SGLT-2 Inhibitors- Hope or Hype? - An updated Review

 

Dr. R. Santhosh Kumar

JSS College of Pharmacy, Rocklands, Ooty 643001.

 

ABSTRACT:

Objective: This literature review aims to identify and investigate existing evidence about sodium-glucose co-transporter 2 (SGLT-2) inhibitors. Evidence acquisition: A literature search in PubMed and google scholar (January 1998 to April 2020) was done. Search terms like “(SGLT-2) inhibitors,” “pharmacokinetic,” “efficacy,” “cardiovascular safety,” and all the drug names of this class and its combination were included. Diabetes mellitus has been the silent killer of mankind, Metformin has been the reliable warrior for 62 years since its approval, and remains to be the first-line drug based on their beneficial effects. Conclusion: In 2015, the American Diabetes Association reported that data on microvascular and macrovascular results were unavailable for almost all the newer antidiabetic agents, which resulted in placing SGLT inhibitors as second- or third-line agents, Ever since, new evidence has emerged, notably for SGLT2 inhibitors, which have inspired and influenced physicians to reconsider their approach towards glucose reduction in type 2 diabetes. Hence a consolidated review on safety and efficacy of the drug is the need of the hour.

 

 

 

INTRODUCTION:

Diabetes mellitus is a metabolic condition that primarily results from impaired insulin production by beta cells of the pancreas [1]. The WHO projects that by 2030, diabetes mellitus (DM) will become the seventh leading cause of death worldwide [2]. Oral agents like metformin, insulin secretagogues (sulfonyl ureas& meglitinides), alpha-glucosidase inhibitors, thiazolidinedione’s, dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter 2 inhibitors and injectables like RA-GLP1 and insulin preparations are used worldwide to treat diabetes [3]. With examples from the history like thalidomide, rofecoxib, phenformin, and several other drugs being withdrawn from the market due to adverse effects, pioglitazone was subjected to withdrawal due to reported effects of heart failure, bladder cancer, edema, weight gain, anemia and risk of osteoporosis in women.

 

 

The ban was recently revoked due to a lack of sufficient data [4]. Another category of inexpensive and efficient drug, sulfonylureas, used by 25% of the world's population, is aligned with the risk of cardiovascular complications and increased mortality. [5,6]. The sedentary lifestyle in today’s world has led to obesity which has now become a serious health concern leading to several other complications [7].  

 

The physicians of this decade are focusing on the management of obesity which is a key strategy in controlling diabetes. Most of the hyperglycemic like sulfonylurea, insulin, thiazolidinedione’s, and glinides increase weight [8,9]. Even though a variety of treatment options are available for T2DM, disease progression remains a challenge and glycemic control varies interpersonally due to various factors despite treatment. With the emergence of the above-mentioned implications and evidence-based consensus to treat T2DM patients with individualized therapy, the SGLT2 inhibitors have grabbed their position in the treatment of diabetes [10,11].

 

SGLT2 inhibitors with their insulin-independent action regulate blood glucose by increasing the excretion of urinary glucose [12]. The SGLT2 inhibitors have pleiotropic effects other than the effect on T2DM which makes it a novel class of drugs [8]. Here we aim to review the various aspects of SGLT2 inhibitor therapy.

 

Evidence acquisition:

A literature search in PubMed and google scholar (January 1998 to April 2020) was done. Search terms like “(SGLT-2) inhibitors,” “pharmacokinetic,”  “efficacy,” “cardiovascular safety,” and all the drug names of this class and its combination were included. Literature published languages other than English was excluded. All the collected literature was critically appraised, usually, metformin is the first line of drug that is given to the patients, and SGLT-2 inhibitors are looked upon, only when the former drug no longer controls the blood sugars. Factors like cost and other comorbidities are considered when recommending therapy for patients.

