Dapagliflozin for the treatment of type 2 diabetes mellitus – an update

ABSTRACT

Introduction

Diabetes is a global health concern with a prevalence of 463 million people. Importantly, despite the availability of numerous antidiabetic medications, type 2 diabetes mellitus (T2DM) is still associated with significant morbidity and mortality worldwide. One particular drug of interest is dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor that is commonly used in the treatment of Type 2 Diabetes Mellitus (T2DM).

Areas covered

This review outlines the current use and pharmacology of dapagliflozin, with a specific focus on recent evidence regarding benefits in patients with cardiovascular and chronic kidney disease. The article includes an overview of the efficacy and safety of this drug and provides the reader with the expert opinion and perspectives of the authors.

Expert opinion

Increasing evidence of the beneficial effects on morbidity and mortality in patients with Type 2 diabetes and concurrent heart failure, acute MI and renal failure are likely to see the usage of dapagliflozin in patients with these comorbidities increase over the next 5 years.

KEYWORDS:

• Cardiac
• dapagliflozin
• diabetes
• glucose
• renal

1. Introduction

Diabetes has an estimated global prevalence of 463 million people and is predicted to increase to 700 million by 2045 [1]. The majority is type 2 diabetes (T2DM), in which impaired insulin action and lack of adequate secretion lead to hyperglycemia.

Despite the availability of multiple antidiabetic medications, T2DM is still associated with significant morbidity and mortality. Chronic hyperglycemia can lead to renal failure, cardiovascular complications including stroke and heart disease, sight loss associated with diabetic retinopathy and maculopathy, and limb amputations due to diabetic neuropathy [2].

Treatment is based around monitoring glycated hemoglobin (HbA1c) as a measure of glycemic control, and using a combination of lifestyle measures and medications to reduce blood glucose, with the aim of preventing these complications. International bodies such as the American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) [3] recommend setting individualized HbA1c targets, taking into consideration factors such as patient preferences, adverse effects, and comorbidities. With this in mind, the ADA/EASD consensus statement states that ‘HbA1c target for most non-pregnant adults with sufficient life expectancy to see microvascular benefits (generally ~10 years) is around 53 mmol/mol (7%) or less.’

International guidance suggests referring patients to Diabetes Self-Management Education and Support programs, with the aim of supporting them to independently manage their diabetes day-to-day. The biguanide drug metformin is considered a first-line therapy for hyperglycemia in T2DM alongside lifestyle interventions including weight management, non-surgical energy restriction for weight loss, medical nutrition therapy, and increased physical activity. Treatment should be re-assessed at regular intervals in order to prevent ‘clinical inertia,’ with second-line antidiabetic medication choice (see Table 1), in cases with suboptimal HbA1C control, dependent on comorbidities and treatment priorities [3]. Dapagliflozin, an SGLT2 inhibitor, is indicated as monotherapy and as an adjunct to other therapies for the treatment of T2DM.

Table 1. oGLD classes and main mechanisms of action [4,5]

Drug Class	Mechanism of Action	Example Drugs
Sulfonylureas	Insulin secretagogue. Bind to and inhibit adenosine triphosphate-dependent potassium channels (K-ATP) in the pancreatic beta cell membrane leading to calcium influx and augmented insulin secretion.	Gliclazide, glimepiride, glipizide, glyburide
Meglitinides	Insulin secretagogue. Bind to and inhibit K-ATP channels in the pancreatic beta cell membrane leading to calcium influx and augmented insulin secretion.	Repaglinide, nateglinide
Biguanides	Stimulates hepatic adenosine monophosphate (AMP)-activated kinase activity, inhibiting hepatic glucose production. Increases insulin sensitivity, leading to increased glucose uptake by muscles.	Metformin
Thiazolidinediones	Activate the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ), increasing expression of the GLUT-4 glucose transporter, leading to increased peripheral glucose uptake and increased insulin sensitivity.	Rosiglitazone, pioglitazone
α-Glucosidase inhibitors	Competitive inhibitors of the digestive enzyme α-glucosidase found in the small intestine brush border epithelial cells. Delay breakdown of complex carbohydrates to glucose.	Acarbose, miglitol, voglibose
Dipeptidyl peptidase-4 (DPP4) inhibitors	Inhibit the DPP- 4 enzyme, which usually deactivates the incretins glucose-dependent insulinotropic polypeptide (GIP) and (glucagon-like peptide 1) GLP-1. Increased levels of GIP and GLP-1 cause decreased glucagon release and augmented insulin secretion.	Sitagliptin, linagliptin, saxagliptin, vildagliptin, alogliptin
Glucagon-like peptide-1 receptor agonists (GLP1-RAs)	Act on GLP-1 receptors to increase insulin secretion while decreasing glucagon release. Also, slow gastric emptying.	Exenatide, liraglutide, lixisenatide dulaglutide, semaglutide
SGLT2 inhibitors	Inhibit SGLT2 found in the proximal renal tubules, leading to inhibition of renal glucose reabsorption.	Dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, tofogliflozin, luseogliflozin

