|Year : 2019 | Volume
| Issue : 1 | Page : 150-158
Cardiovascular effects of sodium glucose co-transporter-2 inhibitors in patients with type 2 diabetes mellitus
Surender Kumar1, Pradeep G Talwalkar2, Sambit Das3, Soumik Goswami4
1 Department Endocrinology, Sir Ganga Ram Hospital, New Delhi, India
2 Department of Diabetes, Talwalkar Diabetes Clinic, Mumbai, Maharashtra, India
3 Department Endocrinology, Apollo Hospital, Bhubaneswar, Orissa, India
4 Department Endocrinology, NRS Medical College, Kolkata, West Bengal, India
|Date of Web Publication||18-Mar-2019|
Department Endocrinology, Sir Ganga Ram Hospital, New Delhi
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Type 2 diabetes mellitus (T2DM), the leading type of diabetes, has a typical association with coronary heart disease. In India, patients with diabetes are at an increased risk of developing coronary disease as compared to people without diabetes and this suggests the requirement of intensive treatment of cardiovascular (CV) risk factors. Consequently, there is a need for an intervention that could target CV risk factors in multiple paths beyond hyperglycemic control alone. Although metformin is the mainstay of treatment in most of the patients with T2DM, a second line of treatment with anti-hyperglycemic agent is warranted in patients with T2DM in the management of CV risk factors beyond glycemic control. Sodium glucose co-transporter-2 (SGLT-2) inhibitors, the oral hypoglycemic drug, that act independent of insulin secretion are associated with a reduced risk of hypoglycemia which is associated with the increased risk of CV events. Moreover, it has been observed that the use of SGLT-2 inhibitors in patients with T2DM is associated with reductions in blood pressure and body weight beyond improved glycemic control. In this article, the clinical efficacy, safety, and tolerability of SGLT-2 inhibitors on glycemic, nonglycemic parameters, and CV outcome including data from the EMPA-REG OUTCOME study are discussed. The EMPA-REG OUTCOME study is the first CV outcome study that demonstrated the association of a glucose lowering agent with the reduced CV mortality and all-cause mortality, and reduced hospitalization for heart failure in patients with T2DM at high risk of CV events. Although the mode of action associated with the CV benefits remains unknown, data from ongoing trials including DECLARE-TIMI (Dapagliflozin Effect on CV Events) and CANVAS (Canagliflozin CV Assessment Study) trials potentially can validate the class-effect for SGLT-2 inhibitors regarding the CV outcomes.
Keywords: Cardiovascular benefits, sodium glucose co-transporter-2 inhibitors, type 2 diabetes mellitus
|How to cite this article:|
Kumar S, Talwalkar PG, Das S, Goswami S. Cardiovascular effects of sodium glucose co-transporter-2 inhibitors in patients with type 2 diabetes mellitus. Indian J Endocr Metab 2019;23:150-8
|How to cite this URL:|
Kumar S, Talwalkar PG, Das S, Goswami S. Cardiovascular effects of sodium glucose co-transporter-2 inhibitors in patients with type 2 diabetes mellitus. Indian J Endocr Metab [serial online] 2019 [cited 2019 Apr 21];23:150-8. Available from: http://www.ijem.in/text.asp?2019/23/1/150/254439
| Type 2 Diabetes and Cardiovascular Disease|| |
In 2014, the World Health Organization estimated that 422 million people had diabetes globally and the prevalence of diabetes among adults >18 years of age was 8.5%. India alone had more than 69 million individuals in 2015 with diabetes and with a predicted 101 million individuals being affected by 2030. Type 2 diabetes mellitus (T2DM), a leading type of diabetes, has a characteristic association with coronary heart disease (CHD). Patients with diabetes have 2- to 4-fold increased risk of developing coronary disease as compared to people without diabetes. Furthermore, 65%–75% of deaths in people with diabetes are considered to be due to the cardiovascular disease (CVD). In addition, it has been observed that patients with T2DM who had no prior myocardial infarction (MI) have comparable risk of MI as patients without diabetes who had prior MI. These data suggest the requirement of intensive treatment of cardiovascular (CV) risk factors in patients with T2DM.
People of Indian Asian origin, who comprise over a fifth of the world's population, are referred as “Asian Indian Phenotype” which denotes the combination of clinical, biochemical, and metabolic abnormalities [Figure 1] that predispose South Asian origin to develop diabetes and CHD.
|Figure 1: Asian Indian phenotype that predispose to develop diabetes and coronary heart disease|
Click here to view
In India, with the socioeconomic transformation, advanced ageing, rapidly increasing levels of overweight, and individuals and children with prediabetes (impaired glucose regulation), increase in T2DM and CHD will result in increased burden in the future.
Despite a normal body mass index by international standards, the increased prevalence of CV risk factors, T2DM, and an earlier onset of CHD among South Asians explains that this population is more susceptible to diabetes and CVD, and that these conditions are interlinked.
