Open-label or unblinded (moderate): Open-label design

Industry funded (moderate): Industry funding reported

HbA1c fell by 1.02% at 12 weeks and 1.57% at 24 weeks. This reduction was larger than with either dual-therapy comparator at both time points.

Fasting glucose decreased by 29.0 mg/dL at 12 weeks and 54.4 mg/dL at 24 weeks. The change was clinically favorable, although similar to the dual-therapy groups.

Post-meal glucose decreased by 47.4 mg/dL at 12 weeks and 84.9 mg/dL at 24 weeks. The triple combination showed an early advantage over voglibose plus metformin at 12 weeks, with similar results by 24 weeks.

Only one level 1 hypoglycemia event was reported in this group, and no patient required hypoglycemia management. The study did not show a meaningful excess hypoglycemia burden.

Treatment-emergent adverse events were reported in 7.5% of patients in this group. Events were mostly mild, and no serious or severe adverse events were reported.

A twice-daily fixed-dose oral triple combination containing glimepiride, voglibose, and extended-release metformin, with dose uptitration at Week 12 for patients still above HbA1c target.

HbA1c fell by 0.68% at 12 weeks and 1.11% at 24 weeks. The group improved, but the reduction was smaller than with the triple combination.

Fasting glucose decreased by 30.4 mg/dL at 12 weeks and 51.3 mg/dL at 24 weeks. The benefit was similar to the other arms.

Post-meal glucose decreased by 41.8 mg/dL at 12 weeks and 76.4 mg/dL at 24 weeks. Improvement was clear, but less pronounced than in the triple-therapy arm at 12 weeks.

One level 1 hypoglycemia event was reported in this group, and no patient needed hypoglycemia management. Severe episodes were not reported.

Treatment-emergent adverse events were reported in 9.6% of patients in this group. Events were mostly mild, and no serious or severe adverse events occurred.

A twice-daily fixed-dose oral dual combination of voglibose and metformin, with dose uptitration at Week 12 for patients who remained above target HbA1c.

HbA1c fell by 0.88% at 12 weeks and 1.28% at 24 weeks. This was better than baseline but still smaller than the reduction seen with the triple combination.

Fasting glucose decreased by 30.9 mg/dL at 12 weeks and 54.0 mg/dL at 24 weeks. The benefit was similar to the other study groups.

Post-meal glucose decreased by 44.2 mg/dL at 12 weeks and 81.3 mg/dL at 24 weeks. The group improved meaningfully, with results similar to triple therapy by Week 24.

No hypoglycemia events were reported in this group during the study. There was no sign of excess hypoglycemia burden.

Treatment-emergent adverse events were reported in 6.9% of patients in this group. Events were mostly mild, with no serious or severe adverse events reported.

A twice-daily fixed-dose oral dual combination of glimepiride and metformin, with dose uptitration at Week 12 in patients above target HbA1c.

Positive: 9; Negative: 0; No effect: 6; Mixed: 0

Extracted 15 outcome signals across the study

All three regimens improved glycemic measures, and the triple combination showed the largest HbA1c benefit with reassuring short-term safety.

HbA1c ↓ by 1.57% at 24 weeks with triple therapy

More patients reached HbA1c <7% with triple therapy

Mostly intermediate or surrogate outcomes

HbA1c fell more with glimepiride plus voglibose plus extended-release metformin than with either dual-drug comparator at both 12 and 24 weeks.

By 24 weeks, 62.3% of patients on triple therapy reached HbA1c below 7%, compared with 30.0% and 35.7% in the dual-therapy groups.

Only two level 1 hypoglycemia events were reported overall, and no serious or severe adverse events occurred.

Mohan B, Kumar SV, Kurmi PH, et al. Efficacy and Safety of Glimepiride, Voglibose, and Metformin ER in Type 2 Diabetes: A Randomized, Active-Controlled Study. J Diabetes. 2026;18(4):e70217. doi:10.1111/1753-0407.70217

The study was open-label, so participants and clinicians knew which treatment was given.

The trial included only adults in India with baseline HbA1c up to 9%, so results may not apply to all people with type 2 diabetes.

Follow-up lasted 24 weeks, so longer-term durability and safety are still uncertain.

The study was funded by the manufacturer, which increases the need for independent confirmation.

