Sodium-Glucose Cotransporter-2 Inhibitors and Nephritis Among Patients With Systemic Lupus Erythematosus.

Importance: Lupus nephritis is a major complication of systemic lupus erythematosus (SLE). Randomized clinical trials have shown nephroprotective and cardioprotective effects of sodium-glucose cotransporter-2 inhibitors (SGLT2is). Objective: To investigate whether the use of SGLT2is is associated with the onset and progression of lupus nephritis and other kidney and cardiac outcomes in patients with SLE and type 2 diabetes. Design, Setting, and Participants: This multicenter cohort study used the US Collaborative Network of the TriNetX clinical data platform to identify patients with SLE and type 2 diabetes from January 1, 2015, to December 31, 2022. Data collection and analysis were conducted in September 2023. Exposures: Individuals were categorized into 2 groups by SGLT2i use or nonuse with 1:1 propensity score matching. Main Outcomes and Measures: The Kaplan-Meier method and Cox proportional hazards regression models were used to calculate the 5-year adjusted hazard ratios (AHRs) of lupus nephritis, dialysis, kidney transplant, heart failure, and mortality for the 2 groups. Results: From 31 790 eligible participants, 1775 matched pairs of SGLT2i users and nonusers (N = 3550) were selected based on propensity scores. The mean (SD) age of matched participants was 56.8 (11.6) years, and 3012 (84.8%) were women. SGLT2i users had a significantly lower risk of lupus nephritis (AHR, 0.55; 95% CI, 0.40-0.77), dialysis (AHR, 0.29; 95% CI, 0.17-0.48), kidney transplant (AHR, 0.14; 95% CI, 0.03-0.62), heart failure (AHR, 0.65; 95% CI, 0.53-0.78), and all-cause mortality (AHR, 0.35; 95% CI, 0.26-0.47) than SGLT2i nonusers. Conclusions and Relevance: In this cohort study of patients with SLE and type 2 diabetes, SGLT2i users had a significantly lower risk of lupus nephritis, dialysis, kidney transplant, heart failure, and all-cause mortality than nonusers. The findings suggest that SGLT2is may provide some nephroprotective and cardioprotective benefits.

Sodium-Glucose Cotransporter-2 Inhibitors and the Risk for Dialysis and Cardiovascular Disease in Patients With Stage 5 Chronic Kidney Disease.

BACKGROUND: No studies have reported the long-term outcomes of initiating sodium-glucose cotransporter-2 inhibitors (SGLT2is) in patients with estimated glomerular filtration rates less than 20 mL/min/1.73 m2 to predialysis. OBJECTIVE: To compare the risk for dialysis, cardiovascular events, and death between SGLT2i users and nonusers in patients with type 2 diabetes (T2D) and stage 5 chronic kidney disease (CKD). DESIGN: Target trial emulation study. SETTING: Taiwan's National Health Insurance Research Database (NHIRD). PARTICIPANTS: By applying sequential target trial emulation principle, 23 854 SGLT2i users and 23 892 SGLT2i nonusers were selected from the NHIRD for patients with T2D and stage 5 CKD from 1 May 2016 to 31 October 2021. MEASUREMENTS: Conditional Cox proportional hazards models were used to compare the risks for dialysis, hospitalization for heart failure, acute myocardial infarction (AMI), diabetic ketoacidosis (DKA), acute kidney injury (AKI), and all-cause mortality between SGLT2i users and nonusers. RESULTS: In the intention-to-treat model, compared with no SGLT2i use, SGLT2i use was associated with lower risks for dialysis (hazard ratio [HR], 0.34 [95% CI, 0.27 to 0.43]), hospitalization for heart failure (HR, 0.80 [CI, 0.73 to 0.86]), AMI (HR, 0.61 [CI, 0.52 to 0.73]), DKA (HR, 0.78 [CI, 0.71 to 0.85]), and AKI (HR, 0.80 [CI, 0.70 to 0.90]), but there was no difference in the risk for all-cause mortality (HR, 1.11 [CI, 0.99 to 1.24]). The Kaplan-Meier curves and subgroup analyses also showed that initiation of an SGLT2i in stage 5 CKD was associated with a lower risk for long-term dialysis than no SGLT2i use. LIMITATION: This result may not apply to patients without T2D. CONCLUSION: This emulated target trial showed that SGLT2i use was associated with a lower risk for dialysis, cardiovascular events, DKA, and AKI than no SGLT2i use in patients with T2D and stage 5 CKD. PRIMARY FUNDING SOURCE: National Health Research Institutes, Taiwan.

