Efficacy and Safety Profile of SGLT-2 Inhibitors as Add-on Therapy in Patients with Type 2 Diabetes: A Comprehensive Review

 Introduction

Diabetes mellitus is a multifactorial metabolic illness characterized by persistent hyperglycemia, and protein, fat, and carbohydrate metabolism disruptions, resulting from deficiencies in insulin synthesis or action. It has the potential to lead to long-term harm, impairing  function and causing failure of multiple organs, such as the kidneys, eyes, nerves, heart, and blood vessels.¹ Diabetes can be divided into several types: Type 1, Type 2, Gestational diabetes, and specific types caused by other factors, with Type 2 being the most prevalent. Type 1 diabetes mellitus (T1DM) makes up approxi- mately 5% to 10% of cases, while Type 2 diabetes mellitus (T2DM) comprises around 90% to 95%.² It is a global health issue reaching epidemic levels and imposing a significant economic burden. The global prevalence of diabetes mellitus (DM) was estimated at 4.63 million in 2019. Projections for 2030 and 2045 suggest that this figure will increase to 10.2% (578 million) and 10.9% (700 million), respectively.³ Currently, India is reported to have 62.4 million individuals affected by diabetes, with this number expected to surpass 100 million by 2030. The prevalence of diabetes among adults in urban areas has reached nearly 20%, while in rural areas, it is about 10%.⁴ It is projected that 15% of individuals with diabetes develop heart disease, 22% experience retinal damage, potentially causing blindness, 38% suffer from persistent kidney dysfunction, and 3% face circulatory issues that could lead to limb amputation. These figures emphasize the importance of effective disease management to prevent such complications, highlighting the need for innovative treatments and advanced medications.⁵ Managing diabetes requires a combination of lifestyle changes and medications. Besides making healthier food choices and staying active, several approved treatments are available. These include different types of insulin (short-acting, intermediate-acting, and long-acting) and oral medications like metformin (a biguanide), thiazolidinediones, sulfonylureas, and meglitinides. Analogues drugs like sulfonylureas (SUs) can come with some serious risks.⁶ These include hypoglycemia (low blood sugar), weight gain, an increased risk of cardiovascular problems, and even higher mortality rates.⁷

Mechanism of Action

Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are a recently approved class of oral anti-diabetic medications that help regulate blood sugar by blocking the reabsorption of glucose in the proximal tubule of the kidney. In addition to improving glycemic control, these inhibitors offer additional benefits, such as weight loss and lowered blood pressure. Furthermore, these inhibitors are related to improved HDL-cholesterol (HDL-C) and LDL-cholesterol (LDL-C) levels.⁸

Research Questions

1. What is the impact of SGLT-2 inhibitors on glycemic control, including HbA1c, fasting blood glucose (FBS), and postprandial blood glucose (PPBS), when they are used alongside current treatment?

2. What is the impact of SGLT-2 inhibitors on body weight over time?

3. Are there any significant differences in the lipid profile [total cholesterol, High-density lipoprotein (HDL), Low-density lipoprotein (LDL), triglycerides] before and after SGLT-2 inhibitor therapy?

4. What are the most frequently occurring side effects associated with SGLT-2 inhibitors? 5. How do SGLT-2 inhibitors compare to other classes of anti-diabetic medications in terms of efficacy and safety?

Methods

Search Strategy

A thorough literature review was performed using various electronic databases, such as PubMed, Cochrane Library, and Google Scholar. The search terms included “SGLT-2 inhibitors,” “Type 2 diabetes,” “efficacy,” “safety profile,” and “add-on therapy.” Articles published from 2015 to 2024 were included.

This review assessed the efficacy and safety by focusing on several key outcome measures.

Primary Efficacy Outcome

The primary measure of efficacy was the change in glycated hemoglobin (HbA1c) from baseline levels. This is an essential marker of long-term blood sugar control in individuals with Type 2 diabetes.

Secondary Efficacy Outcomes

The proportion of patients achieving an HbA1c level of <7.0% (53 mmol/mol), reflects effective diabetes management.

The average changes in fasting plasma glucose (FPG) and postprandial glucose (PPG) levels offer valuable information on daily blood sugar management.

Changes in body weight, as weight management, is a vital aspect of diabetes care.

Safety and Tolerability Indicators

The safety profile was assessed by monitoring the occurrence of adverse events, including:

1. Hypoglycemia episodes can lead to significant health risks.

2. Urinary tract infections (UTIs) and genital tract infections (GTIs) are recognized as common complications linked to the use of SGLT-2 inhibitors.