2. Overview of the market

In their consensus statement [3], the ADA and EASD identified a number of currently unmet needs in diabetes care. In addition to the to the macro- and micro-vascular complications of T2DM, including diabetic retinopathy, nephropathy, and neuropathy, recent research has identified wider-ranging complications of poor glycemic control including HF, non-albuminuric CKD, steatohepatitis, and chronic mental illness. Greater understanding of the advantages and disadvantages of existing treatments in the presence of these complications may improve our ability to optimize the use of antidiabetic medication for the needs of individual patients.

Multiple classes of oral glucose-lowering drugs (oGLD) have previously been developed for use in T2DM, as shown in Table 1.

In addition to their original use as hypoglycemic agents in T2DM, evidence is now emerging which suggests that SGLT2 inhibitors such as dapagliflozin may be useful in the treatment of patients with heart failure (HF). Current HF treatment involves the use of drugs, such as beta-blockers, renin-angiotensin-aldosterone system modulators, digoxin, and diuretics [6].

Diuretics provide symptomatic control for patients but have no impact on patient mortality. Other currently available therapies, while effective in improving outcomes in HF with reduced ejection fraction (HFrEF), do not improve outcomes in HF with preserved ejection fraction (HFpEF) [7,8]. As such, there are also multiple unmet needs in the currently available therapies for HF.

3. Pharmacodynamics

Dapagliflozin is a selective and reversible inhibitor of the SGLT2 transporter [9]. SGLT2 proteins are expressed in the proximal convoluted tubule (PCT) of the kidneys where they are responsible for glucose and sodium reabsorption from the glomerular filtrate. Physiologically, approximately 180 g of glucose is filtered and then reabsorbed daily, most via SGLT2 with the remainder occurring via SGLT1. As a result, no glucose is excreted in the urine of healthy individuals. During hyperglycemia (as in T2DM) there is upregulation of SGLT2, leading to further glucose reabsorption, thus contributing to hyperglycemia, but eventually the capacity is overwhelmed with resultant development of glycosuria. SGLT2 inhibitors block glucose reabsorption, with the resulting glycosuria of approximately 80 g per day directly lowering glucose in a process that is independent of insulin.

4. Pharmacokinetics and metabolism

Once absorbed, dapagliflozin reaches its peak plasma concentration after 2 h. It is metabolized in the kidneys and liver by uridine diphosphate glucuronosyltransferase-1A9. By inhibiting SGLT2 in the PCT, dapagliflozin results in urinary excretion of glucose, which lowers blood glucose [10].

5. Clinical efficacy

Several clinical trials have evaluated the safety and efficacy of dapagliflozin, with more recent randomized controlled trials (RCTs) further exploring cardiorenal outcomes. A recent systematic review and meta-analysis of SGLT2 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with T2DM found a total of 52,827 patients who had been assigned to receive treatment with an SGLT2 inhibitor within the context of an RCT [11]. There is also some evidence that beta cell function is improved by SGLT2 inhibitors, leading to long-term reductions in HbA1c in comparison to other oral antidiabetic drugs [12].