 

History and development of sglt-2 inhibitors:

In 1835, a natural product called Phlorizin was extracted from the bark of Malus pumila (apple), which possessed SGLT inhibitory activity [13]. The bitter flavor of phlorizin reminded the chemists of cinchona which was a reasonable candidate to treat fever, infectious diseases, and malaria. Later, in the 1900s, the trials revealed that phlorizin caused glycosuria which when administered to the canine model produced symptoms of human diabetes (glycosuria, and weight loss). Which lead to the development of phlorizin -induced diabetes animal model [14].

 

In the following decades, the effect of phlorizin on renal physiology was studied through clinical trials. In the 1970s the trails revealed that phlorizin had a comparatively much higher binding affinity than that of [15]. Most in vivo studies incorporating animal diabetic models revealed that phlorizin significantly enhanced insulin sensitivity [16,17,18,19].

 

Further studies revealed that SGLT2 comparatively has low affinity than the SGLT1 receptor, phlorizin inhibits both SGLT1 and SGLT2 [20,21,22]. phlorizin's catalyzed hydrolytic metabolites B-glycosidases, actively inhibit glucose transporter 1 (GLUT1), which can then hinder the absorption of glucose in various tissues. Because of its primary involvement in the small intestine, SGLT1 inhibition can cause many side effects of the gastrointestinal tract, such as diarrhea, dehydration, and malabsorption. [13, 23, 24, 25].

 

Because of the limitations of phlorizin, researchers attempted to discover an orally administrable drug that does not require the use of prodrugs, leading to the development of SGLT2 [26]. C-glucosides, Owing to their potent and precise inhibition of SGLT2, gained prominence in the healthcare industry and were called gliflozins [27]. The US has currently licensed four SGLT2 inhibitors, namely canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin for treating type 2 diabetes [28,29]. Additional SGLT2 inhibitors, including sotagliflozine and bexagliflozin, are in the late development stage. While ipragliflozin, luseogliflozin, and tofogliflozin are licensed only in Japan [30,31].

 

Location and mechanism of the sglt receptors:

SGLT1 is located on the Lumina of the small intestine with smaller amounts in other parts of the gastrointestinal tract of humans [32,34]. SGLT1 in the gut transports glucose and galactose from the gut lumen across the gut wall [32]. SGLT1 is also located in the late proximal tubule of the nephrons of the kidney [33]. SGLT2 is located in the early proximal tubule [33,35]. SGLT2 in normal humans, reabsorb about 90% of the filtered glucose [35].

 

The first stage in the mechanism is the transport of glucose across the apical membrane of the proximal tubule which leads to glucose accumulation within the epithelium. The concentration gradient of glucose between the cell and the plasma results in the second stage of mechanism: the net passive exit of glucose through the basolateral membrane towards the plasma, via GLUT-2. Thus, the two-stage process, along with the absorption of glomerular fluid, results in complete absorption of glucose before the filtrate reaches the end of the proximal tubule [36].

 

Pharmacokinetic considerations of sglt2 inhibitors:

SGLT2 inhibitors have a decent pharmacokinetic profile. They are characterized by an excellent bioavailability, a long t1/2 which enables the drug to be used as a once-daily dose, low accumulation index following repeated administration, negligible renal clearance, and no interactions with other hypoglycaemics [46].

 

The pharmacokinetic properties of some of the commonly used “gliflozins” are summarized in the table (1)

 

CLINICAL TRIALS ON SGLT2 -INHIBITORS:

All the available anti-diabetic drugs have data supporting the micro and macrovascular complications with the SGLT2 inhibitors as an exception as stated by the American Diabetes Association in 2015. After this, several clinical trials were conducted to support the data regarding the same and many trials are still ongoing to explore the pleiotropic effects of SGLT2 inhibitors.

TABLE 1. PHARMACOKINETIC SUMMARY OF SGLT-2 INHIBITORS

 

EMPAREG OUTCOME is a cardiovascular outcome trial on empagliflozin on patients with type 2 diabetes mellitus prone to cardiovascular complications. It demonstrated a decrease in the rate of heart failure hospitalization and a reduction in cardiovascular deaths and provides supportive data regarding the use of empagliflozin for the long term. It also reported that genital infections were more common in the subjects. As far as renal safety is concerned, the number of patients with acute kidney injury was lower when compared to the placebo groups, and hence it was found to maintain renal function [48].