3. Cardiovascular safety outcomes to evaluate any cardiovascular events linked to treatment.

4. Incidents of acute renal failure and hypotension, as these conditions may arise from treatment.

5. The occurrence of bone fractures is important for assessing overall patient safety.

Inclusion criteria

1. Patients aged between 18 to 75 years

2. Individuals affected by Type 2 diabetes

3. Patients with the SGLT-2 class of drugs as add-on therapy

4. Patients with HbA1c greater than 6.5

5. Patients willing to provide consent for the study

Exclusion criteria

1. People diagnosed with Type 1 diabetes

2. Patients with end-stage renal damage

3. Pregnant and lactating women

Discussion

Efficacy

SGLT-2 inhibitors are effective in multiple clinical trials and meta-analyses. While SGLT-2 inhibitors are taken in addition to metformin, these studies typically show significant improvements in blood pressure, weight loss, and HbA1c levels.

Glycemic Control

A study conducted to assess the effectiveness and safety profile of sodium-glucose cotransporter-2 (SGLT-2) inhibitors in Korean patients with Type 2 diabetes mellitus found that the average baseline HbA1c level was 8.5%. The add-on treatment group had a slightly higher average of 8.6%, while the switch treatment group showed a marginally lower average of 8.4%. At week 12, the mean adjusted HbA1c decreased by –0.68% in the overall patients (P<0.001), by –0.94% in the add-on group, and by –0.42% in the switch group.9 In the EMPA-REG OUTCOME trial, empagliflozin significantly decreased HbA1c variability compared to placebo in 7,020 patients affected by Type 2 diabetes and cardiovascular disease. HbA1c levels dropped from 8.5% (SD = 1.2) at baseline to 7.8% (SD = 1.1) at week 28 and 7.2% (SD = 1.0) at week 52. Cox regression analyses indicated that greater HbA1c variability was associated with an increased risk of cardiovascular death, with hazard ratios of 1.97 for the placebo group and 1.53 for the empagliflozin group. Notably, the reduction in cardiovascular mortality observed with empagliflozin was not attributable to changes in HbA1c variability, underscoring its beneficial effects on glycemic regulation.¹⁰ Importantly, the data from both studies highlight the potential of SGLT-2 inhibitors in improving glycemic control and mitigating cardiovascular risk factors. The findings regarding HbA1c variability and its association with cardiovascular death risk further reinforce the importance of tight glycemic control in this patient population. Overall, these studies contribute valuable insights into the role of newer drugs like SGLT-2 in diabetes management, suggesting they are a viable option for achieving better glycemic outcomes while also addressing cardiovascular concerns.

Weight Loss

SGLT2 inhibitors offer weight loss benefits, unlike other anti-diabetic medications that may cause weight gain. A study of 289 adults with Type 2 diabetes found that 45.6% achieved significant weight loss after using SGLT2 inhibitors. Key factors for weight loss included being over 70 years old, having a BMI above 25 kg/m2, and using sulfonylureas. However, concurrent use of Hydrochlorothiazide (HCTZ) reduced the chances of weight loss.¹¹ This weight reduction is especially beneficial for Type 2 diabetes patients struggling with obesity and its related complications.

Blood Pressure Reduction

SGLT-2 inhibitors had a statistically significant BP-lowering effect on hypertension and pre-hypertension, which was further enhanced with increased drug dosage. A meta-analysis of 968 articles demonstrated that, compared to patients given a placebo, those treated with SGLT2 inhibitors experienced greater reductions in blood pressure. The mean changes in systolic and diastolic BP among SGLT-2 inhibitor users were -5.04 mmHg and -1.67 mmHg, respectively. An intensive dose of SGLT-2 inhibitors resulted in a stronger BP-lowering effect than the regular dose.¹² These benefits are particularly valuable for patients with Type 2 diabetes, as they often experience hypertension. The blood pressure reduction further enhances the cardiovascular advantages offered by SGLT2 inhibitors.

Cardiovascular Benefits

SGLT-2 inhibitors have demonstrated notable cardiovascular benefits, especially Empagliflozin. Over a median of 3.1 years, 7020 individuals with type 2 diabetes at high cardiovascular risk received treatment in the EMPA-REG OUTCOME trial. 10.5% of the Empagliflozin group experienced the primary outcome, compared to 12.1% of the placebo group (HR 0.86; 95.02% CI, 0.74-0.99; P=0.04). Empagliflozin decreased hospitalization for heart failure by 35% (2.7% vs. 4.1%), cardiovascular death by 38% (3.7% vs. 5.9%), and death from any cause by 32% (5.7% vs. 8.3%). Myocardial infarction, stroke, and secondary events did not differ significantly.¹³ Similarly, benefits similar to those of Canagliflozin were highlighted by the Canagliflozin Cardiovascular Assessment Study (CANVAS) study.¹⁴ Given the high prevalence of cardiovascular illness among those with Type 2 diabetes, these cardiovascular advantages are essential.