5.1. Phase II studies

Three studies compared dapagliflozin monotherapy to placebo in treatment naïve T2DM, using a change in HbA1c percent from baseline as the primary outcome in all. One study followed 279 patients for a 12-week duration, demonstrating a statistically significant reduction in HbA1c, compared to placebo, of ~8 mmol/mol (0.81%) among those administered with the highest 10 mg dapagliflozin dose [13]. These results are reinforced by larger studies showing even greater reductions in baseline HbA1c levels following 24 weeks of dapagliflozin treatment. The change in mean HbA1c from baseline was −0.77 to −0.82% and −0.89% for 5 mg and 10 mg dapagliflozin doses, respectively, all of which were statistically significantly compared to placebo [14,15].

5.2. Phase III studies

Phase III trials evidenced that dapagliflozin is non-inferior to metformin as a monotherapy in reducing HbA1c levels. List et al., 2009, demonstrated an adjusted mean change in HbA1c from baseline of −0.85%, −0.73%, and −0.18% (approx. −10, −8 and −2 mmol/mol) for patients treated with dapagliflozin 10 mg, metformin, and placebo, respectively [16]. Further phase III clinical studies have gone on to confirm the clinical efficacy of dapagliflozin as an adjunct in poorly controlled T2DM. Three trials compared the addition of dapagliflozin to placebo in 534, 597 and 420 patients taking background metformin, sulfonylurea, and thiazolidinedione, respectively [17–19]. All showed a statistically significant reduction from baseline HbA1c of between 0.82% and 0.97% for a 10 mg dapagliflozin dose. Beyond the benefits of glycemic control, dapagliflozin was shown to mitigate pioglitazone-related weight gain and produced a significantly adjusted mean weight loss of 4.7 kg compared to glipizide at the 52-weeks trial endpoint. This change was sustained after 208-weeks [20].

In patients with T2DM already receiving high doses of insulin, adjunctive dapagliflozin use has similarly been shown to improve glycemic control, mitigate insulin-associated weight gain, and reduce insulin requirements in patients with diabetes treated with insulin and up to two additional oGLDs [21,22].

5.3. Phase IV studies

The benefits of dapagliflozin have also been shown to extend beyond glycemic control in the treatment of people with diabetes. These include lowering blood pressure, renal protection, and improved cardiac function [23], with mechanisms posited for this improvement including improved cardiac energy metabolism and prevention of adverse cardiac remodeling [24]. In T2DM, SGLT2 function is upregulated with increased reabsorption of glucose and sodium. Subsequently, decreased delivery of sodium distal to the PCT and macula densa eventually results in loss of tubuloglomerular feedback. This key autoregulatory mechanism adjusts the renal blood flow and glomerular filtration rate (GFR) to optimize fluid flow through the renal tubule. It is thought that SGLT2 inhibitors such as dapagliflozin enhance delivery of sodium to the macula densa to restore the tubuloglomerular feedback process, thus reducing intraglomerular pressure, reducing proteinuria, and helping to preserve renal function. Additionally, these renal mechanisms will inevitably have a positive impact on cardiovascular function as a secondary effect.

5.3.1. DECLARE-TIMI-58

The DECLARE-TIMI (Thrombolysis in Myocardial Infarction) 58 study [23] was a double-blind, placebo-controlled, multinational RCT investigating the cardiovascular safety of dapagliflozin in T2DM. In total, 17,160 patients were recruited from 882 sites over 33 countries; all participants had T2DM plus either established atherosclerotic cardiovascular disease (aCVD; 40.6%), or risk factors for CVD (59.4%).

The co-primary outcomes were major adverse cardiovascular events (MACE), including cardiovascular death, MI and ischemic stroke, and a composite of hospitalization for heart failure (HHF) and cardiovascular death. Patients were followed for a median of 4.2 years.