 

CANVAS was commenced to assess the cardiovascular efficacy and safety of canagliflozin To assess the renal protective effects of canagliflozin, another trial called the CANVAS-R (CANVAS-Renal) was commenced which was then later joined with the CANVAS trial to form the CANVAS program to detect the overall cardiovascular and renal efficacy and safety of canagliflozin. The patients of this trial had a reduction in the cardiovascular deaths and also a greater risk of amputation particularly with the CANVAS group and not in CANVAS-R group... The renal protective effects of canagliflozin could not be studied thoroughly by the CANVAS program, hence it paved the way for a more specific trial of canagliflozin on patients with kidney disease- CREDENCE trial [49].

 

CREDENCE was conducted on T2DM patients with kidney disease, This research shows a massive reduction in renal complications with a reduced risk of end-stage renal failure. It was also found to be safe with cardiovascular outcomes and hence, canagliflozin can be prescribed in patients with both renal and cardiac disease. Since the trial was stopped prematurely after 2.6 years, the study of the effect of drugs on secondary outcomes might have been limited. But later it was suggested that the limitations were unlikely to have a major effect on their findings [50].

 

DECLARE TIMI 58 assesses the cardiovascular outcomes of dapagliflozin in patients with T2DM. the results revealed that it reduced the cardiovascular complications and hospitalization for cardiac failure. The risk of stroke, amputation, bladder cancer, and fracture associated with the drug was low when compared to the placebo. But the risk of diabetic ketoacidosis and genital infections was high with the drug than with the placebo. The renal protective effects of dapagliflozin are yet to be studied in detail [51].

 

EMPEROR preserved is currently ongoing which will be demonstrating the effects of empagliflozin on patients with heart failure with preserved ejection fraction independent of the diabetes status [52].

 

EMPEROR reduced is also currently undergoing which will be demonstrating the effects of empagliflozin on patients with heart failure with reduced ejection fraction [53].

EMPA- TROPISM which will be exploring the effects of empagliflozin on non-diabetic patients with heart failure with reduced ejection fraction [54].

 

COMPARISON OF SGLT2 INHIBITORS WITH OTHER ANTI-DIABETIC DRUGS:

The SGLT2 inhibitors are compared with other classes of antidiabetics in Table 3 mentioned below. There is only a slight variation in the pharmacokinetics between metformin and SGLT2 inhibitors. Although metformin has been ruling the roost, studies have shown that many patients will not achieve their target HbA1c with metformin therapy alone and those who are intolerant to the drug might not achieve the target HbA1c. Hence metformin should be combined with other antidiabetics and SGLT2 inhibitors here can be safe for combining with metformin or SGLT2 inhibitors alone as a monotherapy are efficacious in people intolerant to metformin [58]. Vildagliptin is not recommended for use in patients with severe hepatic impairment as it is reported that it increases drug exposure by 22%. All the other DPP4 inhibitors have no reports of caution to use in hepatic impairment.

 

The use of dpp4 inhibitors is not recommended in patients with moderate to severe renal impairment and more studies are required to justify this [61]. Both the SGLT2 inhibitors and DPP4 inhibitors have varying risks and benefits making it difficult to decide which class is the best. But better glycaemic control has been achieved when both the drugs are combined and many fixed-dose combinations of DPP4 inhibitors and SGLT2 inhibitors are available now a days [64].

The glucagon-like peptide 1 agonists are very efficacious when compared to the other class of drugs mentioned here but they offer some serious disadvantages like lack of availability of an orally bioavailable form due to rapid metabolism by proteases of the mucosa of the intestine, the variability in its chemical stability by time and increase in pH and temperature, immunogenic reactions associated with this drug, side effects such as nausea and vomiting and above all, the cost associated with it making patient compliance an issue [62].