Although hyperglycemia remains as the major risk factor for microvascular complications, its association with CV outcomes from the intensive glycemic control intervention still remains debatable. As multiple CV risk factors beyond hyperglycemia are associated with T2DM, a multifactorial approach beyond glucose control including management of blood pressure, lipids and weight, cessation of smoking and anti-platelet therapy, if indicated, are recommended., Considering these recommendations, in most patients, it remains challenging to achieve the therapeutic goals owing to the progressive nature of T2DM and the characteristics of the currently available drugs that target only hyperglycemia. Consequently, there is a need for an intervention that could target CV risk factors in multiple paths beyond hyperglycemic control alone.,
As the clinical efficacy of a particular intervention on CV risk potentially depends upon the mode of action of that specific drug, the safety and clinical efficacy of drugs including sulfonylurea (SU), glinides, metformin, thiazolidinediones, insulin, glucagon-like peptide-1 receptor analogues, or dipeptidyl-peptidase-4 (DPP-4) inhibitors on CV events in patients with T2DM still remain unreliable.
Although metformin is the first-line of drug in most of the patients with T2DM, a second line anti-hyperglycemic agents (AHAs) is required in patients with T2DM in the management of hyperglycemia as well as CV risk factors. SUs, one of the traditional AHAs commonly prescribed in patients with DM, are usually associated with weight gain and hypoglycemia, the major determinants of CV risks. Although it is not well established, SUs potentially can cause all-cause mortality and CV-mortality. In addition, DPP-4 inhibitors, the recent addition to the armamentarium in the management of T2DM, have also failed to show CV benefits; trials including TECOS, SAVOR-TIMI53, and EXAMINE  that involved sitagliptin, saxagliptin, and alogliptin showed a neutral effect on CV outcomes among patients with T2DM. Although gliptins are demonstrated to reduce CV risk factors in the preclinical studies and systematic analysis, its neutral effect on the CV outcomes potentially due to the short-term duration of study and involving patients predominantly of high-risk patients. The results of these trials implicate that as the macrovascular complications might be a late complication of the progressive T2DM, an adequate duration of treatment is required. Moreover, in patients with established CV risk, it might be more challenging to reduce the CV risk factors that persist with these treatments.
| Cardiovascular Markers and Sodium Glucose Co-Transporter-2 Inhibitors|| |
With the available evidence that the multiple CV risk factors along with hyperglycemia coexist in most of the patients with T2DM, multifactorial approach is required to address the CV risk factors. As sodium glucose co-transporter-2 (SGLT-2) inhibitors act independent of insulin secretion, these inhibitors are associated with a reduced risk of hypoglycemia that is associated with the increased CV events. Besides improved glycemic control with SGLT-2 inhibitor, it also improves a range of metabolic and hemodynamic factors that increase the risk of CVD with its unique mechanism of action. Moreover, it has been demonstrated that the use of SGLT-2 inhibitors in patients with T2DM are associated with weight loss and reduced visceral fat, reductions in urinary albumin excretion, reductions in blood pressure, increase in high-density lipoprotein and reduced triglycerides, improved endothelial function that reduce arterial stiffness and reductions in uric acid  [Figure 2].
|Figure 2: Potential cardiovascular effects of sodium glucose co-transporter-2 inhibitors|
Click here to view
| Sodium Glucose Co-Transporter-2 Inhibitors and Its Mechanism of Action|| |
Kidney plays a vital role in normal glucose homeostasis by balancing the amount of glucose filtered from the plasma into the renal glomerular filtrate and the amount reabsorbed from this filtrate and returned to the blood circulation.
SGLT-2 with a low affinity but high capacity for glucose transport mediates more than 90% of reabsorption of the filtered glucose, while SGLT-1 with a high affinity and low capacity for glucose facilitates only 10% of the renal absorption of the glucose. Owing to the highly efficient reabsorption of glucose with SGLT-2, drugs that selectively inhibit SGLT-2 have a potentially significant role in the management of diabetes.
The inhibition of SGLT-2, which results in the inhibition of renal glucose reabsorption [Figure 3], is a novel treatment strategy for T2DM owing to the insulin-independent mechanism of action.
|Figure 3: Renal glucose reabsorption before and after sodium glucose co-transporter-2 inhibition|
Click here to view
As depicted in the schematic representation, with the increase in plasma glucose concentration, the reabsorption of glucose also increases gradually. When the plasma glucose level is <200 mg/100 ml, there is no excretion of glucose in the urine. The maximum ability of the renal tubule to reabsorb glucose or the transport maximum for glucose is exceeded as the plasma glucose level reaches a threshold of around 200–250 mg/100 ml. When it passes this threshold, excretion of glucose in the urine ensues. Owing to the physiological disparity between each nephron, the actual and theoretical threshold for both reabsorption and excretion also varies and this is called “Splay”. SGLT-2 inhibitors reduce the renal glucose threshold and thus, resulting in increased urinary glucose excretion (UGE).