In Indian adults with type 2 diabetes not controlled on metformin alone, the fixed-dose triple combination of glimepiride, voglibose, and extended-release metformin lowered HbA1c more than either dual combination over 24 weeks, with few mild side effects.

Fasting glucose ↓ in all treatment groups

Postprandial glucose ↓ in all treatment groups

Hypoglycemia ↔ rare and no severe events were reported

This ADA guideline outlines how to intensify drug treatment in adults with type 2 diabetes, including when combination therapy is appropriate after metformin alone is not enough.

Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2025

This consensus report explains why combination therapy can be useful when HbA1c remains above target and gives context for comparing triple versus dual oral treatment strategies.

Management of hyperglycemia in type 2 diabetes, 2022. A consensus report by the ADA and the EASD

This Mayo Clinic overview gives practical context on common diabetes medicines, treatment escalation, and the balance between glucose control, side effects, and convenience.

Type 2 diabetes - Diagnosis and treatment

Annual ADA clinical practice guideline issue covering broad diabetes management.

NICE clinical guideline for adult type 2 diabetes management.

American Diabetes Association resource matched by keyword relevance (type 2 diabetes)

A Guide for People with Type 2 Diabetes | American Diabetes Association

Learn about the diabetes diagnosis criteria and various tests used like A1C, Fasting Plasma Glucose (FPG), Oral Glucose Tolerance Test (OGTT), and Random Plasma Glucose Test.

Explore the latest diabetes in America data, including type 2 diabetes statistics, prevalence by age and ethnicity, death rates, and the financial burden of diabetes in the U.S.

Diabetes in America: Prevalence, Statistics, and Economic Impact

<h4>Background</h4>Type 2 diabetes mellitus (T2DM) affects over 500 million people worldwide, with traditional therapies often failing to maintain long-term glycaemic control. Ecnoglutide, a novel long-acting GLP-1 receptor agonist, has emerged as a promising therapeutic option. This systematic review and meta-analysis evaluated the efficacy and safety of ecnoglutide in adults with T2DM.<h4>Methods</h4>Following PRISMA guidelines, we systematically searched PubMed, Cochrane Library, ScienceDirect, ClinicalTrials.gov, and Google Scholar through September 2025. Randomized controlled trials comparing ecnoglutide with placebo or active comparators in adults with T2DM were included. Primary outcomes were changes in HbA1c and body weight. Secondary outcomes included fasting plasma glucose, insulin resistance markers, lipid profile, liver enzymes, and adverse events. Risk of bias was assessed using the Cochrane RoB-2 tool. Meta-analysis was performed using random-effects models, with mean differences and risk ratios calculated at 95% confidence intervals.<h4>Results</h4>Four RCTs comprising 1643 participants (1162 receiving ecnoglutide, 444 controls) were included. Ecnoglutide significantly reduced HbA1c (MD = -0.44, 95% CI -0.55 to -0.33, p < 0.00001), body weight (MD = -5.63, 95% CI -7.90 to -3.35, p < 0.01), and fasting plasma glucose (MD = -0.81, 95% CI -1.03 to -0.59, p < 0.00001). Improvements were observed in insulin sensitivity, lipid profile, and liver enzymes. Adverse events occurred more frequently with ecnoglutide (RR = 1.09, p < 0.01), although predominantly gastrointestinal and mild-to-moderate, with no significant differences in serious adverse events.<h4>Conclusions</h4>Ecnoglutide demonstrates robust efficacy in glycaemic control, weight reduction, and cardiometabolic parameters with an acceptable safety profile in adults with T2DM, supporting its therapeutic potential as a next-generation GLP-1 receptor agonist.

Comparative Efficacy and Safety of Ecnoglutide in Type 2 Diabetes: A Systematic Review and Meta-Analysis.