Compared to placebo, the dapagliflozin group had lower HbA1c throughout the trial (mean absolute difference 0.42%, 95% CI 0.4–0.45), significant weight reduction (1.8 kg, 95% CI 1.7–2.0), and a small reduction in both systolic and diastolic blood pressure (2.7 mmHg, 95% CI 2.4–3; 0.7 mmHg, 95% CI 0.6–0.9, respectively). Patients receiving dapagliflozin also had a lower rate of the composite outcome ‘cardiovascular death and HHF’ (hazard ratio 0.83; 4.9% vs 5.8%). As there was no significant difference in the rate of cardiovascular death alone between the two groups, this lower rate was entirely attributed to the lower rate of HHF in the dapagliflozin group (hazard ratio 0.73; 95% CI 0.61 to 0.88). This finding was significant across the study population in those receiving treatment for both primary and secondary cardiovascular prevention of CVD.

The conclusion that dapagliflozin does not reduce the rate of cardiovascular death contrasts with previous studies of cardiovascular outcomes in patients receiving SGLT2 inhibitors. The EMPA-REG OUTCOME trial [25] investigated the cardiovascular safety of empagliflozin and demonstrated a lower cardiovascular and all-cause death rate among patients receiving empagliflozin. In a head-to-head comparison of SGLT2 inhibitors, empagliflozin and canagliflozin were both found to reduce the risk of MACE, whereas dapagliflozin did not give statistically significant protection [26].

One possible reason for this finding could be that patients included in the EMPA-REG outcome trial were at higher risk, as they all had established CVD and had lower eGFR as only those with eGFR <30 ml/min/1.73 m² were excluded, in contrast to DECLARE where only those with a creatinine clearance above 60 ml/min 1.73 m² were included.

As SGLT2 inhibitors act within the kidney nephron, with downstream effects on natriuresis, blood pressure reduction, improved tubular glomerular feedback, vascular compliance, and endothelial function, it is possible that patients with preexisting CKD may gain more benefit from them, therefore excluding these patients may limit mortality benefit seen in DECLARE. For this reason, direct comparisons between different drugs within the SGLT2 inhibitor class are difficult when synthesizing evidence from different studies with different patient populations. It is worth noting that some studies directly comparing different SGLT2 inhibitors within the same population do exist, including Sha et al., 2015, which determined that patients taking the recommended dose of canagliflozin (300 mg) renally excreted a significantly higher quantity of glucose than those taking 10 mg dapagliflozin; however, the clinical significance of these findings in patients with diabetes would need to be assessed [27].

In summary, there are multiple drugs within the SGLT2 inhibitor class sharing a common mechanism of action, and despite the fact that this review focuses on dapagliflozin in particular, many of our conclusions can also be applied to other drugs within the class.

5.3.2. DAPA-HF

Given that the effects of SGLT2 inhibitors on HF hospitalization risk were observed early following patient randomization in studies such as DECLARE [23], it is thought they may occur independently of the drug’s glucose-lowering effects, which would reduce cardiac risk in the longer term. The DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) study [28] aimed to explore the effects of dapagliflozin in patients with HF regardless of whether or not they also had a diagnosis of T2DM.

DAPA-HF enrolled 4744 patients with both New York Heart Association Class II, III, or IV HF and an ejection fraction ≤40% (i.e. HFrEF). Exclusion criteria included patients with eGFR <30 ml/min/1.73 m2, rapidly declining renal function, diagnosis of T1DM and hypotension. Eligible patients were randomized to receive either 10 mg dapagliflozin once daily (OD) or placebo in addition to standard recommended therapy for HF (drugs and/or devices). Patients with T2DM continued to receive their usual antidiabetic medications with doses adjusted as required to prevent hypoglycemia.

DAPA-HF had a composite primary outcome of HHF, urgent treatment for HF with IV medication, and CV death. Patients receiving dapagliflozin had a lower risk of all three components, with 386/2373 (16.3%) in the dapagliflozin group reporting at least one compared to 502/2371 (21.2%) in the placebo group (hazard ratio 0.70, 95% CI 0.65–0.85, P < 0.001).

The first episodes of worsening HF (either hospitalization with or urgent IV treatment of HF) were seen in 237 (10%) of patients in the dapagliflozin group, compared to 326 (13.7%) receiving placebo (hazard ratio 0.70, 95% CI 0.59–0.83). CV death occurred in 227 (9.6%) patients receiving dapagliflozin, and 273 (11.5%) receiving placebo (hazard ratio 0.82, 95% CI 0.71–0.97).

