Introduction
The burden of diabetes in the United States is considerable and growing. An estimated 30.3 million Americans had diabetes in 2015 (9.4% of the population) [
1], and projections suggest a prevalence of ~ 55 million by 2030 [
2], with ~ 90–95% of these individuals having type 2 diabetes (T2D) [
1].
A high proportion of diabetes-related disease burden and cost can be attributed to comorbidities and complications [
3], including congestive heart failure (HF), atherosclerotic cardiovascular disease (CVD), peripheral vascular disease, chronic kidney disease (CKD), neuropathy, and retinopathy [
1,
3]. Although the rate of diabetes-related complications is decreasing, the increasing prevalence of T2D means the number of individuals who develop diabetes-related illnesses remains substantial [
4]. There is, therefore, an urgent need to reduce T2D-associated morbidity and mortality through the effective management of glycemia, CV risk factors, and other risk factors of chronic disease.
Early intervention to achieve glycemic control and reduce CV and renal risk is important, because a high proportion of patients with T2D already have risk factors before diagnosis [
5]. In the National Health and Nutrition Examination Survey (NHANES), 61.9% of patients with undiagnosed T2D had hypertension, 82.6% had hypercholesterolemia, 56.8% had obesity, and an additional 29.5% were overweight [
5]. Current American Diabetes Association (ADA) and American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) guidelines recommend regular assessment of CV risk factors in patients with diabetes and treatment of any modifiable risk factors outside the normal range [
6,
7]. Both guidelines also emphasize the importance of patient-centered care, in which treatment is tailored to patients’ individual preferences and needs, including effects on CV outcomes, risk factors, glycemic control, body weight, and renal function [
7,
8].
Agents from two classes of glucose-lowering therapies, sodium-glucose cotransporter (SGLT)-2 inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs), have been shown to significantly reduce the incidence of CV events in patients with T2D. In large-scale CV outcomes trials (CVOTs), the SGLT-2 inhibitors empagliflozin, canagliflozin, and dapagliflozin [
9‐
11], and the GLP-1RAs liraglutide, semaglutide, dulaglutide, and albiglutide [
12‐
15], significantly reduced the risk of CV events. In addition, although the GLP-1RA exenatide once weekly did not show superiority to placebo in the overall population of the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) CVOT [
16], a follow-up analysis showed CV events were significantly reduced in patients with established CVD [
17]. While most CVOTs showed reduction of CV events in patients with CVD at baseline [
11‐
14,
17,
18], some also demonstrated this in patients without established CVD [
9,
10,
15].
This review describes the rationale for early initiation of SGLT-2 inhibitors, when the potential to modify outcomes may be greatest, to provide protection against CV events and prevent the development of HF, CKD, and microvascular complications.
This article is based on previously conducted studies and does not include any new studies with human participants or animals performed by the author.
Rationale for Early Risk Management
Evidence from clinical trials indicates that early intervention and achievement of glycemic control reduces the long-term risk of microvascular and macrovascular complications in T2D. Two landmark studies, the UK Prospective Diabetes Study (UKPDS) in patients with newly diagnosed T2D and the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study in patients with a mean T2D duration of ~ 8 years at baseline, demonstrated that intensive glycemic control [treatment with a sulfonylurea or insulin, or metformin for patients with body weight > 120% of ideal, in the UKPDS and treatment to a glycated hemoglobin A1c (HbA1c) level of < 6.5% in ADVANCE] not only reduced the occurrence of microvascular complications but also significantly reduced the long-term incidence of macrovascular events, including myocardial infarction (MI) [
19,
20].
In the Intensified Multifactorial Intervention in Patients With Type 2 Diabetes and Microalbuminuria (Steno-2) study (median diabetes duration of 4–6 years at baseline), intensive multifactorial treatment that targeted several CV risk factors was associated with significant reductions in the risk of mortality (45%;
p = 0.005), CV events (45%;
p < 0.001), and microvascular complications (range, 33%–48%) compared with conventional therapy over 21.2 years of follow-up [
21]. However, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study [
22] and the Veterans Affairs Diabetes Trial (VADT) [
23], in which the duration of diabetes at baseline was longer (median of 10 years and mean of 11.5 years, respectively), the results are less clear. Although these studies showed no significant effect of intensive glycemic control on CV complications [
22,
23], the intensive therapy arm of the ACCORD study was stopped early (after 3.5 years) because of a significant increase in mortality [
22]. This was despite a significantly reduced risk of nonfatal MI with intensive therapy [
22].