Renal Protection

Canagliflozin (100 mg daily) was compared to a placebo in a double-blind, randomized study that included 4401 people with Type 2 diabetes and albuminuric chronic renal disease. Renin-angiotensin system blockage was used to treat patients with albuminuria (albumin-to-creatinine ratio of 300 to 5000 mg/g) and an estimated glomerular filtration rate (GFR) of 30 to < 90 mL/min/1.73 m². A composite of end-stage kidney disease (ESKD), a doubling of serum creatinine, or death from cardiovascular or renal causes was the main result. The Canagliflozin group had a 30% reduced relative risk of the main outcome than the placebo group after a median follow-up of 2.62 years (hazard ratio [HR], 0.70; 95% CI, 0.59-0.82; P = 0.00001). There was a 32% decrease in the risk of ESKD (HR, 0.68; 95% CI, 0.54-0.86; P=0.002) and a 34% reduction in the risk of ESKD or death from renal causes (HR, 0.66; 95% CI, 0.53-0.81; P<0.001). Hospitalization for heart failure decreased by 39% (HR, 0.61; 95% CI, 0.47–0.80; P<0.001), and cardiovascular outcomes, such as mortality, myocardial infarction, or stroke, decreased by 20% (HR, 0.80; 95% CI, 0.67–0.95; P = 0.01). The incidence of fractures and amputations did not differ significantly. This study showed that in people with Type 2 diabetes and kidney disease, canagliflozin effectively decreased the risk of cardiovascular events and kidney failure.¹⁵ Given that diabetic nephropathy is a frequent and serious side effect of Type 2 diabetes, kidney protection is very beneficial.

Safety Profile

Although SGLT-2 inhibitors are generally well-tolerated, they come with certain adverse effects that clinicians should remain cognizant of the condition. Recognizing these safety concerns is essential for maximizing the benefits and minimizing the risks of using SGLT2 inhibitors in clinical practice.

Genital and Urinary Tract Infections

At present, Canagliflozin, Dapagliflozin, and Empag-liflozin constitute the trio of SGLT-2 inhibitors sanctioned for therapeutic intervention in Type 2 Diabetes Mellitus (T2DM). Rigorous safety evaluations of these pharmacological agents have documented occurrences of mild-to-moderate genital mycotic infections in individuals undergoing treatment with SGLT-2 inhibitors.¹⁶ Another real-world observation study revealed that the incidence rate of urinary tract infection (UTI) was 33.49% in the SGLT-2 inhibitor group and 11.72% in the non-SGLT-2 inhibitor group. The incidence rates of UTI were comparable between patients treated with Dapagliflozin and those treated with Empagliflozin (34.00% and 33.03%, respectively). Patients treated with SGLT-2 inhibitors had a 3.70 higher risk of UTI compared with those treated with non-SGLT2 inhibitors (95% CI 2.60–5.29). Furthermore, this investigation identified gender, age, and occupational status as pivotal risk determinants for urinary tract infections (UTIs).¹⁷ Healthcare providers must discuss these potential risks with their patients and offer strategies to minimize them.

Diabetic Ketoacidosis (DKA)

SGLT-2 inhibitors have been associated with an elevated risk of euglycemic diabetic ketoacidosis (DKA), a severe condition marked by elevated ketone levels and metabolic acidosis, but without significant increases in blood sugar levels. This risk is notably higher in individuals with Type 1 Diabetes Mellitus (T1DM).

Those with substantial insulin deficiencies, or those adhering to low-carbohydrate diets. It is crucial to detect and address this adverse effect early.¹⁸ Healthcare providers should inform patients about the signs of DKA and stress the importance of regular monitoring and Promptly seeking medical attention upon noticing any symptoms.

Fracture Risk

Canagliflozin has been linked to an increased risk of fractures, possibly due to reductions in bone mineral density and changes in calcium and phosphate metabolism. A proportion of participants experienced non-traumatic lower extremity amputations, primarily minor. The risk of amputation was consistent across ischemic and infectious causes and both 100 mg and 300 mg doses. A history of prior amputation and other established risk factors significantly increased the likelihood of amputation. No interaction between treatment and participant characteristics explained this increased risk. Across all subgroups, amputation events remained less frequent than major adverse cardiovascular events. The CANVAS study demonstrated that Canagliflozin raised the risk of amputations (mostly minor) in the population studied. These findings emphasize the need for caution when prescribing this medication to individuals at high risk of fractures or those with osteoporosis.¹⁹ Healthcare providers should assess bone health and thoroughly evaluate fracture risk factors when considering SGLT2 inhibitors.