Additionally, the risk of all-cause death was also lower in the dapagliflozin group, with a total of 276 patients (11.6%) in the dapagliflozin group and 329 patients (13.9%) in the placebo group dying of any cause during the study (hazard ratio, 0.83; 95% CI, 0.71 to 0.97). As DAPA-HF, like EMPA-REG, used a lower renal function cutoff for excluding patients than DECLARE (eGFR <30 ml/min/1.73 m2 compared to CrCl <60 ml/min in DECLARE), DAPA-HF further supports the conclusion that patients with a greater degree of renal disease may benefit more from SGLT2 inhibitors with regard to mortality.

5.3.3. DAPA-CKD

The DAPA-CKD (DAPAgliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease) [29] trial aimed to assess the efficacy and safety of dapagliflozin in CKD patients with and without a T2DM diagnosis.

DAPA-CKD was a double-blinded, multicentre RCT. In total, 4304 patients from 386 sites in 21 countries were recruited, and eligible patients were those with an eGFR of 25–75 ml/min/1.73 m2 and a urinary albumin–creatinine ratio (ACR) of 200–5000 mg/g. Patients who had received immunotherapy for renal disease within the 6-months prior to screening were ineligible for participation, alongside those with a background of T1DM, polycystic kidney disease, lupus nephritis, or ANCA-associated vasculitis.

Participants received either dapagliflozin 10 mg OD or placebo, with groups stratified by T2DM diagnosis and urinary ACR ≤1000 or >1000. The primary outcome was also a composite measure consisting of the following: a ≥ 50% decline in eGFR seen ≥28 days; the onset of end-stage renal disease (defined as ≥28 days of dialysis, renal transplant, or eGFR <15 ml/min/1.73 m2); death from any renal or cardiovascular cause.

Median follow-up length was 2.4 years; however, the trial was stopped prior to its planned end date due to the evidenced efficacy of dapagliflozin in preventing adverse renal outcomes. Patients in the dapagliflozin group had a lower risk of the composite outcome (hazard ratio 0.56, 95% CI 0.45–0.68, P < 0.001), as well as a smaller mean annual decrease in eGFR than the placebo group (difference of 1.92 ml/min/1.73 m2/year, 95% CI, 1.61 to 2.24).

Finally, in agreement with the findings of DAPA-HF, DAPA-CKD also found a lower risk of CV death or HF in the dapagliflozin group (hazard ratio 0.71, 95% CI, 0.55–0.92; P = 0.009), as well as a lower risk of all-cause death (hazard ratio, 0.69; 95% CI, 0.53 to 0.88; P = 0.004). These results complement and support data from the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial [30], which demonstrated cardioprotective and renoprotective effects of another SGLT2 inhibitor, canagliflozin, in patients with T2DM and CKD. Thus, the United States and European Union have recently licensed use of dapagliflozin in CKD regardless of diabetes status. This is a caveat for patients having an eGFR above 25 ml/min/1.73 m2, as demonstrated in the DAPA-CKD population, as end-stage renal disease would ultimately require renal replacement therapy and there is no real evidence of dapagliflozin use below this level [31].

5.3.4. Real-world evidence and post-marketing surveillance

The applicability of these findings to real-world practice has been investigated in three large observational studies: CVD-REAL [32], CVD-REAL 2 [33] and CVD-REAL 3 [34].

The CVD-REAL (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors) [26] study addressed whether the decreased risk of HF and CV death conferred by SGLT2 inhibitors in experimental studies [23,25,35] translated to real-world practice.

Data from medical claims, primary and secondary care records, and national registries were used to identify patients who had filled a prescription for either an SGLT2 inhibitor or different oGLD, with no issues of a drug in the same class within the preceding year. Outcomes were compared between the SGLT2 inhibitor group and the alternative oGLD group, with robust propensity matching and sensitivity analyses carried out.