The ADA, American Heart Association (AHA), and American College of Cardiology (ACC) reviewed these apparently contradictory data and determined that the differences were at least partly due to patient characteristics [
24]. Patients most likely to have reduced CVD risk with intensive glycemic control were those with a shorter T2D duration who had not yet developed atherosclerosis, whereas, in older or frail patients, those with a long duration of T2D or patients with advanced atherosclerotic disease, the risks associated with intensive glycemic control may exceed its benefits [
24]. In a post hoc analysis of ACCORD, the greatest risk of mortality with intensive therapy appeared to be among patients who continued to have an HbA1c level of > 7.0% [
25], highlighting the need for personalized medicine and individualized treatment goals, as recommended by treatment guidelines [
6,
7]. These findings were supported by a subsequent analysis of VADT, which found that intensive glycemic control reduced the risk of CV events in patients with a T2D duration of < 15 years, but was associated with increased risk in those with a disease duration of ≥ 15 years and was potentially harmful in those with a disease duration of ≥ 20 years [
26].
A 10-year post-trial follow-up of UKPDS found a significant reduction in the risk of CV events in patients with newly diagnosed T2D who had received intensive glycemic control, but only after enough time had passed to demonstrate an effect on these outcomes [
19]. This study demonstrated a legacy effect of early intensive therapy because the difference in the CV event rate 10 years post-trial was apparent even though there was no longer a difference in HbA1c levels between the intensive and conventional therapy groups [
19].
A similar legacy effect was seen in patients with type 1 diabetes who had received intensive or conventional therapy for 6.5 years in the Diabetes Control and Complications Trial (DCCT) [
27]. Thirty-year post-trial follow-up data showed that, among young patients who had not yet developed CVD, early intensive diabetes therapy significantly reduced the later risk of a CV event by 30% compared with conventional therapy (
p = 0.016) [
27].
Real-world evidence has also shown a legacy effect of early intensive glycemic control in patients with T2D. The Diabetes & Aging Study found that, after 13 years’ follow-up, patients who achieved an HbA1c of < 6.5% during the first year after diagnosis had a lower risk of microvascular and macrovascular complications than those with HbA1c ≥ 6.5% and a lower mortality risk than those with HbA1c ≥ 7.0% during the first year [
28].
Early use of combination therapy in patients with newly diagnosed T2D has also been shown to reduce the progression of atherosclerosis, in addition to improving glycemic control, compared with conventional therapy [
29,
30]. In the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT) study, first-line treatment with exenatide, pioglitazone, and metformin was associated with a greater reduction in HbA1c and more patients achieving glycemic targets after 2 years compared with initial treatment with metformin and sequential addition of a sulfonylurea and insulin glargine [
29]. The greater reduction in HbA1c was maintained at 6 years, and the early combination therapy group also had significantly reduced carotid intimal media thickness compared with the conventional therapy group [
30].
These studies demonstrate that early achievement of glycemic targets has the greatest effect on macrovascular complications, with a legacy effect even if intensive glycemic control is not maintained. However, it also raises the question whether continued intensive therapy would provide much earlier benefits beyond the legacy effect.
Mechanism of Glycemic Control of SGLT-2 Inhibitors
SGLT-2 inhibitors act by insulin-independent mechanisms to improve glycemic control and CV risk factors in patients with T2D. SGLT-2 inhibitors reduce reabsorption of glucose from the proximal tubule of the kidneys, which in turn increases glucosuria [
31]. Because inhibition of SGLT-2 also reduces sodium reabsorption, SGLT-2 inhibitors have a natriuretic effect, which may partially explain the observed reduction in blood pressure (BP) [
32]. These reductions in BP are not accompanied by increases in heart rate, indicating a lack of reflex sympathetic nervous system activation [
33]. The natriuretic effects of SGLT-2 inhibitors, which may lead to reductions in plasma volume and cardiac preload, also occur without activation of the renin–angiotensin–aldosterone system [
34]. Although the specific effects of SGLT-2 inhibitors on intrarenal hemodynamics are unclear, changes in tubuloglomerular feedback may be involved in neurohormonal stimulation and fluid and electrolyte homeostasis, and the net effect of SGLT-2 inhibition in the diabetic kidney appears to be protective and associated with preservation of renal function [
34].