With the reduction in the renal threshold for glucose excretion, SGLT-2 inhibitors prevent the renal reabsorption of glucose and thereby, increase the UGE and improve glycemic control. The inhibition of SGLT-2 leads to the hindrance of only ~30%–50% renal reabsorption of the glucose. They act independent of insulin secretion and thus are not associated with any risk of hypoglycemia. They can be used as monotherapy or combination therapy with other drugs. In addition, owing to its osmotic diuretic effect, it potentially may reduce blood pressure and may also be associated with weight loss. Considering these advantages, SGLT-2 inhibitors may have a revolutionary role in the management of diabetes.,
Several clinical trials have demonstrated that SGLT-2 inhibitors as monotherapy and add-on therapy are efficacious in patients with T2DM inadequately controlled with conventional AHAs.,,,, Based on the agent and dosage used, SGLT-2 inhibitors reduce glycosylated hemoglobin by 0.5%–1% and fasting plasma glucose (FPG) by 15–35 mg/dL. Moreover, SGLT-2 inhibitors are also associated with modest reductions in weight (−1.5–−3.5 kg) and systolic blood pressure (SBP) (−3–−5 mm Hg). Although increased urination and the genital mycotic infections are the most common adverse effects associated with the use of SGLT-2 inhibitors, it is well tolerated and associated with the reduced risk of hypoglycemia.,,,,
In addition, several studies, which investigated the physiologic response to SGLT-2 inhibitors-induced glycosuria in patients with T2DM, demonstrated that it improved β cell function and insulin sensitivity regardless of the decrease in insulin secretion and tissue glucose disposal and the increase in endogenous glucose production. As a result, SGLT-2 inhibitors-induced glycosuria resulted with the fasting and postprandial glycemia got reduced [Figure 4].,,
|Figure 4: β-cell glucose sensitivity before and after treatment with dapagliflozin|
Click here to view
Although there have been reports of diabetic ketoacidosis (DKA) associated with the use of SGLT-2 inhibitors in patients with T1DM and T2DM, lesser frequency of DKA was reported in patients with T2DM. Clinical trials which investigated the efficacy and safety of SGLT-2 inhibitors in patients with T2DM demonstrated that canagliflozin associated with 0.07% of DKA in >17,500 patients, dapagliflozin with <0.1% in >18,000 patients and empagliflozin with <0.1% for blinded DKA events in ≈ 7000 patients.,,
With the significantly increased association of T2DM with the CV risk, numerous guidelines highlight the need to prevent and reduce CV complications. Prevailing evidence suggest that the glycemic control plays a vital role in the reduction of the CV complications; however, it still remains debatable about the effect of glucose control over the CV outcomes from the randomized trials that involves the intensive glycemic control.
As per the American Association of Clinical Endocrinologists' guideline recommendation, SGLT-2 inhibitor is the acceptable alternative to metformin among patients with recent-onset T2DM or mild hyperglycemia (A1c <7.5%). In patients who present with an A1c >7.5%, metformin plus another agent including SGLT-2 inhibitor in addition to lifestyle therapy is recommended. As per the American Diabetes Association guideline, SGLT-2 inhibitors are added to the background of metformin or sulfonylurea plus metformin if glycemic goals are not met.
SGLT-2 inhibitors that are approved for use in the management of T2DM in the United States, European Union, and other countries are canagliflozin, dapagliflozin, and empagliflozin. Ertugliflozin and sotagliflozin (a dual inhibitor of SGLT-2 and SGLT-1) are currently in Phase 3 clinical trials. SGLT-2 inhibitors that have approval in Japan only are ipragliflozin, tofogliflozin, and luseogliflozin.
| Effect on Glycemic Parameters|| |
In treatment-naïve T2DM patients, SGLT-2 inhibitors including canagliflozin, dapagliflozin and empagliflozin as monotherapy for 24–26 weeks of study period reduced HbA1c by 0.6%–1.0% as compared with the placebo and also associated with the decreased risk of hypoglycemia ranging from 0% to 3%. In addition, considerable improvements in the FPG levels were also observed.,,
A 52-week, double-blind, multicenter, active-controlled, randomized trial, in which the efficacy, safety, and tolerability of dapagliflozin evaluated in patients with T2DM and inadequately controlled with metformin monotherapy as compared with sulfonylurea glipizide, demonstrated that although dapagliflozin showed comparable efficacy, it is associated with the significant weight loss of-3.2 kg versus 1.2 kg with glipizide and decreased risk of hypoglycemia (3.5%) versus glipizide (40.8%; P < 0.0001).
A randomized, double-blind, Phase 3 noninferiority trial, which assessed the efficacy and safety of canagliflozin, showed that at 52 weeks canagliflozin 300 mg was superior in reducing HbA1c by 0.93% as compared with glimepiride (0.81%) in patients with T2DM who were inadequately controlled with metformin. The incidence of hypoglycemic risk was significantly lesser with canagliflozin 100 mg (6%) and 300 mg (5%) than with glimepiride (34%) with a P < 0·0001 for both parameters. It has also been observed that the occurrence of severe hypoglycemia was also lesser with canagliflozin 100 mg (<1%) and 300 mg (<1%) as compared with glimepiride (3%).
