Industry funded (moderate): Industry funding reported

Xiaoke Pill lowered hypoglycemia risk compared with glibenclamide, especially in drug-naive participants, and reduced the annual hypoglycemia rate in the metformin group. This was the clearest advantage seen in the trial.

HbA1c fell by 0.70% in the drug-naive group and 0.45% in the metformin group with Xiaoke Pill. Glycemic improvement was real, but it was similar to glibenclamide rather than clearly better.

Fasting plasma glucose decreased in both study strata with Xiaoke Pill, and the size of improvement was similar to glibenclamide. The trial did not show a clear glucose advantage beyond non-inferiority.

No serious adverse event was reported during the study. Based on the available report, Xiaoke Pill did not show a serious safety signal over 48 weeks.

A compound traditional Chinese medicine product containing low-dose glibenclamide plus multiple herbal components, tested as monotherapy in drug-naive patients and as add-on therapy to stable metformin in a separate stratum.

Glibenclamide produced more hypoglycemia than Xiaoke Pill in the main safety comparisons, particularly for total and mild hypoglycemia in the drug-naive group and for hypoglycemia rate in the metformin stratum.

HbA1c fell by 0.66% in the drug-naive group and 0.59% in the metformin group with glibenclamide. The glycemic effect was similar to Xiaoke Pill and supported the active comparator performance.

Fasting plasma glucose decreased with glibenclamide in both study strata. The reduction was clinically favorable, but not clearly different from Xiaoke Pill.

No serious adverse event was reported during the study. The paper did not identify a serious safety difference between glibenclamide and Xiaoke Pill over 48 weeks.

Sulfonylurea comparator therapy tested alone in drug-naive patients and as add-on therapy to stable metformin in a separate stratum.

Positive: 5; Negative: 1; No effect: 2; Mixed: 0

Extracted 8 outcome signals across the study

The main pattern was similar glucose lowering in both groups, with a clearer safety advantage for Xiaoke Pill because hypoglycemia occurred less often.

Hypoglycemia events ↓ with Xiaoke Pill compared with glibenclamide

HbA1c ↓ similarly in both treatment arms

Mostly intermediate or surrogate outcomes

In the drug-naive group, Xiaoke Pill lowered the odds of any hypoglycemia by 38% and mild hypoglycemia by 41% versus glibenclamide.

In the metformin group, Xiaoke Pill lowered the annual hypoglycemia rate by 62% compared with glibenclamide.

HbA1c fell by 0.70% with Xiaoke Pill and 0.66% with glibenclamide in the drug-naive group, and by 0.45% versus 0.59% in the metformin group.

No serious adverse event was reported during the 48-week trial.

Ji L, Tong X, Wang H, et al; Evidence-Based Medical Research of Xiaoke Pill Study Group. Efficacy and Safety of Traditional Chinese Medicine for Diabetes: A Double-Blind, Randomised, Controlled Trial. PLoS One. 2013;8(2):e56703. doi:10.1371/journal.pone.0056703

All participants were treated in China, so generalizability may be limited.

The study used an active comparator, not a placebo-only herbal control.

Xiaoke Pill already contains glibenclamide, so the herbal effect cannot be isolated fully.

Some secondary outcomes were subgroup-based or not fully detailed in the main text.

In adults with type 2 diabetes and poor glycemic control, Xiaoke Pill lowered hypoglycemia risk compared with glibenclamide while delivering similar HbA1c improvement over 48 weeks.

Fasting plasma glucose ↓ similarly in both treatment arms

Serious adverse events ↔ none were reported

This ADA guideline issue gives current clinical standards for glucose targets, medication selection, and hypoglycemia prevention in adults with type 2 diabetes.

This institutional resource explains common treatment options for type 2 diabetes, including medication intensification and the need to balance glucose control with treatment safety.

Mayo Clinic - Type 2 Diabetes Treatment Options

NICE clinical guideline for adult type 2 diabetes management.

NIDDK management overview including self-care strategies.

CDC prevention and diabetes risk-reduction resource.

WHO fact sheet for broad public health diabetes context.