SGLT-2 inhibitors are also associated with increased lipolysis, with an early shift in substrate utilization from carbohydrates to fats [
32]. Coupled with increased glucosuria and other as yet unknown mechanisms, such as a reduction in sympathetic nervous system activity [
35], the net effect of SGLT-2 inhibitor treatment is a reduction in both body weight and fat mass [
32]. Studies have also shown decreases in hepatic fat [
36,
37] and fibrosis [
37‐
39] with SGLT-2 inhibitors in patients with T2D and nonalcoholic fatty liver disease, and reduced epicardial fat accumulation in patients with T2D [
40]. Reductions in body weight and BP (independent of glucosuria) have also been observed with SGLT-2 inhibitor therapy in patients with T2D and CKD [estimated glomerular filtration rate (eGFR) 30–59 mL/min/1.73 m
2] in whom there is reduced glucosuria compared to patients with normal or mildly impaired renal function [
41].
Because the SGLT-2 inhibitor mechanism of action is independent of insulin, and differs from those of other classes of glucose-lowering therapy, which typically affect beta-cell function, hepatic glucose production, or glucose uptake by the muscles, SGLT-2 inhibitors can potentially act synergistically with other agents [
32]. Unlike other glucose-lowering therapy classes, efficacy with SGLT-2 inhibitors does not decline with worsening beta-cell function [
32]. Furthermore, SGLT-2 inhibitors are associated with a low risk of hypoglycemia [
31].
Mechanisms of CV and Renal Protection with SGLT-2 Inhibitors
As described in the section “
Mechanism of glycemic control of SGLT-2 inhibitors”, the effects of glycemic control on CV outcomes can take years to manifest [
19]; therefore, the observed effects of SGLT-2 inhibitors in the CVOTs and the CVD-REAL study are likely to result from mechanisms beyond glycemic control [
33]. The cardioprotective and renoprotective effects of SGLT-2 inhibitors in patients with T2D are likely multifactorial and encompass additive effects on glycemia and CV risk factors (including BP and body weight) [
58,
59]; there are potentially other pathophysiologic mechanisms of atherosclerosis (Table
1) [
58]. The effect of SGLT-2 inhibitors on renal function also plays an important role in CV risk reduction.
Table 1
Change from baseline in cardiovascular risk factors with SGLT-2 inhibitors [
58]
Blood pressure (mm Hg) | |
Systolic | − 2.46 (− 2.86, − 2.06) |
Diastolic | − 1.46 (− 1.82, − 1.09) |
Lipid levels (mg/dL) | |
Total cholesterol | 0.77 (0.33, 1.21) |
HDL cholesterol | 3.89 (3.23, 4.56) |
Triglycerides | − 2.08 (− 2.51, − 1.64) |
Lipid levels, mmol/L | |
Total cholesterol | 0.02 (0.01, 0.03) |
HDL cholesterol | 0.10 (0.08, 0.12) |
Triglycerides | − 0.02 (− 0.03, − 0.02) |
Glycemic measures | |
Fasting blood glucose (mg/dL) | − 2.40 (− 2.68, − 2.11) |
Fasting blood glucose (mmol/L) | − 0.13 (− 0.15, − 0.12) |
HbA1c (%) | − 2.48 (− 2.73, − 2.24) |
Adiposity indicators | |
Body weight (kg) | − 1.88 (− 2.11, − 1.66) |
Waist circumference (cm) | − 2.89 (− 4.32, − 1.46) |
Indicators of renal function | |
eGFR (mL/min/1.73 m2) | − 0.98 (− 1.69, − 0.27) |
Urea (mmol/L) | 0.99 (0.35, 1.64) |
There is emerging evidence that, in addition to their effects on CV risk factors, SGLT-2 inhibitors may have other direct effects on CV function. Because of their natriuretic and diuretic effects, SGLT-2 inhibitors reduce plasma volume and therefore lower cardiac preload [
34]. Unloading the heart by this mechanism may explain why SGLT-2 inhibitors have beneficial effects on left ventricular diastolic function, as well as on left ventricular mass [
60,
61]. The reduction in plasma volume with SGLT-2 inhibitors does not appear to be associated with a reflex increase in sympathetic activity [
60]. Whether SGLT-2 inhibitors suppress abnormal sympathetic activity, thereby providing patients with diabetes some protection against arrhythmias in the acute setting, is currently being investigated [
62].