Dapagliflozin 10 mg provided statistically significant and clinically relevant improvements in glycemic control compared with placebo (with mean placebo-corrected HbA1c decrease in the different studies ranging from −0.5% to −0.8%), when given as add-on therapy to metformin or sulfonylurea.,
In addition, in a 52 week, randomized, double-blind, active-controlled, Phase 3 noninferiority trial, compared the efficacy and safety of canagliflozin with glimepiride in patients with T2DM inadequately controlled with metformin, canagliflozin 100 mg was noninferior to glimepiride and canagliflozin 300 mg was superior to glimepiride. Canagliflozin 100 mg and 300 mg also provided sustained reduction in FPG over 52 weeks; however, glimepiride was associated with the increase in FPG after 18 weeks of treatment.
Both empagliflozin doses of 10 and 25 mg as an add-on therapy to metformin also significantly improved of glycemic control (with adjusted mean changes from baseline in HbA1c were −0.70% with empagliflozin 10 mg, and −0.77% with empagliflozin 25 mg and −0.13% with placebo (both P < 0.001). Empagliflozin 10 mg and 25 mg as add-on to basal insulin for 78 weeks also improved glycemic control.
A head-to-head trial which evaluated the efficacy and safety of canagliflozin compared with sitagliptin in patients with T2DM and uncontrolled with the dual therapy of metformin and sulfonylurea have demonstrated that canagliflozin 300 mg was superior in reducing the HbA1c (−1.03%) as compared to sitagliptin 100 mg (−0.66%) at 52 weeks. Statistically significant decrease in FPG was also observed in patients treated canagliflozin as compared to sitagliptin-treated patients. The occurrence of hypoglycemia was comparable between both the treatment groups.
Dapagliflozin 10 mg was also shown to have noninferior efficacy versus metformin extended release when both were given as monotherapy for 24 weeks.
| Effects on Body Weight|| |
Several clinical trials have shown that the use of SGLT-2 inhibitors is associated with the weight loss ranging from −1.6 to −5 kg versus placebo.,, Furthermore, the reduction in body weight was maintained over 104 weeks as demonstrated by the clinical trials which evaluated the long-term efficacy of SGLT-2 inhibitors.,, Numerous studies have shown that the weight loss associated with the SGLT-2 inhibitors therapy was owing to the reduced fat mass which accounts for 60%–90% and fluid loss following osmotic diuresis.
Although the urinary energy loss caused by SGLT-2 inhibitor is ~200 kcal/day, chronic glycosuria causes an adaptive increase in energy intake. Therefore, combining SGLT-2 inhibition with dietary restriction potentially can lead to augmented weight loss.
| Effect on Blood Pressure|| |
Clinical trials have demonstrated that SGLT-2 inhibitors as monotherapy or as add-on therapy are associated with significant reduction in systolic (–3–−5 mm Hg) blood pressure from the baseline as compared with other oral AHA baseline.,, In addition, SGLT-2 inhibitors are associated with significant reduction in diastolic (–1 to −3 mm Hg) blood pressure from the baseline. Furthermore, 24-h ambulatory BP monitoring was used and the modest reductions in blood pressure were not associated with increased heart rate.,,,
A 24-week randomized, double-blind, placebo-controlled study which has been extended to 28-week study evaluated the clinical efficacy and safety of dapagliflozin in T2DM patients who were at high risk for future CVD events. The study demonstrated that dapagliflozin was associated with the sustained reduction in SBP ranging from 2 to 3 mmHg from 24 to 52 weeks.
Although the exact mechanism by which SGLT-2 inhibitors reduces BP is still not known, it has been assumed that it is related to their effects on osmotic diuresis and mild natriuresis. Besides these, the local inhibition of the renin-angiotensin-aldosterone system that occurs following an increased delivery of sodium to the juxtaglomerular apparatus is an additional mechanism by which SGLT-2 inhibitor potentially induced reduction in BP.
SGLT-2 inhibitors provided statistically significant and clinically relevant improvements in SBP control compared with active-comparator (with mean placebo-corrected SBP decrease in the different studies ranging from −3 to −5 SBP), when given as monotherapy.,
| Cardiovascular Safety Outcome Trials for Anti-Diabetic Agents|| |
Although the availability of the AHAs for patients with T2DM is enormous, before EMPA-REG trial data was published in 2015, not a single agent is known obviously to reduce CV events. Metformin, the mainstay therapy for patients with T2DM, is observed as associated with CV benefits; however, a large, well-designed, randomized clinical trial needs to confirm this association.
Before the 2008 Food and Drug Administration (FDA) guidance for industry, HbA1c was the efficacy endpoint for approval of antidiabetic therapies. In addition, CV risk assessment was based only through adverse events reported by investigators but no central, blinded adjudication process or planned analyses have been used. However, the CV safety concerns from an excess of serious heart failure events with pioglitazone, the US FDA issued guidance that necessitated drug approval for glucose-lowering agents in T2DM to include a robust assessment of CV safety.