Background Type 2 diabetes mellitus (T2DM) is a chronic, non-communicable condition that causes insulin resistance and β-cell malfunction over time. The traditional food scene in India has changed dramatically as a result of rising urbanization and increased consumption of processed, Westernized diets heavy in refined carbs, saturated fats, and added sugars. These dietary changes have greatly contributed to the increased prevalence of type 2 diabetes. Medical nutrition therapy (MNT) is a systematic approach to nutrition management that aims to improve metabolic regulation and treatment results. MNT is often provided by a registered dietitian in collaboration with a diabetologist, and it focuses on personalized, evidence-based dietary guidelines. In this regard, NutroActive Industries Pvt. Ltd., India, has created a diabetic low glycemic load (GL) food product. The product kit contains Diabexy flour, Diabexy sugar substitute drops, Diabexy almond cookies, and Diabexy coconut burfi. These products are intended to provide a structured, low-GL meal plan that may support glycemic management. Although their formulation is nutritionally appropriate, clinical data for its effectiveness and safety are sparse. This randomized pilot trial sought to explore the potential effects of these products in improving glycemic parameters, such as fasting plasma glucose (FPG), postprandial glucose (PPG), and glycated hemoglobin (HbA1c), as well as their tolerance and safety. Method A total of 30 individuals with type 2 diabetes were randomly assigned to control and intervention groups. Baseline characteristics, including age, vital signs, and anthropometric parameters, were comparable between groups (p > 0.03), indicating adequate randomization. Ten participants demonstrated significantly lower postprandial glucose responses to Diabexy atta compared with glucose (iAUC: 52 vs. 241 mmol·min/L), corresponding to a low glycemic index (GI) of 22%. In the intervention group, the low-GL kit was associated with stable HbA1c, changes in fasting insulin that were interpreted alongside HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) to assess insulin dynamics, and improved quality-of-life scores. Safety assessments showed no adverse effects on liver, kidney, or lipid parameters. Indigestion was reported in one participant during the study period; however, it was transient and not considered related to the low-GL intervention kit. Overall, these findings suggest a potential metabolic benefit of Diabexy atta as part of a low-GL dietary approach, within the limitations of this pilot study. Conclusion In this randomized, open-label pilot study, the low-GL dietary intervention was associated with reductions in postprandial glucose levels, stabilization of HbA1c, and improvements in insulin resistance compared with standard care. No clinically significant safety concerns were observed over the study period based on clinical and laboratory assessments. While these findings suggest a potential metabolic benefit of the low-GL approach in individuals with T2DM, they should be interpreted cautiously given the small sample size, short duration, and exploratory nature of the study. Larger, well-controlled trials are warranted to confirm these preliminary observations.

Efficacy and Safety of a Diabetic Low Glycemic Load Kit With Standard Care in Patients With Type 2 Diabetes: An Open-Label Randomized Pilot Study.