Another potential mechanism of benefit for SGLT-2 inhibitors in CVD is through mediation of improvements in endothelial function [
63,
64]. The Dapagliflozin Effectiveness on Vascular Endothelial Function and Glycemic Control in T2DM (DEFENCE) study found that treatment with dapagliflozin for 16 weeks significantly improved flow-mediated dilation in the brachial artery compared with metformin [
64]. Patients in this study had early T2D (mean duration, ~ 6 years) and good glycemic control (mean A1C, < 7%) [
64].
SGLT-2 inhibitor therapy is also associated with an increase in ketone bodies, which results in the cardiac uptake and oxidization of β-hydroxybutyrate rather than fatty acids [
65]. This may promote increased hepatic synthesis of ketones (including β-hydroxybutyrate) that can be used as an alternative cardiac fuel, potentially providing a more efficient energy source than either glucose or fatty acids [
66].
The beneficial effects of SGLT-2 inhibitors in HF outcomes may result from their ability to inhibit sodium–hydrogen exchangers in the heart and kidneys, which could potentially increase the natriuretic effects of other agents routinely administered to patients with HF (e.g., diuretics and mineralocorticoid receptor antagonists) [
67]. This may attenuate cardiomyocyte injury and prevent the onset of left ventricular hypertrophy and ultimately HF [
67].
Preliminary studies suggest SGLT-2 inhibitors reduce epicardial fat [
68], and may also exhibit antifibrotic effects in myocardial and pericardial cells [
69‐
72]. In a study of postinfarction rats, dapagliflozin administration led to decreases in myofibroblast infiltration and collagen deposition that were independent of the glucose-lowering effects [
70]. At the cellular level, other mechanisms are likely also involved in the renoprotective and cardioprotective effects of SGLT-2 inhibitors, including anti-inflammatory and anti-oxidative effects [
73], although further research is required to elucidate these mechanisms.
Safety Considerations for SGLT-2 Inhibitor Therapy
SGLT-2 inhibitors are generally well tolerated and do not increase the risk of hypoglycemia when used with metformin, GLP-1RAs, DPP-4 inhibitors, or thiazolidinediones [
74,
75]. The most common adverse events with SGLT-2 inhibitors are genital mycotic infections [
74,
76‐
79]. These occur in up to 10% of patients and in both men and women, although the incidence is lower among circumcised men [
76,
78]. Genital mycotic infections are usually of mild to moderate intensity and can be mitigated through hygiene and the occasional use of antifungal agents. However, an alternative to SGLT-2 inhibitor therapy may be preferable for patients with a history of multiple yeast infections.
Volume depletion-related adverse events, including hypotension and dizziness, have also been reported with SGLT-2 inhibitor therapy [
76‐
79]. Volume depletion occurs more frequently among patients who are older, have a longer duration of T2D, and have eGFR < 60 mL/min/1.73 m
2, and those receiving a concomitant diuretic, angiotensin-converting enzyme inhibitor, or angiotensin receptor blocker therapy [
76‐
79]. Before starting treatment with SGLT-2 inhibitors, volume status should be assessed and hypovolemia corrected. Increasing fluid intake and reducing or discontinuing diuretic treatment can reduce the risk of volume depletion-related events.
Serious, but rare, adverse events associated with SGLT-2 inhibitor therapy include diabetic ketoacidosis (DKA), amputations, fractures, and Fournier’s gangrene [
76‐
79]. The risk of such events can be reduced by assessing patients for risk factors before starting treatment with SGLT-2 inhibitors, and monitoring for, and educating patients about, the signs and symptoms of these events during treatment.