<h4>Background</h4>Dapagliflozin has been shown in preclinical and clinical settings to improve arterial function and left ventricular (LV) diastolic performance, yet the interrelationship between these effects has not been established.<h4>Objective</h4>To determine whether improvements in endothelial function accompany-and relate to-early changes in LV diastolic function after short-term dapagliflozin in type 2 diabetes (T2D).<h4>Methods</h4>We conducted a prespecified secondary analysis of a prospective, open-label, active-controlled trial of patients with T2D on background metformin that were randomized to daily dapagliflozin 10 mg or glibenclamide 5 mg for 12 weeks. All patients underwent echocardiographic and endothelial function assessments at baseline and 12 weeks. The primary endpoint for echocardiographic diastolic parameters was the change in E/e'. Endpoints for endothelial function were change in brachial artery flow-mediated dilation (FMD) and nitric oxide (NO) bioavailability. Arterial load comprises arterial impedance, measured as the brachial artery resistivity index, and the afterload components, the systemic vascular resistance and the ventriculo-arterial coupling index, as a marker of arterial stiffness.<h4>Results</h4>Among 96 patients (mean age 59 years; 40% female; baseline HbA1c 7.8%; 75% at intermediate risk H2FPEF score), glycemic control improved similarly in both groups (median [IQR] HbA1c change: -0.78 [0.11]% vs. -0.80 [0.10]%; between-group p = 0.887). Dapagliflozin reduced the E/e' ratio (mean change - 0.38 [0.24]; within-group p = 0.184), whereas glibenclamide increased (+ 0.79 [0.24]; p = 0.001), resulting in a significant between-group difference of - 1.17 (0.34; p = 0.001). Dapagliflozin treatment was associated with a 67% lower likelihood of being in a higher E/e' quartile (OR 0.325; 95% CI 0.147-0.715; p = 0.005). In the pooled cohort, changes in E/e' correlated directly with changes in brachial resistive index (r = 0.28; p = 0.005) and inversely with changes in NO bioavailability (r = - 0.26; p = 0.010) and FMD (r = - 0.23; p = 0.023). No significant correlations were observed for systemic vascular resistance or ventricle-arterial coupling.<h4>Conclusions</h4>In patients with T2D at intermediate risk for HFpEF, dapagliflozin was associated with more favorable changes in left ventricular diastolic function parameters compared with glibenclamide, accompanied by improvements in endothelial function and reductions in arterial impedance. These observations support the hypothesis of a vascular-myocardial pathway through which SGLT2 inhibition may exert cardioprotective effects in this population.<h4>Trial registration</h4>ClinicalTrials.gov Identifier NCT02919345.

Dapagliflozin-induced integrated improvements in left ventricular diastole, endothelial function, and arterial load: a randomized clinical trial.

<h4>Aim</h4>The Xiaoke Pill containing Chinese herb extracts and Glibenclamide, is used in therapy for type 2 diabetes mellitus (T2DM), and is effective in reducing the risk of hypoglycemia and improving diabetes symptoms compared with Glibenclamide. We describe a quantitative proteomics project to measure the T2DM serum proteome response to the Xiaoke Pill and Glibenclamide.<h4>Methods</h4>Based on a recently conducted 48-week clinical trial comparing the safety and efficacy of Glibenclamide (n = 400) and Xiaoke Pill (n = 400), after matching for age, sex, BMI, drug dose and whether hypoglycemia occurred, 32 patients were selected for the serum based proteomic analysis and divided into four groups (with/without hypoglycemia treated with Xiaoke Pill or Glibenclamide, n = 8 for each group). We screened the differential serum proteins related to treatments and the onset of hypoglycemia using the iTRAQ labeling quantitative proteomics technique. Baseline and follow-up samples were used.<h4>Results</h4>The quantitative proteomics experiments demonstrated that 25 and 21 proteins differed upon treatment with the Xiaoke Pill in patients without and with hypoglycemia, respectively, while 24 and 25 proteins differed upon treatment with Glibenclamide in patients without and with hypoglycemia, respectively. The overlap of different proteins between the patients with and without hypoglycemia given the same drug treatment was much greater than between the patients given different drug treatments.<h4>Conclusions</h4>We conclude that the serum proteins response to the two different anti-diabetic drug treatments may serve as a sensitive biomarker for evaluation of the therapeutic effects and continue investigations into the mechanism.

The serum protein responses to treatment with Xiaoke Pill and Glibenclamide in type 2 diabetes patients.