With the FDA recommended rigorous assessment of CV safety, clinical trials which assessed the CV safety of DPP-4 inhibitors (TECOS, SAVOR-TIMI 53, and EXAMINE) demonstrated no CV benefit as compared with placebo plus active comparator.,, Clinical trial, which assessed the CV safety of empagliflozin in patients with T2DM and at the high risk of CV, demonstrated that an anti-hyperglycemia agent reduced CV mortality and all-cause mortality and also, reduced hospitalization for heart failure.
| Cardiovascular Outcome Trials With Sodium Glucose Co-Transporter-2 Inhibitors|| |
In the EMPA-REG OUTCOME trial, the effects of empagliflozin on CV morbidity and mortality in 7020 patients with T2DM at high risk for CV as compared to placebo were studied. The trial demonstrated that empagliflozin (pooled 10 and 25 mg/day doses) significantly reduced the primary major adverse CV event (MACE) outcome (CV death, nonfatal MI, nonfatal stroke) by 14% compared to placebo (hazard ratio [HR] = 0.86, 95% confidence interval [CI] = 0.74–0.99, P = 0.04 for superiority). Although there were no significant between-group differences in the rates of MI or stroke, in the empagliflozin group, there were significantly lower rates of death from CV causes (3.7%, vs. 5.9% in the placebo group; 38% relative risk reduction), hospitalization for heart failure (2.7% and 4.1%, respectively; 35% relative risk reduction), and death from any cause (5.7% and 8.3%, respectively; 32% relative risk reduction). The key secondary outcome that includes the primary outcome plus hospitalization for unstable angina (UA) occurred in 599 of 4687 patients (12.8%) in the empagliflozin group and 333 of 2333 patients (14.3%) in the placebo group (HR = 0.89; 95% CI = 0.78–1.01; P < 0.001 for noninferiority and P = 0.08 for superiority) (P = 0.08 for superiority). Among patients receiving empagliflozin, although there was an increased rate of genital infection, no increase in other adverse events was associated with empagliflozin.
The trial also demonstrated that there was no increase in the incidence of hypoglycemia, renal impairment, urinary tract infections, volume-related side effects, bone fractures, or thromboembolic events. Consequently, the study endorses that safety profile of the SGLT-2-inhibitor could be class effect. Although there are prevailing reports of DKA in T2DM patients treated with SGLT-2 inhibitors, the EMPA-REG OUTCOME trial demonstrated that the incidence of DKA was low (0.035%) and comparable to the placebo. However, whether the results of EMPA-REG trial are applicable to other patient profiles or represent a class effect remains to be determined.
Owing to their beneficial effects of SGLT-2 inhibitors class of drugs including improved glycemic control, reduced body weight and blood pressure, lesser side effect profile and excellent safety profile, it is expected that it will advance in its placement in the therapeutic algorithm for the management of T2DM.
CV outcomes trials for other agents in SGLT-2 inhibitor drug class are still ongoing and data from these trials can provide a potential class-effect on CV outcomes [Table 1].
|Table 1: Cardiovascular outcome trials of sodium glucose co-transporter-2 inhibitors|
Click here to view
DECLARE-TIMI, a multicenter, randomized, double-blind, placebo-controlled, parallel group trial, is the largest SGLT-2 inhibitor CV outcomes trial to date. The trial will investigate the effect of dapagliflozin (10 mg once daily) on the time to first event included in the composite endpoint of CV death, MI or ischemic stroke as primary end point and regarding the secondary outcome is time to first event included in the composite endpoint of CV death or hospitalization due to heart failure.
CANVAS, a multicenter, randomized, double-blind, placebo-controlled, parallel group trial, is designed to assess the efficacy and tolerability of canagliflozin (100 and 300 mg once daily) versus placebo in patients with inadequately controlled T2DM and increased CV risk. The primary outcome is a composite of CV death, nonfatal MI, or nonfatal stroke.
CANVAS-R trial that involves more than ~5800 patients evaluates the effect of canagliflozin on the progression of albuminuria in patients with T2DM and inadequate glycemic control and an increased risk of CV events. The primary endpoint is the number of participants with progression of albuminuria.
CREDENCE trail, which will assess the effect of canagliflozin in reducing the progression of renal impairment (Stages 2 or 3 chronic kidney disease and macroalbuminuria) and CV mortality in patients with T2DM, includes MACE plus as a secondary outcome measure.
Ertugliflozin, the fourth SGLT-2 inhibitor, is currently being assessed in Phase 3 clinical trial, a randomized, double-blind, placebo-controlled, parallel group CV outcomes trial. The primary outcome is a composite of three-point MACE.
| Meta-Analysis and Pooled Data Analysis|| |
With the beneficial effects of SGLT-2 inhibitors on a number of CVD risk factors, a meta-analysis which involved 25 studies and analyzed the CV safety of SGLT-2 inhibitors including dapagliflozin and canagliflozin in patients at high risk for CV, demonstrated that SGLT-2 inhibitor is not associated with the increased risk of MACEs as compared with the control group with the HR of 0.89 (0.70, 1.14).