The study was multinational, collecting data from the USA, Norway, Denmark, Sweden, Germany, and the UK, and included 309,056 episodes of treatment initiation (154,528 in each group). It was found that real-world SGLT2 inhibitor use was associated with a lower rate of HHF (HR 0.61, 95% CI 0.51–0.73, P < 0.001) supporting the conclusions of DECLARE [23] and DAPA-HF [28]. The SGLT2 inhibitor group also had a lower risk of death overall (HR 0.49, 95% CI 0.41–0.57, P < 0.001). No significant heterogeneity was seen across countries, despite different national preferences for specific SGLT2 inhibitors, suggesting that the cardiovascular benefits of SGLT2 inhibitors constitute a class effect present across different drugs of the class.

Two further CVD-REAL studies, CVD-REAL 2 and 3, focused on broader cardiovascular outcomes (stroke and MI) and progression of renal disease, respectively. Both were also multinational observational studies assessing new users of various SGLT2 inhibitors compared to other oGLDs. Both studies used data from a different selection of countries for CVD-REAL, including a different selection of SGLT2 inhibitors. Results for both studies were again consistent across countries, despite different drug preferences.

In CVD-REAL 2, SGLT2 inhibitor use was associated with a lower risk of all-cause death (HR 0.51, 95% CI 0.37–0.70, P < 0.001), HHF (HR 0.64, 95% CI 0.50–0.82, P = 0.001), MI (HR 0.81, 95% CI 0.74–0.88, P < 0.001), and stroke (HR 0.68, 95% CI 0.55–0.84, p < 0.001). In CVD-REAL 3, SGLT2 inhibitor use was also associated with a reduction in the rate of eGFR decline (1 · 53 mL/min/1 · 73 m2/year, 95% CI 1 · 34–1 · 72, p < 0 · 0001). Together, these studies have supported the cardioprotective and renoprotective findings associated with dapagliflozin use seen in experimental trials.

6. Safety and tolerability

Despite all the demonstrated clinical benefits of dapagliflozin, concern remains regarding the prevalence of adverse effects (AE) related to the SGLT2 drug class [9].

Phase III clinical trials have reported contrasting outcomes regarding urinary tract infections (UTI). This has been a contentious issue, as increased glucosuria from SGLT inhibitors is a plausible mechanism by which they would increase genitourinary infection risk [36]. Pooled data from 12 dapagliflozin clinical efficacy trials in T2DM showed 7.3% and 6.5% of patients receiving 5 and 10 mg of dapagliflozin, respectively, developed UTI symptoms as compared to only 4.5% receiving a placebo [37]; however, infections were commonly mild or moderate and responded well to treatment. Although previous studies have suggested an association between dapagliflozin use and an increase in risk of UTI [38], a more recent review by Dave et al., 2019, instead demonstrated that the risk of UTIs with SGLT2 inhibitor initiation was not significantly different from that posed by other classes of second-line antidiabetic medication in real-world clinical practice [39]. Patients with T2DM are inherently predisposed to developing UTIs, with an increased risk of approximately 60% [36], and the DECLARE and DAPA-HF trials both revealed fewer UTI events among those taking dapagliflozin [23,28].

However, genital infections including fungal vulvovaginitis and balanitis are more frequently associated with dapagliflozin use. These infections were reported in 4.1–5.7% of patients, as compared to a 0.9% infection rate on placebo, in a pooled study of 4545 patients [40]. They occur more frequently in women, with 13.2% women compared to 3.3% men developing genital fungal infection in one study (aOR 4.22, 95% CI 2.48–7.19, P < 0.001) [41]. The DECLARE study supported this finding, with genital infections again more common with dapagliflozin compared to placebo (HR 8.36, 95% CI 4.19–16.68) [23]. Overall, these infections were also easily treated and rarely led to drug or study discontinuation.