DKA primarily occurs in patients who are insulin-deficient, and is generally not seen in those with earlier stage T2D [
80]. Patients taking SGLT-2 inhibitors who develop DKA may have normal or less elevated than anticipated blood glucose levels because of the reduced threshold for glucose excretion with this drug class [
80]. Patients should be evaluated for predisposing factors for DKA before starting treatment with an SGLT-2 inhibitor [
76‐
80]. To reduce the risk of DKA, SGLT-2 inhibitor therapy should be temporarily discontinued 1–2 days before elective surgery, and before extreme physical activity such as marathon running, and stopped immediately in patients with sepsis or undergoing emergency surgery [
80]. In addition, excessive alcohol consumption and ketogenic or very low carbohydrate diets should be avoided [
80].
An increased risk of lower limb amputations was seen with canagliflozin in the CANVAS program but not with other SGLT-2 inhibitors in CVOTs [
9‐
11]. However, while amputations were more frequent with canagliflozin versus placebo in the CANVAS program, this was not observed in the CREDENCE trial [
9,
53]. Amputations were more common among patients with a prior history of amputations and among those with severe vascular disease or neuropathy [
76,
81]. SGLT-2 inhibitor therapy should be avoided in patients considered to be at increased risk of lower limb amputation, and discontinued in patients who develop ulcers and infections of the lower limbs [
76].
Fractures were previously a concern with SGLT-2 inhibitor therapy, but long-term data do not suggest an increased risk [
82]. However, factors that may increase a patient’s risk for fracture should be considered when prescribing an SGLT-2 inhibitor therapy [
76].
Fournier’s gangrene is a rare but potentially life-threatening complication of SGLT-2 inhibitor therapy. This adverse event should be managed with broad-spectrum antibacterial agents and surgical debridement as necessary; SGLT-2 inhibitor therapy should be discontinued [
76‐
79].
Although serious adverse events have been reported with SGLT-2 inhibitor therapy, the risk should be weighed against the potential benefits of reduced CV and renal complications. Furthermore, the risk of adverse events is likely to be lower among patients with earlier-stage T2D than that reported in clinical trials and real-world studies, because those data were obtained from across the patient population, including older patients and those with longer duration or greater severity of T2D [
80].
Place of SGLT-2 Inhibitors in Early Diabetes Therapy
Current ADA guidelines recommend monotherapy with metformin in combination with lifestyle management as first-line therapy from the time of T2D diagnosis to achieve glycemic control [
8]. AACE/ACE guidelines also recommend that pharmacologic treatment be started together with lifestyle management following diagnosis [
7]. Patients with an HbA1c < 7.5% at diagnosis should receive monotherapy, with metformin being the preferred first-line treatment, although other agents can also be used [
7]. For patients whose HbA1c is ≥ 7.5% at diagnosis, AACE/ACE guidelines recommend starting on dual therapy with metformin and another class of glucose-lowering therapy, with GLP-1RAs and SGLT-2 inhibitors preferred [
7]. For patients with HbA1c > 1.5% above goal at diagnosis, the ADA and European Association for the Study of Diabetes (EASD) guidelines recommend first-line treatment with a dual combination [
8,
83]. The ADA and EASD recommend an SGLT-2 inhibitor as the first post-metformin treatment in patients with established CVD, congestive HF, or CKD [
8,
83]. The ACC/AHA primary prevention guidelines also recommend SGLT-2 inhibitor or GLP-1RA therapy after first-line metformin to reduce CV risk in patients with T2D and additional CV risk factors [
84].
The AACE/ACE and ADA guidelines recommend that patients should be initially assessed every 3 months, and additional glucose-lowering treatments should be added as needed at each assessment to meet glycemic targets [
7,
8]. For add-on therapy in patients without CVD, the ADA guidelines state that treatment choice should be guided by patient needs, including avoidance of adverse effects (e.g., hypoglycemia and body weight gain), cost considerations, or other needs [
8], while the AACE/ACE guidelines recommend a hierarchy of use for add-on glucose-lowering therapy based on safety and efficacy and consideration of the properties of each agent for individual patients [
7]. The AACE/ACE guidelines also recommend that GLP-1RAs or SGLT-2 inhibitors with proven CV benefits should be prescribed to patients with CVD regardless of glucose level [
7]. The ADA/EASD consensus statement not only recommends SGLT-2 inhibitors in patients with HF or a high risk of HF but also recommends that their use be considered in patients with CKD (with or without CVD) to prevent or reduce progression of CKD [
83], although there is some debate regarding the quality of evidence for these recommendations. In patients with T2D and overweight or obesity (without CVD or CKD), glucose-lowering therapy should include add-on therapy with an SGLT-2 inhibitor (in those with an adequate eGFR) or a GLP-1RA with good weight loss efficacy, in addition to lifestyle management, nonsurgical energy restriction, and consideration of weight loss medications and metabolic surgery [
83].