<h4>Background</h4>There has been increasing public interest in a functional medicine (FM) approach to the care of type 2 diabetes (T2D). However, it is unclear if this approach can further improve diabetes management beyond conventional diabetes care. This study compared the addition of a FM approach (intensive lifestyle modifications and tailored dietary supplements) plus usual care (FM) to conventional endocrinology management alone (usual care, UC).<h4>Methods</h4>In a 24-month unblinded randomized trial, participants with type 2 diabetes (T2D) were randomized to receive either FM or UC. The primary endpoint was discontinuation of insulin with no increase in HbA1c or HbA1c < 7% at 12 months. Secondary endpoints included changes in HbA1c, insulin dosage by weight, cardiometabolic biomarkers, hypoglycemic episodes, total number of medications and quality-of-life scores.<h4>Results</h4>A total of 107 individuals were screened - 34 were randomized into FM and 37 into UC. Participants were 46% female and median age was 62 years. Median baseline HbA1c was 7.75%. Of those randomized, 47 participants completed the study (FM: 20; UC: 27); 15.8% of patients in FM arm achieved the primary endpoint compared to 11.1% in the UC arm (p = 0.68). Secondary exploratory endpoints including change in HbA1c, insulin dosage by weight, hypoglycemia, BMI, weight and quality-of-life did not differ significantly between arms.<h4>Conclusion</h4>The addition of FM did not lead to significant improvement in glycemic, metabolic or quality-of-life outcomes compared to usual care for individuals with type 2 diabetes.

A functional medicine approach to diabetes control and quality of life: an open-label randomized pilot study.

<h4>Importance</h4>Severe hypoglycemia is a life-threatening, iatrogenic complication of diabetes medications associated with increased risks of falls, cardiovascular events, cognitive decline, and mortality.<h4>Objective</h4>To determine whether proactive outreach by a clinical pharmacist applying an evidence-based hypoglycemia-prevention algorithm (Hypoglycemia on a Page) would result in safer prescribing of diabetes regimens among patients with type 2 diabetes (T2D) with hypoglycemia risk.<h4>Design, setting, and participants</h4>This randomized clinical trial was conducted between July 20, 2023, and January 22, 2024, with follow-up outcomes collected through January 2025. The study included adults with T2D at high risk of hypoglycemia based on a validated hypoglycemia risk tool. The trial was conducted within Kaiser Permanente Northern California, a large, integrated health care delivery system.<h4>Intervention</h4>Patients were randomized 1:1 to either a protocol-driven outreach by a clinical pharmacist (intervention) arm or a usual care (control) arm.<h4>Main outcome and measure</h4>The main outcome was the comparison of the proportion of patients who were prescribed safer (less hypoglycemia-prone) diabetes regimens, defined as discontinuation of sulfonylureas and/or rapid-acting or short-acting or mixed insulins, using an intention-to-treat analysis.<h4>Results</h4>From an eligible population of 1204 patients, 200 were enrolled into the clinical trial. Among these, 191 patients were in the intention-to-treat cohort (mean [SD] age, 71.3 [11.5] years; 100 females [52.4%]). The 2 study arms were similar at baseline in terms of race and ethnicity, sex, mean (SD) hemoglobin A1c (HbA1c) level (intervention: 8.0 [1.3]; control: 8.3 [1.8]), and number (percentage) of patients receiving insulin (intervention: 82 [85.4%]; control:85 [89.5%]) and sulfonylurea (intervention: 25 [26.0%]; control: 21 [22.1%]). At 6 months, patients in the intervention arm were more likely to be prescribed a safer diabetes regimen than those in the control arm (27 [28.1%] vs 15 [15.8%]; risk difference [RD], 12.3% [95% CI, 0.6% to 24.0%]). Patients in the intervention arm also experienced significantly fewer hypoglycemia-related emergency department or inpatient encounters (0 vs 5 [5.3%]; RD, -5.3% [95% CI, -11.8% to -1.3%]). There was no worsening of HbA1c control in the intervention arm compared with the control arm (47 [61.8%] vs 49 [63.6%] with HbA1c <8%; RD, -1.8% [95% CI, -17.0% to 13.5%]).<h4>Conclusions and relevance</h4>In this randomized clinical trial, adding proactive, protocol-driven clinical pharmacist outreach into collaborative team-based care improved medication optimization and patient outcomes. This approach provides an evidence-based strategy for reducing the risk of developing severe hypoglycemia in individuals with T2D at high risk, enhancing patient safety, and potentially reducing overall health care cost.<h4>Trial registration</h4>ClinicalTrials.gov Identifier: NCT06746714.