A meta-analysis involving nine randomized clinical trials including one Phase 2 trial, seven Phase 3 trial, and one Phase 3 CV outcome trial for canagliflozin as part of the submission to the FDA demonstrated that the MACE plus that includes hospitalization for UA were observed in 18.9% of patients receiving canagliflozin and 20.5% of patients receiving active comparators with a HR of 0.91 (95% CI = 0.68–1.21).
In a pooled data analysis of four placebo-controlled, Phase 3 trials, 24 weeks treatment with empagliflozin resulted in significant glycemic control, weight loss, BP reduction, and positive effect on lipid and uric acid.
In a meta-analysis of CV outcomes from 21 clinical trials, which assessed the efficacy of dapagliflozin among patients at high risk of CV, 128 MACE plus UA events were observed. 67 events occurred in patients receiving dapagliflozin and 61 events in patients receiving control (HR = 0.806; 95% CI = 0.562–1.156). With 95 MACE events observed among patients at high risk of CV, fifty events occurred in patients receiving dapagliflozin and 45 in patients receiving control (HR = 0.802; 95% CI = 0.527–1.221).
In a pooled data analysis of two Phase 2 trials, which evaluated the long-term efficacy, safety and tolerability of dapagliflozin versus placebo in patients with T2DM and CVD, demonstrated that dapagliflozin provided a greater mean reduction in HbA1c versus placebo at 52 weeks (−0.58% [95% CI = −0.68–−0.49]) and 104 weeks (−0.35% [95% CI = −0.59–−0.12]). Mean body weight and SBP reductions versus placebo were maintained at 52 weeks, −2.23 kg and −3.25 mmHg, respectively, and at 104 weeks, −3.16 kg and −2.03 mmHg, respectively. Dapagliflozin was associated with a better three-item composite endpoint of clinical benefit (glycemia, weight and SBP) compared with placebo at week 24 (10.1% vs. 1.1%) and week 104 (LT2, 6.7% vs. 1.4%) [Figure 5].
|Figure 5: Better three -item composite endpoint of clinical benefit (glycemia, weight and SBP) with Dapagliflozn compared to placebo|
Click here to view
In a post hoc analysis of data pooled from two Phase 3 clinical trials, hypertensive patients with T2DM who were on stable angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy were randomly assigned to dapagliflozin 10 mg or placebo. The study demonstrated that dapagliflozin was associated with increased reductions in albuminuria compared with placebo (−33.2%; 95% CI −45.4–−18.2) over 12 weeks. was also present After adjusting for confounding factors like changes in HbA1c, SBP, body weight and estimated glomerular filtration rate, dapagliflozin was associated with the reduction in albuminuria (−23.5%, 95% CI = −37.6–−6.3). The study concluded that besides its favorable renal effects, dapagliflozin associated with significant improvements in glycemic control and reductions in SBP, may lead to reduced long-term renal and CV risk.
| Summary|| |
SGLT-2 inhibitor that is effective in glycemic control in patients with T2DM is also associated with the modest reductions in body weight and BP. Given that less serious adverse events associated with SGLT-2 inhibitors, it is well tolerable among patients with T2DM. Numerous meta-analyses of SGLT-2 inhibitors and CV outcome consistently demonstrated that SGLT-2 inhibitor is not associated with increased risk of CV outcome. The EMPA-REG OUTCOME study demonstrated reduced risk of CV death (38%), risk of hospitalization for heart failure (35%) and improved survival by reducing the risk of death from any cause (32%) with a glucose lowering agent. Although the reductions in the risks of CV death and death from any cause sustained throughout the study, the mode of action associated with the CV benefits remains unknown. Data from ongoing trials including DECLARE-TIMI and CANVAS trials may share some guidance whether CV outcome of SGLT-2 inhibitor is the class-effect or not.
The authors would like to acknowledge AstraZeneca Pharma India Ltd., and Indegene Lifesciences for Medical writing and editing support.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham Study. JAMA 1979;241:2035-8.
Moss SE, Klein R, Klein BE. Cause-specific mortality in a population-based study of diabetes. Am J Public Health 1991;81:1158-62.
Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229-34.
Ali MK, Narayan KM, Tandon N. Diabetes and coronary heart disease: Current perspectives. Indian J Med Res 2010;132:584-97.
] [Full text]
Johansen OE. Cardiovascular disease and type 2 diabetes mellitus: A multifaceted symbiosis. Scand J Clin Lab Invest 2007;67:786-800.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al.
Management of hyperglycemia in type 2 diabetes: A patient-centered approach: Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012;35:1364-79.
Authors/Task Force Members, Rydén L, Grant PJ, Anker SD, Berne C, Cosentino F, et al.
ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: The Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J 2013;34:3035-87.