Each of the SGLT-2 inhibitors approved in the United States is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with T2D [
76‐
79]; empagliflozin has an additional indication for reducing the risk of CV death [
77] and canagliflozin is indicated to reduce the risk of MACE [
76] in patients with both T2D and established CVD.
A PubMed search conducted in July 2019 identified 15 studies in which SGLT-2 inhibitors were used early in the course of T2D [
64,
85‐
97]. Ten studies evaluated dapagliflozin [
64,
85‐
89,
91,
93,
94,
98], two studied canagliflozin [
90,
97], two assessed empagliflozin [
92,
96], and one evaluated ertugliflozin [
95]. Seven studies investigated SGLT-2 inhibitors as monotherapy [
85‐
90,
98], while, in eight studies, SGLT-2 inhibitors were given in combination with metformin (Table
2) [
64,
91‐
97].
Table 2
Studies in which sodium-glucose cotransporter-2 inhibitors have been used in combination with MET in patients with early-stage type 2 diabetes
| Study 1: randomized, double-blind | Treatment-naive (mean duration of diabetes: 2 years) | MET + PBO | 201 | 24 | − 1.35% |
DAPA 5 mg/day + PBO | 203 | − 1.19% |
DAPA 5 mg/day + MET | 194 | − 2.05%* |
Study 2: randomized, double-blind | MET + PBO | 208 | − 1.44% |
DAPA 10 mg/day + PBO | 219 | − 1.45% |
DAPA 10 mg/day + MET | 211 | − 1.98%* |
Hadjadj et al., 2016 [ 96] | Randomized, double-blind | Drug-naive | EMPA 12.5 mg BID + MET 1000 mg BID | 169 | 24 | − 2.08%†,‡ |
EMPA 12.5 mg BID + MET 500 mg BID | 165 | − 1.93%‡,§ |
EMPA 5 mg BID + MET 1000 mg BID | 167 | − 2.07%†,‡ |
EMPA 5 mg BID + MET 500 mg BID | 161 | − 1.98%‡,§ |
EMPA 25 mg OD | 164 | − 1.36% |
EMPA 10 mg OD | 169 | − 1.35% |
MET 1000 mg BID | 164 | − 1.75% |
MET 500 mg BID | 168 | − 1.18% |
Muscelli et al., 2016 [ 92] | Open-label | Treatment-naive | EMPA 25 mg/day + MET | 32 | 4 | NR† |
On stable MET monotherapy ≥ 1500 mg for ≥ 3 months | EMPA 25 mg/day + MET | 34 | NR† |
Rosenstock et al., 2016 [ 97] | Randomized, double-blind | Drug-naive mean duration of diabetes 3 years) | CANA 100 mg/day + MET | 237 | 26 | − 1.77§,\\ |
CANA 300 mg/day + MET | 237 | − 1.78%§,\\ |
CANA 100 mg/day | 237 | − 1.37% |
CANA 300 mg/day | 238 | − 1.42% |
MET | 237 | − 1.30% |
Shigiyama et al., 2017 [ 64] | Randomized, open-label | On stable MET ≥ 750 mg ± another oral glucose-lowering therapy for ≥ 12 weeks (mean duration of diabetes: ~ 6 years) | DAPA 5 mg/day + MET 750 mg/day | 37 | 16 | − 0.2%** |
MET 1500 mg/day | 37 | − 0.4%** |
Handelsman et al., 2018 [ 93] | Randomized, double-blind | On stable MET ≥ 1500 mg for ≥ 8 weeks and no other glucose-lowering therapy for > 2 weeks | DAPA 10 mg/day + SAXA 5 mg/day + MET | 232 | 52 | − 1.29% |
SITA 100 mg/day + MET | 229 | − 0.81% |
Mathieu et al., 2018 [ 94] | Open-label | On stable MET monotherapy ≥ 1500 mg for ≥ 8 weeks (mean duration of diabetes: 7 years) | DAPA 10 mg/day + MET | 482 | 16 | − 1.6% |
SAXA 5 mg/day + MET | 349 | − 1.3% |
Pratley et al., 2018 [ 95] | Randomized, double-blind | On stable MET monotherapy ≥ 1500 mg for ≥ 8 weeks | ERTU 5 mg/day + MET | 250 | 52 | − 1.0% |
ERTU 15 mg/day + MET | 248 | − 0.9% |
SITA 100 mg/day + MET | 247 | − 0.8% |
ERTU 5 mg/day + SITA 100 mg/day + MET | 243 | − 1.4% |
ERTU 15 mg/day + SITA 100 mg/day + MET | 244 | − 1.4% |
| Randomized, open-label, crossover | Treatment-naive | DAPA 10 mg/day | 22 | 8 per treatment | − 0.5%†† |