 

Hence the SGLT2 inhibitors can be preferred over GLP-1 Peptide agonist drugs. Sulfonyl ureas on the other hand are less efficacious in terms of glycaemic control, half-life, and cardiovascular safety when compared to the SGLT2 inhibitors. Therefore SGLT2 inhibitors are superior in all aspects when compared to sulfonylureas [59].

 

Table 2

 

EFFICACY OF SGLT2 INHIBITORS:

The SGLT2 inhibitors exhibit a decent efficacy profile.  Empagliflozin has shown to decrease the HbA1c level from the baseline by 1% and it is efficacious as monotherapy and also in combination; as the second drug with metformin or as the third drug with metformin+ sulfonylurea [68,69,70, and 71]. Canagliflozin lowers HbA1c approximately by 1% and it is efficacious as monotherapy as well as in combination; as a second drug with metformin, insulin, DPP4 inhibitors, sulfonyl urea’s and also as a third drug [68, 72, 73, and 74]. Dapagliflozin lowers HbA1c by 1.45% and is efficacious as monotherapy as well as in combination as a second drug with either of metformin/glimepiride/insulin/pioglitazone/sitagliptin
[75, 76, 77, 78].

 

Ertugliflozin lowers HbA1c by 1.7% and is efficacious in monotherapy as well as in combination with metformin and sit gliptin [79, 80, 81, 82].

 

ADVERSE EFFECTS:

RISK OF HYPOGLYCEMIA:

The risk of hypoglycemia is most common and frightening with any class of glucose-lowering agents. The insulin-independent mechanism of SGLT2 inhibitors usually results in a decreased risk of hypoglycemia [83]. The incidence of SGLT2-related hypoglycemia is low, except if given in combination with insulin or an insulin secretagogue [84-87].

 

The incidence of hypoglycemia was not observed with dapagliflozin, canagliflozin, or empagliflozin respectively as monotherapy, but hypoglycemia was observed when either of these three drugs was administered with insulin or sulphonylureas [89-94]. As far as luseogliflozin is concerned, hypoglycemia was not observed with both monotherapies or in combination [88].

 

RISK OF GENITAL MYCOTIC INFECTIONS:

Vulvovaginitis caused by candida species is the most commonly occurring infection in women; particularly in diabetic women who are at a risk of 80% when compared to non-diabetic individuals [95].

 

The genital candidiasis in diabetics consuming SGLT2 inhibitors is observed, because of the excretion of sugars through urine, which promotes mycotic colonization and facilitates a favorable environment for the growth of bacteria [96]. The risk of this infection is more in women but only a few rare events of men contracting this infection have been observed [97]. The risk of infection was higher even in dapagliflozin either as monotherapy or in combination [98]. 

 

 

These infections may usually occur within the first months, however risk of infection may persist during ongoing treatment [99,95].

 

These infections are of mild to moderate severity [101]. Individuals with a history of genitourinary infections tend to contract this infection while undergoing SGLT2 therapy [102]. The risk of genital mycotic infection can be mitigated by hydration and maintaining good perineal hygiene [103]. Usually, these infections respond to treatment with a single dose of fluconazole or topical agents [104].

 

URINARY TRACT INFECTIONS:

The results from a systematic analysis [105] stated that UTI was observed in patients consuming canagliflozin but the meta-analyses reports of the same do not state an incidence of urinary tract infections [106]. Dapagliflozin meta-analyses stated an increase in UTI when compared to the placebo [107,108].

 

But no incidence of UTI was observed with empagliflozin [109,110]. Uncommon incident Cases of pyelonephritis and urosepsis with SGLT2 inhibitors were reported to the FDA and their causal relationship remains a mystery [111]. Patients with a history of recurrent UTI, neurogenic bladder, indwelling catheters, and paraparesis should be considered before starting SGLT2 therapy [112,113,114].

 

HYPOTENSION:

The inhibition of SGLT2 receptors in the kidney by the “flozins” results in a decrease of tubular reabsorption of glucose resulting in increased urinary glucose excretion [115,116]. This inhibition also increases the excretion of sodium resulting in natriuretic [117].