<h4>Aim</h4>This systematic review and meta-analysis directly compared the efficacy and safety of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors as insulin add-ons in patients with inadequately controlled type 2 diabetes mellitus.<h4>Method</h4>A comprehensive search of the Cochrane Library, Web of Science, PubMed, and Scopus was conducted for studies published between January 2015 and June 2025. Eligible studies were independently screened. Risk of bias was assessed using RevMan v5.4.1 for randomized trials and using the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool for observational studies.Certainty of evidence was evaluated using GradePro. Meta-analyses were performed using RevMan v5.4.1.<h4>Results</h4>Eleven studies were included. SGLT2i in combination with insulin reduced body weight (MD -1.07 kg; p = 0.004) and systolic blood pressure (MD -2.91 mmHg; p = 0.01). Reductions were observed in HbA1c (MD -0.29%; p = 0.07), fasting plasma glucose (MD -21.27 mg/dL; p = 0.09), mean amplitude of glycaemic excursions (MD -1.85 mg/dL; p = 0.87), insulin dose (MD -2.0; p = 0.10), and triglycerides (MD -23.43 mg/dL; p = 0.25) with SGLT2i and insulin, but were not statistically significant. Observational evidence suggested lower cardiovascular mortality with SGLT2i plus insulin therapy (OR 0.54; p < 0.00001). Subgroup analyses demonstrated greater reductions in HbA1c and fasting plasma glucose among patients receiving premixed insulin, particularly in studies with longer treatment duration (24 weeks), longer diabetes duration (>13 years), and baseline HbA1c≥ 8%.<h4>Conclusion</h4>Among insulin-treated patients with inadequately controlled T2DM, SGLT2i and DPP4i provide comparable glycaemic control; however, SGLT2i confer additional cardiometabolic benefits, particularly weight reduction and improved systolic blood pressure. Subgroup findings indicate that these benefits may be more pronounced in patients receiving premix insulin, those with higher baseline HbA1c levels, those with longer treatment duration, and those with longer diabetes duration. Although observational evidence suggests potential cardiovascular mortality reduction with SGLT2i plus insulin therapy, further large-scale randomized trials are required to confirm long-term clinical outcomes. WHAT IS KNOWN ABOUT THIS RESEARCH TOPIC?: In patients with inadequately controlled type 2 diabetes mellitus (T2DM) receiving insulin therapy, the addition of newer oral antihyperglycemic agents (OHAs), including SGLT2 inhibitors and DPP4 inhibitors, has been shown to improve glycemic control while potentially reducing insulin dose requirements and mitigating insulin-associated adverse effects such as weight gain and hypoglycemia. Previous comparative evidence has mainly been derived from indirect meta-analyses. The study by S. H. Min et al. primarily evaluated outcomes such as HbA1c, fasting plasma glucose (FPG), body weight, hypoglycaemia, and urinary tract infections. However, direct comparative studies assessing a broader range of clinical parameters in insulin-treated patients with type 2 diabetes are still limited. WHAT DOES THIS STUDY ADD AND ITS FUTURE IMPLICATIONS?: This review provides the first direct meta-analysis comparing SGLT2 inhibitors and DPP4 inhibitors as add-on therapy to insulin among inadequately controlled T2DM patients. Beyond conventional glycaemic endpoints, this review evaluates glycaemic variability (MAGE), insulin dose requirements, body mass index, blood pressure, lipid parameters, renal outcomes, and a broad range of safety events, offering a multidimensional assessment of comparative effectiveness. The findings highlight clinically meaningful differences in cardiometabolic profiles between the two drug classes, supporting more optimized and patient-centred strategies for insulin combination therapy in diabetes management.

Beyond insulin therapy: Comparing relative benefits of adding SGLT2 versus DPP4 inhibitors in poorly controlled type 2 diabetic patients: A systematic review and meta-analysis.

<h4>Objective</h4>To systematically evaluate and compare the efficacy and safety of three fixed-ratio combination products-insulin degludec/liraglutide (IDegLira), insulin glargine/lixisenatide (iGlarLixi), and insulin degludec/insulin aspart (IDegAsp)-in patients with type 2 diabetes.<h4>Methods</h4>We systematically searched PubMed, Embase, Cochrane Library, CNKI, Wanfang, and VIP up to July 2025 for randomized controlled trials (RCTs) comparing the three combinations of primary interest (IDegLira, iGlarLixi, IDegAsp) and their individual components (insulin degludec, insulin glargine, liraglutide, and lixisenatide). Inclusion of the individual components enabled indirect comparisons. Data extraction, risk-of-bias assessment, and GRADE evaluation were performed. Network meta-analysis was conducted using Stata 14.0, with treatments ranked by the surface under the cumulative ranking curve (SUCRA).<h4>Results</h4>Twenty-one RCTs involving 12,815 patients were included. Both IDegLira (OR = 1.69, 95% CI: 1.08-2.65) and iGlarLixi (OR = 1.67, 95% CI: 1.17-2.37) had a higher incidence of treatment-emergent adverse events (TEAEs) than IDegAsp; no other significant pairwise differences were observed. Based on SUCRA values, which provide a probabilistic ranking (indicating the likelihood of being the best rather than direct statistical superiority), IDegLira had the highest probability of being optimal for reducing HbA1c (89.4%), fasting plasma glucose (81.8%), and incidence of hypoglycemic events (57.6%), while IDegAsp ranked highest regarding the incidence of TEAEs (97.9%). Inconsistency in the hypoglycemia network, likely due to varied definitions, warrants cautious interpretation.<h4>Conclusions</h4>Among the three fixed-ratio combination products, IDegLira appears most effective for glycemic control (in terms of HbA1c and FPG reduction), whereas IDegAsp demonstrates the best safety profile regarding incidence of TEAEs.

Comparative efficacy and safety of three fixed-ratio combination products in type 2 diabetes: A network meta-analysis.