Stark Casagrande S, Fradkin JE, Saydah SH, Rust KF, Cowie CC. The prevalence of meeting A1C, blood pressure, and LDL goals among people with diabetes, 1988-2010. Diabetes Care 2013;36:2271-9.
Inzucchi SE, Zinman B, Wanner C, Ferrari R, Fitchett D, Hantel S, et al.
SGLT-2 inhibitors and cardiovascular risk: Proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res 2015;12:90-100.
Bennett WL, Maruthur NM, Singh S, Segal JB, Wilson LM, Chatterjee R, et al.
Comparative effectiveness and safety of medications for type 2 diabetes: An update including new drugs and 2-drug combinations. Ann Intern Med 2011;154:602-13.
Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, et al.
Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373:232-42.
Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al.
Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317-26.
White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, et al.
Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327-35.
Fadini GP, Avogaro A. Cardiovascular effects of DPP-4 inhibition: Beyond GLP-1. Vascul Pharmacol 2011;55:10-6.
Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev 2011;91:733-94.
Chao EC. SGLT-2 inhibitors: A new mechanism for glycemic control. Clin Diabetes 2014;32:4-11.
Whalen K, Miller S, Onge ES. The role of sodium-glucose co-transporter 2 inhibitors in the treatment of type 2 diabetes. Clin Ther 2015;37:1150-66.
Scheen AJ. Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs 2015;75:33-59.
Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, et al.
Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest 2014;124:499-508.
Merovci A, Solis-Herrera C, Daniele G, Eldor R, Fiorentino TV, Tripathy D, et al.
Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest 2014;124:509-14.
Merovci A, Mari A, Solis C, Xiong J, Daniele G, Chavez-Velazquez A, et al.
Dapagliflozin lowers plasma glucose concentration and improves ß-cell function. J Clin Endocrinol Metab 2015;100:1927-32.
Stenlöf K, Cefalu WT, Kim KA, Alba M, Usiskin K, Tong C, et al.
Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab 2013;15:372-82.
Ferrannini E, Ramos SJ, Salsali A, Tang W, List JF. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: A randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care 2010;33:2217-24.
Roden M, Weng J, Eilbracht J, Delafont B, Kim G, Woerle HJ, et al.
Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol 2013;1:208-19.
Nauck MA, Del Prato S, Meier JJ, Durán-García S, Rohwedder K, Elze M, et al.
Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: A randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care 2011;34:2015-22.
Erondu N, Desai M, Ways K, Meininger G. Diabetic ketoacidosis and related events in the canagliflozin type 2 diabetes clinical program. Diabetes Care 2015;38:1680-6.
Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: A predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care 2015;38:1638-42.
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al.
Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.
Skyler JS, Bergenstal R, Bonow RO, Buse J, Deedwania P, Gale EAM, et al
. Intensive glycaemic control and the prevention of cardiovascular events: Implications of the ACCORD, ADVANCE, and VA diabetes trials: A position statement of the American Diabetes Association and a Scientific Statement of the American College of Cardiology Foundation and the American Heart Association. Diabetes Care 2009;32:187-92.
Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, et al.
Consensus statement by the American Association of clinical endocrinologists and American college of endocrinology on the comprehensive type 2 diabetes management algorithm-2016 executive summary. Endocr Pract 2016;22:84-113.
American Diabetes Association. 2016 Standards of Medical Care in Diabetes. Diabetes Care 2016;39:S52-9.
Lapuerta P, Zambrowicz B, Strumph P, Sands A. Development of sotagliflozin, a dual sodium-dependent glucose transporter 1/2 inhibitor. Diab Vasc Dis Res 2015;12:101-10.
Poole RM, Dungo RT. Ipragliflozin:First global approval. Drugs 2014;74:611-7.
Poole RM, Prossler JE. Tofogliflozin:First global approval. Drugs 2014;74:939-44.
Markham A, Elkinson S. Luseogliflozin:First global approval. Drugs 2014;74:945-50.
Bailey CJ, Iqbal N, T'joen C, List JF. Dapagliflozin monotherapy in drug-naïve patients with diabetes: A randomized-controlled trial of low-dose range. Diabetes Obes Metab 2012;14:951-9.
Cefalu WT, Leiter LA, Yoon KH, Arias P, Niskanen L, Xie J, et al.
Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet 2013;382:941-50.
Strojek K, Yoon KH, Hruba V, Elze M, Langkilde AM, Parikh S. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: A randomized, 24-week, double-blind, placebo-controlled trial. Diabetes Obes Metab 2011;13:928-38.
Rosenstock J, Jelaska A, Kim G, Broedl UC, Woerle HJ. Empagliflozin as add-on to basal insulin for 78 weeks improves glycemic control with weight loss in insulin-treated (T2DM). Can J Diabetes 2013;37:S13-84.
Schernthaner G, Gross JL, Rosenstock J, Guarisco M, Fu M, Yee J, et al.
Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: A 52-week randomized trial. Diabetes Care 2013;36:2508-15.