 

The risk of hypotension with SGLT2 inhibitors was found to be high when compared to other hypoglycemics [119]. Dosage adjustment of “flozins” may be required in volume-depleted patients who are on loop diuretic therapy or thiazide therapy. Contrarily, if the patients are not volume depleted due to other factors, SGLT2  inhibitors can be safely co-administered with diuretics as it causes only a little synergistic effect in decreasing BP[120,121]. To prevent symptoms of hypotension, acute kidney injury, and falls due to volume depletion, it should be assessed whether appropriate doses of hypotensive medications affecting the renin-angiotensin-aldosterone system (RAAS) are prescribed [122].

 

RISK OF CANCER:

The FDA in 2011 published an advisory about the use of dapagliflozin and its correlation with an augmented risk for cancer (Breast and Bladder) [123].  Females were observed with breast cancer and males with bladder cancer [124]. The risk of cancer was not observed in phase 2-3 randomized controlled trials with canagliflozin or empagliflozin [122,125,126].

 

BONE SAFETY:

Dapagliflozin seems to have no impact on bone development. After 50 and 102 weeks of use, no substantial differences in BMD of the lumbar spine, total hip, and femoral neck were observed. However, an elevated incidence of fracture was seen in diabetic patients with significant renal impairment [132,129,130].  

 

A warning was published by the FDA in 2015 regarding the risk of fracture associated with canagliflozin.

The physicians must consider the risk for fractures before prescribing elderly people with canagliflozin [133,134,135].

 

Several studies propose the following mechanisms on the effect of T2DM on bone metabolism:

•     Elderly diabetic patients are at higher risk of falling correlated with peripheral neuropathy [126].

•     Increased urinary pentosidine, is linked to an elevated risk of lacerations in patients with T2DM. This indicates that the aggregation of complex glycation byproducts that stiffen bone collagen can reduce bone strength in T2DM [127].

•     The chronic hyperglycemia linked to single-gene mutations in the leptin gene or its receptor causes severe cytolipidemia-induced osteopenia. [128,131,132]

 

AMPUTATIONS:

The risk of amputation is linked with diabetes due to chronic hyperglycemia and microvascular complications such as peripheral artery disease (PAD), peripheral neuropathy, or the risk of infections [136]. Likewise, in the Announce analysis, there was no amputation risk with dapagliflozin. This risk was not observed with dapagliflozin and empagliflozin [137,138].

 

The publication of the CANVAS program elucidated the risk of amputation associated with canagliflozin for which a boxed warning was published by the FDA.[137]. From the program, it was evident that canagliflozin was mainly associated with lower limb amputation the toe. The patients with the following disease conditions were at risk of amputation: neuropathy, ulcers, and peripheral arterial disease, and previous history of amputations. But patients without the above disease conditions also were at risk of amputations while consuming canagliflozin [140].

 

Conflicting results have been found in numerous observational studies. A review of more than 900 000 individuals showed that new users of SGLT2-sulphonylurea, metformin or thiazolidinedione’s had a two-fold risk of amputations, and a marginal rise in incidence in contrast with DPP or GLP1-agonists were seen [138].

 

 

Since the risk of amputation is not evident or limited to canagliflozin alone, it is not recommended to use SGLT2 inhibitors in patients with ischemic extremities, peripheral vascular disease, and history of amputation is not recommended. The physicians must consider the risk before prescribing patients with these drugs [139].

 

DIABETIC KETOACIDOSIS:

Diabetic ketoacidosis may develop in patients with type 1 and type2 diabetes who are on SGLT2 inhibitor medications. [139,140]. The increased levels of ketone in the serum may be due to a decrease in insulin requirement, increased fatty acid oxidation rate, decreased clearance of ketones by the kidney, and stimulation of glucagon secretion.

 

Diabetic ketoacidosis was not observed with canagliflozin [140] or empagliflozin [141] but with dapagliflozin, the incidence was high [142]. The incidence of DKA was particularly high in T1DM patients who are on SGLT2 inhibitors and comparatively less in T2DM people on SGLT2 inhibitors [143] But T2DM people with low c- peptide levels are at a greater risk of DKA [144].