Metformin and the risks of cellulitis, foot infections, and amputation in patients with type 2 diabetes.

BACKGROUND: Patients with diabetes tend to have cellulitis, foot infections, and amputation. We conducted this research to compare the risks of cellulitis, foot infections, and amputation between metformin no-use and use in persons with type 2 diabetes. METHODS: Using propensity score matching, we identified 23 234 pairs of metformin nonusers and users from the National Health Insurance Research Database of Taiwan, since January 1, 2000, to December 31, 2017. Cox proportional hazards models were adopted to examine the risks of incident cellulitis, recurrent cellulitis, foot infections, and amputation between metformin use and no-use. RESULTS: The mean follow-up period of metformin use and no-use was 6.31 (3.93) and 5.54 (3.97) years, respectively. Compared with metformin no-use, the adjusted hazard ratio and 95% confidence interval for metformin use in cellulitis development, recurrent cellulitis, foot infections, and amputation were 1.08 (1.04-1.12), 1.33 (1.14-1.55), 1.91 (1.75-2.09), and 1.88 (1.35-2.62), respectively. The longer cumulative duration of metformin usage had association with higher risks of these outcomes than metformin no-use. CONCLUSION: This population-based cohort study revealed that metformin use had association with significantly higher risks of incident cellulitis, recurrent cellulitis, foot infections, and amputation than metformin no-use in patients with type 2 diabetes.

Effects of glucagon-like peptide-1 receptor agonists on liver-related and cardiovascular mortality in patients with type 2 diabetes.

BACKGROUND: Patients with type 2 diabetes (T2D) tend to have nonalcoholic fatty liver disease (NAFLD) with poorer prognosis. We performed this research to compare the risks of cardiovascular diseases, cirrhosis, liver-related mortality, and cardiovascular mortality between glucagon-like peptide-1 receptor agonist (GLP-1 RA) use and no-use in patients with T2D without viral hepatitis. METHODS: From January 1, 2008, to December 31, 2018, we used propensity-score matching to identify 31,183 pairs of GLP-1 RA users and nonusers from Taiwan's National Health Insurance Research Database. Multivariable-adjusted Cox proportional hazards models were used to examine the outcomes between the study and control groups. RESULTS: The median (Q1, Q3) follow-up time for GLP-1 RA users and nonusers were 2.19 (1.35, 3.52) and 2.14 (1.19, 3.68) years, respectively. The all-cause mortality incidence rate was 5.67 and 13.06 per 1000 person-years for GLP-1 RA users and nonusers, respectively. Multivariable-adjusted analysis showed that GLP-1 RA use had significantly lower risks of all-cause mortality (aHR 0.48, 95%CI 0.43-0.53), cardiovascular events (aHR 0.92, 95%CI 0.86-0.99), cardiovascular death (aHR 0.57, 95%CI 0.45-0.72), and liver-related death (aHR 0.32, 95%CI 0.13-0.75). However, there was no significant difference in the risk of liver cirrhosis development, hepatic failure, and hepatocellular carcinoma compared to GLP-1 RA no-use. CONCLUSIONS: This nationwide cohort study showed that GLP-1 RA use was associated with a significantly lower risk of all-cause mortality, cardiovascular events, and cardiovascular death in patients with T2D among Taiwan population. More prospective studies are warranted to verify our results.

Sodium-Glucose Cotransporter 2 Inhibitors and Risk of Retinopathy in Patients With Type 2 Diabetes.

