5. Pfeifer M, Townsend RR, Davies MJ, Vijapurkar U, Ren J (2017) Effects of canagliflozin, a sodium glucose co?transporter 2 inhibitor, on blood pressure and markers of arterial stiffness inpatients with type 2 diabetes mellitus: a post hoc analysis. Cardiovasc Diabetol 16: 29. https://cardiab.biomedcentral.com/articles/10.1186/s12933-017-0511-0
6. Vallon V, Thomson SC (2016) Targeting renal glucosereabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia 60: 215-225. https://link.springer.com/article/10.1007/s00125-016-4157-3
7. Bashier A, Khalifa AA, Rashid F, Abdelgadir EI, Al Qaysi AA, et al. (2017) Efficacy and safety of SGLT2 inhibitors in reducingglycated hemoglobin and weight in emirati patients with type 2diabetes. J Clin Med Res 9: 499-507. https://www.jocmr.org/index.php/JOCMR/article/view/2976
8. Inzucchi SE, Zinman B, Fitchett D, Wanner C, Ferrannini E, et al. (2018) How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REGOUTCOME trial. Diabetes Care 41: 356-363. http://care.diabetesjournals.org/content/41/2/356
9. Sano M, Takei M, Shiraishi Y, Suzuki Y (2016) Increased hematocrit during sodiumglucose co-transporter 2 inhibitor therapy indicates recovery of tubulointerstitial function in diabetic kidneys. J Clin Med Res 8: 844-847. https://www.jocmr.org/index.php/JOCMR/article/view/2760.
10. Clar C, Gill JA, Court R, Waugh N (2012) Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2diabetes. BMJ Open 2: e001007. https://bmjopen.bmj.com/content/2/5/e001007.short
11. Anderson SL (2014) Dapagliflozin efficacy and safety: aperspective review. Ther Adv Drug Saf 5: 242-254. https://journals.sagepub.com/doi/abs/10.1177/2042098614551938