 

FOURNIER GANGRENE:

The FDA identified 55 cases of Fournier gangrene in the period 2013 to 2019, which recommended the physicians to discontinue the gliflozins in serve cases. The patients were treated with broad-spectrum antibiotics along with surgical debridement [145].

 

PHARMACOECONOMICS OF SGLT2 INHIBITORS:

Pharmacoeconomic analyses suggest that dapagliflozin when co-administered metformin increases the overall quality of life, with a decrease in the rate of incidence of diabetes complications when compared to the combination of metformin+ sulfonylurea or metformin+DPP4 inhibitors making it a cost-effective treatment alternative [146].

 

The results of meta-analyses of ipragliflozin as an add on to metformin apart from lowering blood glucose in T2DM, provided other benefits such as weight reduction, reduction in blood pressure, reduction in TG levels and this combination reduces the risk urinary tract and genital mycotic infections making it a cost-effective treatment alternative [147].

 

In general, SGLT2 inhibitors seem to be the most cost-effective in the treatment of T2DM compared with other anti-diabetics and insulin. Further studies are needed to determine the cost-effectiveness of other SGLT2 inhibitors and the cost-effectiveness of these drugs should also be examined in populations with renal and hepatic dysfunction [148].

 

DISCUSSION:

This article addressed the literature available on the safety and efficacy of SGLT-2 inhibitors by comparing these drugs with the other classes, SGLT-2 inhibitors were chosen since they have been gaining popularity for the treatment of type 2 diabetes. The American diabetes association has recommended the use of sglt-2 inhibitors for the patient with comorbidities and history of kidney and heart disease. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a practice-changing development for people with type 2 diabetes and chronic kidney disease (CKD) that have gone from a three-pointer to an easy lay-up. Evidence from the CREDENCE trial confirmed that canagliflozin substantially reduces the risk of kidney failure and cardiovascular events on top of renin-angiotensin system blockade, with kidney and cardiovascular protection also observed in three large-scale SGLT2 cardiovascular outcome trials involving almost 35,000 people.

 

The clear and consistent benefits for kidney and cardiovascular outcomes with SGLT2 inhibitors have led to revised treatment recommendations from many major international guidelines. In short, SGLT2 inhibitors should be prioritized in people with type 2 diabetes and a starting eGFR of >30 mL/min/1.73 m² to prevent the progression of kidney disease, cardiovascular events, or both, especially in those with UACR >300 mg/g (Level A recommendation).

 

CONCLUSION:

SGLT2 inhibitors have proven efficacious in lowering HbA1c and Fasting blood glucose levels thus delaying the disease progression of T2DM and bringing it into control. SGLT2 inhibitors with its effect on reducing body weight have become the most sought after treatment option for obese T2DM people. Surprisingly its cardioprotective effects are being discussed now making it a success. Despite several adverse events of the class being reported, only a few like genital mycotic infections, urinary tract infections, and fractures are more common. Further studies on a larger population are required to confirm the other adverse effects associated with the drugs. 

 

The SGLT2 inhibitors have additional effects like dapagliflozin to treat human renal carcinoma and canagliflozin to treat hepatocellular carcinoma [149,150]. The SGLT2 inhibitors are excellent as monotherapy as well as being a part of double and triple therapy with other antidiabetics. SGLT2 inhibitors are also cost-effective when combined with metformin which has proven to increase the quality of life of T2DM patients.

 

Several fixed-dose combinations of SGLT2 inhibitors with biguanides and DPP4 inhibitors are approved by the FDA, giving this class a very prominent position in the treatment of T2DM.

 

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Received on 29.06.2020            Revised on 08.08.2020

Accepted on 12.09.2020   ©Asian Pharma Press All Right Reserved

Asian J. Pharm. Res. 2021; 11(1):29-38.

DOI: 10.5958/2231-5691.2021.00007.1