Comparative Analysis with Other Antidiabetic Agents

SGLT-2 inhibitors offer several advantages over other classes of antidiabetic agents, including insulin, sulfonylureas, DPP-4 (dipeptidyl peptidase 4) inhibitors, and GLP-1 (glucagon-like peptide-1) receptor agonists. The comparative benefits and limitations of SGLT-2 inhibitors highlight their unique position in diabetes management.

Insulin

Although insulin is very effective in lowering HbA1c levels, it often leads to weight gain and carries a substantial risk of hypoglycemia. Compared to SGLT-2 inhibitors promote weight loss and have a much lower risk of causing hypoglycemia, making them a preferable choice for many patients, especially those who are obese or at high risk of hypoglycemia.²⁰ Additionally, the convenience of taking SGLT-2 inhibitors orally, as opposed to insulin injections, can improve patient adherence and overall satisfaction.

Sulfonylureas

Sulfonylureas are potent in reducing HbA1c levels but they come with the drawbacks of weight gain and heightened risk of hypoglycemia. In contrast, SGLT-2 inhibitors offer similar HbA1c reductions while promoting weight loss and improving cardiovascular outcomes, without the associated risk of hypoglycemia.²¹ Their ability to decrease the risk of cardiovascular events makes SGLT-2 inhibitors a particularly good option for patients with cardiovascular comorbidities.

DPP-4 Inhibitors

DPP-4 inhibitors, like Sitagliptin and Saxagliptin, are typically well-tolerated and carry a minimal risk of hypoglycemia. However, they do not offer the added advantages of weight loss and cardiovascular protection seen with SGLT-2 inhibitors. As a result, SGLT-2 inhibitors may be a more suitable option for individuals with cardiovascular disease. or those requiring weight reduction.²² Additionally, combining SGLT-2 with DPP-4 inhibitors can offer complementary advantages, enhancing overall glycemic control.

GLP-1 Receptor Agonists

GLP-1 receptor agonists, like Liraglutide and Semaglutide, also aid in weight loss and offer cardiovascular benefits. However, their injectable form can be less appealing to some patients compared to the oral administration of SGLT-2 inhibitors. Combining SGLT-2 inhibitors with GLP-1 receptor agonists can produce synergistic effects, Enhancing both glycemic management and cardiovascular protection.²³

This combination therapy is particularly effective for individuals with Type 2 diabetes who need severe glucose management and have a high cardiovascular risk.

Clinical Guidelines and Recommendations

Key diabetes guidelines, including those from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), advise integrating SGLT-2 inhibitors into treatment regimens for Type 2 diabetes, particularly in patients with established cardiovascular disease or chronic kidney disease.

American Diabetes Association (ADA)

According to the ADA guidelines, SGLT-2 inhibitors are recommended as a second-line therapy following metformin for patients diagnosed with Type 2 diabetes mellitus (T2DM), particularly those who also have atherosclerotic cardiovascular disease (ASCVD), heart failure, or chronic kidney disease (CKD). These recommendations underscore the significant cardiovascular and renal benefits associated with SGLT-2 inhibitors, advocating for their use in managing diabetes alongside these specific comorbidities.²⁴ Moreover, the ADA guidelines stress the importance of tailoring treatment plans to individual patient needs, considering factors such as patient preferences, existing health conditions, and the potential for adverse effects when making decisions about anti-diabetic medications. This strategy seeks to enhance the management of T2DM while also addressing the broader health challenges and complexities that patients may encounter.

European Association for the Study of Diabetes (EASD)

The EASD guidelines similarly recommend the use of SGLT-2 inhibitors in patients with Type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD) or chronic kidney disease (CKD). They emphasize the importance of customizing treatment plans according to each patient’s unique characteristics and health conditions. Additionally, the guidelines suggest combining SGLT-2 inhibitors with other anti-diabetic medications to achieve the best therapeutic results.²⁵ Moreover, the EASD guidelines stress the need for regular monitoring of renal function and electrolyte levels in patients on SGLT2 inhibitors to ensure treatment safety and efficacy, while minimizing potential risks associated with these drugs.

Conclusion

SGLT-2 inhibitors are a valuable supplement to the therapeutic arsenal for managing Type 2 diabetes mellitus. Their unique insulin-independent mechanism of action, combined with significant benefits in glycemic control, weight reduction, blood pressure lowering, and cardiovascular and renal protection, makes them an attractive option for many patients. However, their use must be balanced against potential adverse effects, including genital infections, diabetic ketoacidosis, and increased risk of fractures and amputations. Overall, SGLT-2 inhibitors offer a promising approach to improving the health and quality of life for patients with T2DM. Continued research and real-world evidence will further define their role in diabetes management and expand their therapeutic potential in other clinical settings.

Conflict of Interest

Nil