The risk of more serious complications such as diabetic ketoacidosis (DKA) is rare. Results from DECLARE showed that DKA was more likely to occur in those in the dapagliflozin group compared to the control (0.3% vs 0.1%, HR 2.18, 95% CI 1.10–4.30). This occurred in a total of 27 T2DM patients, of which 22 were also receiving insulin, thus putting them at greater risk. Fournier’s gangrene has not been definitively proven as an AE of dapagliflozin; however, it has been reported during post-marketing surveillance [42]. Six cases of Fournier’s gangrene were reported during DECLARE, of which only one patient was receiving dapagliflozin. Despite conflicting reports regarding a possible increase in the risk of amputations with SGLT2 inhibitor use, particularly canagliflozin [43], this has not been demonstrated with dapagliflozin [23].

Due to SGLT2 inhibitors mechanism of action being independent of insulin, the risk of hypoglycemia is believed to be marginal. No significant increase in hypoglycemia risk is present in patients receiving dapagliflozin as monotherapy or as an adjunct to treatments, such as metformin, sitagliptin, pioglitazone, or insulin [17,19,21,22,44]. Extra caution may be required when added to medication of the sulfonylurea class; as an add-on to glimepiride, 10 mg of daily dapagliflozin increased the frequency of hypoglycemic episodes by 3.1% from a baseline of 4.8% [18].

Again, reassuringly, no major episodes of hypoglycemia were recorded. This evidence clearly supports the importance of education regarding increased awareness of hypoglycemia among this specific T2DM cohort. Currently, AEs including bladder cancer, acute kidney injury (AKI), fractures, amputation, and major hypoglycemic episodes are not believed to be significantly higher with dapagliflozin use.

7. Conclusion

With the findings of the DECLARE trial, dapagliflozin has evolved from simply being an oral antihyperglycemic agent to a therapy for HF. Considering the cardiovascular benefits, dapagliflozin demonstrated greater protection against HF as compared to less dramatic effects on secondary outcomes such as MACE. Similarly, DAPA-HF and DAPA-CKD have provided evidence that dapagliflozin has both cardio and renoprotective effects, and may reduce the risk of all-cause death in patients with HF or impaired renal function. Since these effects of dapagliflozin are seen in patients both with and without T2DM, it is likely that they are mediated through mechanisms independent of the hypoglycemic properties of SGLT2 inhibitors.

8. Expert opinion

Research developments relating to SGLT2 inhibitors have been very promising in recent years. Dapagliflozin use has been shown to be both safe and effective in both patients with T2DM and T1DM, with the drug now also licensed for use as an adjuvant to insulin in the latter cohort following pooled data from two large phase III clinical trials at DEPICT-1 and DEPICT 2 [45]. These demonstrated that adjuvant dapagliflozin in poorly controlled T1DM patients significantly reduced both their HbA1c reading and the daily insulin dose needed even up to 1 year after follow-up.

However, within the field of T2DM and dapagliflozin, it is three large randomized clinical trials (DECLARE TIMI-58, DAPA-HF, DAPA-CKD) [23,28,29] that have contributed significantly to the evidence base. Each study evaluated dapagliflozin from a different perspective, building on existing knowledge and widening the indications for its use beyond T2DM. The encouraging cardiorenal outcomes have also formed the basis for further clinical trials currently underway. Two future trials include DAPA-MI (DAPAgliflozin effects in patients without diabetes with Myocardial Infarction) [46] and DICTATE-AHF (the efficacy and safety of DapaglIflozin in aCuTe heArT failurE trial) [47].

The DAPA-MI study will aim to build on the results of the DECLARE TIMI-58 study [46] and is an international, double-blinded, parallel, randomized clinical trial aiming for completion in late 2023. It will study an estimated population of 6,400 non-diabetic patients presenting with acute MI and associated reduced left ventricular ejection fraction. Along with standard therapy, participants will be randomized to additionally receive either dapagliflozin or a placebo and then be followed up for 3 years duration. The primary outcome measure will be the occurrence of HHF or cardiovascular death. This will aim to evaluate if dapagliflozin can also be indicated for use in the acute MI population to reduce the risk of hospitalization for consequent HF.