<h4>Importance</h4>Elucidating the role of hypoxia-inducible factor-1α (HIF-1α) in pancreatic β-cell dysfunction is essential for understanding the pathophysiology of type 2 diabetes mellitus (T2DM) and improving clinical risk assessment.<h4>Objective</h4>To evaluate associations between protein expression level of HIF-1α in peripheral blood and key glycemic parameters-fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), fasting insulin (FINS), and the homeostatic model assessment of insulin resistance (HOMA-IR)-in patients with T2DM.<h4>Data sources</h4>PubMed, Embase, Cochrane Library, Web of Science (WOS), Wanfang, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), and Chinese Biomedical Literature Service System (SinoMed) were searched from inception to July 28, 2025, for Chinese and English publications.<h4>Study selection</h4>Observational studies examining the relationship between HIF-1α levels and glycemic outcomes in T2DM populations.<h4>Data extraction and synthesis</h4>Two reviewers independently extracted data and assessed study quality using AHRQ criteria. Random-effects meta-analysis was used to calculate mean differences (MD) with 95% confidence intervals (CI).<h4>Main outcomes and measures</h4>Differences in FPG, HbA1c, FINS, and HOMA-IR between high and low HIF-1α groups with T2DM.<h4>Results</h4>Thirty-six studies (<i>n</i> = 5,979) were included. Elevated peripheral HIF-1α was significantly associated with increased FPG (MD = 1.13, 95% CI [0.59, 1.67]), HbA1c (MD = 0.93, 95% CI [0.63, 1.24]), FINS (MD = 1.13, 95% CI [0.24, 2.02]), and HOMA-IR (MD = 1.40, 95% CI [0.62, 2.18]). Subgroup analysis indicated that geographic location significantly modified the FPG association (<i>p</i> = 0.0105). Sensitivity analyses confirmed the robustness of these findings.<h4>Conclusion</h4>Elevated peripheral HIF-1α levels correlate with impaired β-cell function and increased insulin resistance. The discordance between elevated systemic levels and known tissue-specific reductions suggests that peripheral HIF-1α may reflect a compensatory response to hypoxia rather than a primary driver of T2DM pathogenesis.<h4>Systematic review registration</h4>https://www.crd.york.ac.uk/PROSPERO/view/CRD420251118501, CRD420251118501.

The role of peripheral blood HIF-1α in pancreatic β-cell dysfunction and insulin resistance among patients with type 2 diabetes: a systematic review and meta-analysis.

Open-label or unblinded study (moderate): Open-label design

Relies on surrogate outcomes (moderate): No hard clinical outcomes reported

Triple combination therapy lowered HbA1c more than dual therapy in type 2 diabetes

This 24-week Indian trial compared a triple fixed-dose tablet with two dual-drug tablets in adults with type 2 diabetes who were still above target on metformin alone. All groups improved, but the triple combination lowered HbA1c more and helped more people reach an HbA1c below 7%, without more serious safety problems.

All three treatments improved glucose control, so the main question is the size of the extra benefit from the triple combination. The primary endpoint was an objective lab measure, which strengthens confidence, but the open-label design and industry funding still matter. The study also used fixed-dose combinations and dose uptitration rules that may not fully match every real-world setting.

Whether a fixed-dose triple oral therapy improves glycemic control more than dual therapy

These findings apply most directly to adults aged 18 to 65 years with type 2 diabetes in India who remain above target despite stable metformin monotherapy, and who do not have major renal, hepatic, or gastrointestinal exclusion conditions. The results are most relevant to patients with HbA1c between 7.5% and 9.0%.

Triple combination therapy lowered HbA1c more than dual therapy in type 2 diabetes

Wiley

Summary

Study Design

Interventions

Study Type

Outcomes

Duration and Size

Study Population

Age Range

Sex

Geography

Other Criteria

Comparison with other Studies

Journal Reference

Related and Discussions

Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2025

Management of hyperglycemia in type 2 diabetes, 2022. A consensus report by the ADA and the EASD

Type 2 diabetes - Diagnosis and treatment

Standards of Care in Diabetes—2024

Type 2 diabetes in adults: management

A Guide for People with Type 2 Diabetes | American Diabetes Association

Diabetes Diagnosis & Tests | ADA

Diabetes in America: Prevalence, Statistics, and Economic Impact

Stay informed. Stay ahead.