Pharmacist Intervention for Safer Prescribing in Patients With Type 2 Diabetes at High Risk: A Randomized Clinical Trial.

<h4>Introduction</h4>In SURPASS-SWITCH, switching from dulaglutide to tirzepatide resulted in greater improvements in glycemic control and body weight in adults with type 2 diabetes (T2D). This study aimed to investigate the efficacy and safety of switching from weekly dulaglutide to weekly tirzepatide in adults with T2D in prespecified baseline subgroups from SURPASS-SWITCH.<h4>Research design and methods</h4>This phase IV, randomized, open-label, active-controlled, parallel-group, multicenter, multinational trial included adults with hemoglobin A1c (HbA1c) ≥7.0% to ≤9.5%, on a stable dose of dulaglutide for at least 6 months, on a stable dose of 0-3 oral antihyperglycemic medications for at least 3 months, with stable body weight, and body mass index (BMI) ≥25 kg/m<sup>2</sup> at screening. Participants were randomly assigned 1:1 to continue with and escalate to dulaglutide 4.5 mg or maximum tolerated dose (MTD) or switch to tirzepatide with escalation to 15 mg or MTD. Changes from baseline in HbA1c and body weight at week 40 in baseline subgroups of age (<65, ≥65 years), HbA1c (≤8.5%, >8.5%), duration of T2D (≤5, >5 to ≤10, >10 years), baseline dulaglutide dose (0.75 mg, 1.5 mg), duration of dulaglutide dose (<1, ≥1 year), BMI (<27, ≥27; <30, ≥30 to <35, ≥35 kg/m<sup>2</sup>), and ethnicity (Hispanic or Latino, non-Hispanic or non-Latino), and sex (female, male) were determined.<h4>Results</h4>Reductions in HbA1c and body weight at week 40 were significant and consistently greater with tirzepatide across all prespecified baseline subgroups. HbA1c reduction was greater in the subgroups with higher baseline HbA1c and low baseline BMI. Weight reduction was greater for participants in the non-Hispanic or non-Latino subgroup. The safety profile was similar across subgroups. Nausea and diarrhea were usually the most frequently reported treatment-emergent adverse events in each subgroup.<h4>Conclusions</h4>In this subgroup analysis of SURPASS-SWITCH, switching to tirzepatide from dulaglutide was generally well-tolerated and associated with significant and consistent improvements in HbA1c and weight reductions versus dulaglutide across all baseline subgroups evaluated. These results indicate that switching to tirzepatide may provide a clinical option across a range of baseline characteristics when treatment goals are not being met with dulaglutide.<h4>Trial registration number</h4>NCT05564039.

Safety and efficacy of switching from dulaglutide to tirzepatide across clinically relevant baseline characteristics in participants with T2D: subgroup analysis of SURPASS-SWITCH.

Includes self-reported outcomes (moderate): Self-reported outcomes used

No post-intervention follow-up (moderate): 0 weeks of follow-up after treatment ended

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

Xiaoke Pill lowered hypoglycemia risk with similar HbA1c control

This multicenter trial compared Xiaoke Pill, a traditional Chinese medicine compound containing low-dose glibenclamide, with glibenclamide alone in 800 adults with type 2 diabetes. Over 48 weeks, both treatments improved HbA1c and fasting glucose similarly, but Xiaoke Pill caused fewer hypoglycemia episodes, especially in drug-naive patients and in people already taking metformin.

Xiaoke Pill was compared with glibenclamide alone, not with newer diabetes treatments. The trial supports similar glucose lowering and fewer hypoglycemia episodes, but it does not prove that the herbal components improve long-term complications. Treatment decisions should still consider access, safety monitoring, and whether sulfonylurea therapy is appropriate in the first place.

Whether Xiaoke Pill can match glibenclamide for glucose control with less hypoglycemia

These findings apply most directly to adults aged 21 to 70 with type 2 diabetes, poor glycemic control, and either no prior glucose-lowering drugs or stable metformin use. The results are less certain for non-Chinese populations, people with advanced complications, or those using insulin or other modern drug combinations.

Xiaoke Pill lowered hypoglycemia risk with similar HbA1c control

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