The DICTATE-AHF trial [47] is a smaller study aiming to recruit 240 people with T2DM admitted to hospital due to hypovolemic acute heart failure (AHF). Currently, management of AHF includes optimizing chronic HF medication while administering diuretics in order to address fluid overload acutely. Unlike other trials, this will be the first study looking into the early acute phase of management in these patients. All participants will receive standard diuretic therapy with either additional dapagliflozin or a placebo. This trial has developed a clear protocol for diuretic therapy depending on the participants’ diuretic drug history in order to standardize care and allow for effective measurement of the efficacy of added dapagliflozin as an intervention. This is relevant to the care of T2DM patients as approximately a half of patients presenting with AHF are also found to have hyperglycemia. Thus, these patient cohorts are often interlinked, meaning positive outcomes from this trial will build on the already present recommended evidence for dapagliflozin use in diabetes and HF as a chronic therapy [48].

Additionally, it is important to note that two doses are available when prescribing dapagliflozin (5 mg and 10 mg); however, the studies that have demonstrated cardio- and renoprotective effects of dapagliflozin have used the 10 mg dose. It is recommended that the 10 mg dosage of dapagliflozin is considered first when prescribing for cardio-renal protection.

8.1. Where is drug likely to be in 5 years’ time?

It is estimated that seven million acute MIs occur worldwide every single year, with HF as a complication associated with poorer hospital survival [49]. As such, MI is a leading global cause of morbidity and mortality [50], and if dapagliflozin proves to be effective in preventing these outcomes, its use is likely to become much more widespread within the next 5 years, particularly with regard to patients with T2DM and acute MI.

Similarly, further evidence of the benefit of dapagliflozin in patients with T2DM and HF may see an increase in the use of the drug in patients with these two comorbidities.

The results from DAPA-CKD along with emerging data from trials of other SGLT2 inhibitors also confirm the benefit in a wide range of people with chronic kidney disease (CKD). It is likely that this class of medications will be widely used to slow decline in renal function, not just in T2DM, but in many others with CKD. An important gap is in those with T1DM; if dapagliflozin is shown to be beneficial in people with T1DM and CKD this would likely increase use in this group, despite the recognized increased risk of ketoacidosis. In this review, it could be argued that due to the significant benefits of dapagliflozin in early renal disease, which is independent of glucose-lowering, dapagliflozin could replace metformin as a first-line treatment for T2DM, as it could prevent renal complications in this group of patients. However, current guidelinesfor example, from ADA/EASD do not support this view, perhaps due to the low cost of metformin and the fact that numbers needed to treat would likely be very high, meaning it would be difficult to subsequently establish this benefit in a clinical trial [51].

Finally, dapagliflozin could potentially have beneficial effects on other macro and microvascular complications of T2DM, such as nonalcoholic fatty liver disease (NAFLD) and diabetic neuropathy due to its lowering effects on blood glucose, as well as some of the mechanisms posited for renal and cardiac protection (e.g. increased vascular compliance; lowering of blood pressure); however, this would need to be evaluated in further clinical studies.

Declaration of interest

J Wilding has received consultancy fees/clinical trial support (paid to his institution) from Astellas, AstraZeneca, Boehringer Ingelheim, Janssen Pharmaceuticals, Napp, Mundipharma, Eli Lilly and Company, Novo Nordisk, Rhythm Pharma, Sanofi and Takeda. He has also received lecture fees from AstraZeneca, Boehringer Ingelheim, Merck & Co. Napp, Novo Nordisk and Takeda. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

One referee served as an employee for Cardiovascular & Metabolic Disease Research at Bristol-Myers Squibb (BMS) and was involved with the organization that discovered dapagliflozin. The reviewer wishes to point out that they however retired from BMS in 2013 and BMS sold dapagliflozin to AstraZeneca more than five years ago. They also wish to clarify that they no longer own stock in BMS or any other company that markets diabetes drugs. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Drug summary box

Drug name (generic)	Dapagliflozin
Phase (for indication under discussion)	Launched
Indication (specific to discussion)	Type 2 diabetes
Pharmacology /mechanism of action	Sodium/glucose cotransporter 2 inhibitor
Route of administration	Oral
Chemical structure
Pivotal trial(s)	DECLARE-TIMI; DAPA-HF; DAPA-CKD; CVD-REAL

Additional information

Funding

This manuscript was not funded