Henry RR, Murray AV, Marmolejo MH, Hennicken D, Ptaszynska A, List JF. Dapagliflozin, metformin XR, or both: Initial pharmacotherapy for type 2 diabetes, a randomised controlled trial. Int J Clin Pract 2012;66:446-56.
Liakos A, Karagiannis T, Athanasiadou E, Sarigianni M, Mainou M, Papatheodorou K, et al.
Efficacy and safety of empagliflozin for type 2 diabetes: A systematic review and meta-analysis. Diabetes Obes Metab 2014;16:984-93.
Yang XP, Lai D, Zhong XY, Shen HP, Huang YL. Efficacy and safety of canagliflozin in subjects with type 2 diabetes: Systematic review and meta-analysis. Eur J Clin Pharmacol 2014;70:1149-58.
Zhang M, Zhang L, Wu B, Song H, An Z, Li S. Dapagliflozin treatment for type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials. Diabetes Metab Res Rev 2014;30:204-21.
Bolinder J, Ljunggren Ö, Johansson L, Wilding J, Langkilde AM, Sjöström CD, et al.
Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab 2014;16:159-69.
Ridderstråle M, Andersen KR, Zeller C, Kim G, Woerle HJ, Broedl UC; EMPA-REG HH-SU Trial Investigators. Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: A 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol 2014;2:691-700.
Leiter LA, Yoon KH, Arias P, Langslet G, Xie J, Balis DA, et al.
Canagliflozin provides durable glycemic improvements and body weight reduction over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin: A randomized, double-blind, phase 3 study. Diabetes Care 2015;38:355-64.
Ferrannini G, Hach T, Crowe S, Sanghvi A, Hall KD, Ferrannini E. Energy balance after sodium-glucose cotransporter 2 inhibition. Diabetes Care 2015;38:1730-5.
Tikkanen I, Narko K, Zeller C, Green A, Salsali A, Broedl UC, et al.
Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care 2015;38:420-8.
Weber MA, Mansfield TA, Cain VA, Iqbal N, Parikh S, Ptaszynska A. Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: A randomised, double-blind, placebo-controlled, phase 3 study. Lancet Diabetes Endocrinol 2016;4:211-20.
Townsend RR, Machin I, Ren J, Trujillo A, Kawaguchi M, Vijapurkar U, et al.
Reductions in mean 24-hour ambulatory blood pressure after 6-week treatment with canagliflozin in patients with type 2 diabetes mellitus and hypertension. J Clin Hypertens (Greenwich) 2016;18:43-52.
O'Brien E, Parati G, Stergiou G, Asmar R, Beilin L, Bilo G, et al.
European society of hypertension position paper on ambulatory blood pressure monitoring. J Hypertens 2013;31:1731-68.
Cefalu WT, Leiter LA, de Bruin TW, Gause-Nilsson I, Sugg J, Parikh SJ. Dapagliflozin's effects on glycemia and cardiovascular risk factors in high-risk patients with type 2 diabetes: A 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. Diabetes Care 2015;38:1218-27.
Bolen S, Tseng E, Hutfless S, Segal JB, Suarez-Cuervo C, Berger Z, et al
. Diabetes Medications for Adults with Type 2 Diabetes: An Update. Report No: 16-EHC013-EF. Comparative Effectiveness Reviews, No. 173. Johns Hopkins University Evidence-based Practice Center. Rockville (MD): Agency for Healthcare Research and Quality (US); 2016.
DeFronzo RA. The EMPA-REG study: What has it told us? A diabetologist's perspective. J Diabetes Complications 2016;30:1-2.
Neal B, Perkovic V, de Zeeuw D, Mahaffey KW, Fulcher G, Stein P, et al.
Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS) – A randomized placebo-controlled trial. Am Heart J 2013;166:217-23.e11.
Vasilakou D, Karagiannis T, Athanasiadou E, Mainou M, Liakos A, Bekiari E, et al.
Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: A systematic review and meta-analysis. Ann Intern Med 2013;159:262-74.
Hach T, Gerich J, Salsali A, et al
. Empagliflozin improves glycemic parameters and cardiovascular risk factors in patients with type 2 diabetes (T2DM): Pooled data from four pivotal phase III trials. Diabetes 2013;62 Suppl 1:LB19.
Sonesson C, Johansson PA, Johnsson E, Gause-Nilsson I. Cardiovascular effects of dapagliflozin in patients with type 2 diabetes and different risk categories: A meta-analysis. Cardiovasc Diabetol 2016;15:37.
Leiter LA, Cefalu WT, de Bruin TW, Xu J, Parikh S, Johnsson E, et al.
Long-term maintenance of efficacy of dapagliflozin in patients with type 2 diabetes mellitus and cardiovascular disease. Diabetes Obes Metab 2016;18:766-74.
Heerspink HJ, Johnsson E, Gause-Nilsson I, Cain VA, Sjöström CD. Dapagliflozin reduces albuminuria in patients with diabetes and hypertension receiving renin-angiotensin blockers. Diabetes Obes Metab 2016;18:590-7.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]