Japan Study: DPP-4 Inhibitor Smooths Blood Sugar Swings on Insulin

Japanese Researchers Find Smarter Way to Smooth Out Blood Sugar on Insulin

A study from Japan published in Diabetology International (2022) offers a practical insight for Type 2 diabetes patients who struggle with unpredictable blood sugar levels despite taking multiple daily insulin injections. Researchers at Toho University Graduate School of Medicine in Tokyo found that adding a DPP-4 inhibitor medication to a low dose of metformin worked better than simply doubling the metformin dose — not for lowering average blood sugar, but for smoothing out the daily highs and lows.

What Makes This Study Unique

This research stands out for a couple of important reasons. First, Japanese clinical practice commonly uses lower metformin doses (about 750 mg/day) than the typical US approach, where doses of 1,500–2,000 mg/day are standard. This gave researchers a rare opportunity to compare adding a second drug class versus simply increasing an existing one. Second, the study used continuous glucose monitoring (CGM) — the same technology behind popular US devices like the Dexterity and Libre — to measure not just average blood sugar, but the full pattern of daily fluctuations.

What the Researchers Did

Twenty adults with Type 2 diabetes whose blood sugar was not well controlled (HbA1c between 7.0% and 9.0% — well within the range many US patients experience) were already on multiple daily insulin injections plus low-dose metformin. Participants were split into two groups for 12 weeks each in a crossover design:

• Group 1 (LMET + DPP-4i): Continued low-dose metformin (750 mg/day) and added vildagliptin, a DPP-4 inhibitor (100 mg/day). Note: Vildagliptin is not available in the US, but closely related drugs like sitagliptin/Januvia and alogliptin/Nesina are widely prescribed here.
• Group 2 (HMET): Metformin dose was doubled to 1,500 mg/day — closer to standard US practice.

Key Findings — In Plain English

Both approaches produced similar HbA1c results, body weight changes, and insulin doses. However, the DPP-4 inhibitor group showed significantly less blood sugar variability across multiple CGM measures, including:

• Smaller daily blood sugar swings (lower standard deviation of glucose readings)
• Fewer high blood sugar spikes (lower High Blood Glucose Index)
• More stable overall glucose patterns throughout the day

Importantly, rates of low blood sugar (hypoglycemia) were similar between both groups — meaning the DPP-4 inhibitor approach did not increase dangerous lows.

How This Compares to US Guidelines

US guidelines from the American Diabetes Association (ADA) already support DPP-4 inhibitors as an add-on therapy for patients not meeting blood sugar goals. However, US practice typically escalates metformin doses first. This Japanese study suggests that for patients already on insulin, adding a DPP-4 inhibitor — even alongside a lower metformin dose — may be the smarter move for reducing the daily blood sugar rollercoaster, which is linked to cardiovascular risk and reduced quality of life.

Why This Matters for US Patients

If you're taking multiple daily insulin injections and still experiencing significant blood sugar highs and lows, this research supports asking your doctor about adding a DPP-4 inhibitor rather than simply increasing your metformin. Smoother blood sugar throughout the day may reduce your risk of complications and help you feel more consistently well. Tracking your own glucose variability with a CGM device can help you and your care team make this decision with real data.

At mdsdiabetes.com, MDS Diabetes offers resources to help you understand your CGM data and work more effectively with your healthcare provider to reduce glucose variability — whether you're on insulin, oral medications, or both.

Full Citation

Yoshikawa, Uchino, Nagashima (2022). Dipeptidyl peptidase-4 inhibitor improves glycemic variability in multiple daily insulin-treated type 2 diabetes: a prospective randomized-controlled trial. Diabetology International. Country: Japan. Toho University Graduate School of Medicine, Tokyo. PMID: 35059248. DOI: 10.1007/s13340-021-00513-6