MET 1000 mg/day titrated to ≤ 2000 mg/day | 22 | − 0.5%** |
The studies that evaluated the combination of an SGLT-2 inhibitor plus metformin demonstrated a significant difference in HbA1c reduction compared with the same dose of metformin as monotherapy [
64,
91,
96,
97] or compared with baseline [
92]; the magnitude of the HbA1c reduction varied depending on study duration and background therapy at the start of treatment. Two studies have also demonstrated that the magnitude of the change in HbA1c with an SGLT-2 inhibitor, with or without metformin, was similar in treatment-naive patients as in patients who had already received metformin [
92] or insulin with metformin, pioglitazone, or rosiglitazone [
86]. In a study of patients with T2D receiving stable metformin therapy, early addition of dapagliflozin plus saxagliptin was associated with a significantly greater reduction in HbA1c after 26 weeks compared with addition of sitagliptin (
p = 0.0008); the between-group difference in HbA1c reduction increased at 52 weeks [
93]. Similarly, in the 52-week Evaluation of Ertugliflozin Efficacy and Safety Factorial (VERTIS FACTORIAL) study, significantly greater HbA1c reductions were observed with the combination of ertugliflozin plus sitagliptin as add-on therapy to metformin versus those with either agent individually after 26 weeks of treatment (
p < 0.001), with sustained HbA1c reductions at 52 weeks [
95].
In addition to being the guideline-recommended approach, early combination therapy in T2D makes clinical sense for several reasons [
99]. First, a meta-analysis of clinical trials has demonstrated that the early use of combination therapy significantly increases the likelihood of achieving the glycemic target of HbA1c < 7% compared with metformin monotherapy [
100]. Combining drugs with different mechanisms of action will have an additive effect on glycemic control while using lower doses of each drug, thereby reducing the potential for adverse events [
99].
Second, the number of therapy choices to include in combination treatment is greatest early in the course of the disease when patients are relatively young and before they have developed significant comorbidities, including renal impairment, which may preclude the use of certain drugs. SGLT-2 inhibitors can be used without dose reduction in patients with mild-to-moderate renal impairment [
74], but, from current evidence, they are not recommended in patients with advanced kidney disease (eGFR < 45 mL/min/1.73 m
2 for canagliflozin, dapagliflozin and empagliflozin and < 60 mL/min/1.73 m
2 for ertugliflozin) and are contraindicated in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m
2) [
76‐
79]. Another reason for using SGLT-2 inhibitors early in the course of T2D is the likelihood of response to treatment, perhaps because renal function is generally better. A multivariate logistic regression analysis found that, in clinical practice, shorter T2D duration was a significant predictor of response to dapagliflozin [
101]. Even among older patients (mean age at diagnosis, 57 years), early intensive glycemic control has shown benefit, with reduced risk of mortality and microvascular and macrovascular complications among those with HbA1c < 6.5% during the first year after treatment [
28]. These findings underscore the potential role of SGLT-2 inhibitors in early therapy.