Importance: Diabetic nephropathy and diabetic retinopathy share many similarities in pathophysiological processes. Preclinical studies have shown that sodium-glucose cotransporter 2 inhibitors (SGLT2is) have a protective role in the risk of diabetic retinopathy. Objective: To compare the risk of sight-threatening retinopathy associated with SGLT2is and other second-line glucose-lowering medications (including pioglitazone, sulfonylureas, and dipeptidyl peptidase-4 inhibitors [DPP-4is]) in patients with type 2 diabetes (T2D). Design, Setting, and Participants: This cohort study in Taiwan applied a new-user and active-comparator design. Patient demographic and clinical data were obtained from the National Health Insurance Research Database. Adult patients with newly diagnosed T2D from January 1, 2009, to December 31, 2019, were recruited and followed up until December 31, 2020. Propensity score matching was used to identify pairs of patients treated with SGLT2i vs DPP-4i, SGLT2i vs pioglitazone, and SGLT2i vs sulfonylurea from January 1, 2016, to December 31, 2019. Data were analyzed between August 18, 2022, and May 5, 2023. Exposures: Treatment with SGLT2i, DPP-4i, pioglitazone, and sulfonylureas starting on January 1, 2016. Main Outcomes and Measures: The main outcome was sight-threatening retinopathy in participants. Cox proportional hazards regression models were used to assess relative hazards of sight-threatening retinopathy between the matched case and control groups. Results: A total of 3 544 383 patients with newly diagnosed T2D were identified. After 1:1 propensity score matching, 65 930 pairs of patients treated with SGLT2i vs DPP-4i, 93 760 pairs treated with SGLT2i vs pioglitazone, and 42 121 pairs treated with SGLT2i vs sulfonylurea were identified. These matched patients included 236 574 males (58.6%), with a mean (SD) age of 56.9 (11.8) years. In the matched cohorts, SGLT2i had a significantly lower risk of sight-threatening retinopathy than DPP-4i (adjusted hazard ratio [AHR], 0.57; 95% CI, 0.51-0.63), pioglitazone (AHR, 0.75; 95% CI, 0.69-0.81), and sulfonylureas (AHR, 0.62; 95% CI, 0.53-0.71). The Kaplan-Meier curves showed that SGLT2i was associated with a significantly lower cumulative incidence of sight-threatening retinopathy than DPP-4i (3.52 vs 6.13; P < .001), pioglitazone (4.32 vs 5.76; P < .001), and sulfonylureas (2.94 vs 4.67; P < .001). Conclusions and Relevance: This cohort study found that SGLT2i was associated with a lower risk of sight-threatening retinopathy compared with DPP-4i, pioglitazone, and sulfonylureas. This finding suggests that SGLT2i may play a role not only in reduced risk of diabetic nephropathy but also in the slow progression of diabetic retinopathy in patients with T2D.

Parental Income Level and Risk of Developing Type 2 Diabetes in Youth.

Importance: In recent years, the global incidence of type 2 diabetes in young people has increased, especially among minoritized, Indigenous, or financially disadvantaged populations. However, few studies have examined whether poverty is associated with increased risk of youth-onset type 2 diabetes. Objective: To examine the association of family income level with the risk of youth-onset type 2 diabetes. Design, Setting, and Participants: This nationwide, population-based retrospective cohort study used data from the 2008 National Health Insurance Research Database of Taiwan, with follow-up through December 31, 2019. Participants included children and adolescents aged 0 to 19 years. Data analysis was performed from June 9, 2022, to January 16, 2023. Exposures: Family income, classified as very low, low, middle, and high. Main Outcomes and Measures: Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs) for the risks of youth-onset type 2 diabetes and all-cause mortality for all income groups vs the high-income group. Results: The cohort included a total of 5 182 893 children and adolescents (mean [SD] age, 11.2 [5.2] years; 2 477 807 girls [48.3%]). The mean (SD) follow-up duration was 9.0 (0.3) years. The incidence rates of youth-onset type 2 diabetes were 0.52 cases per 1000 person-years for the very-low-income group, 0.40 cases per 1000 person-years for the low-income group, 0.35 cases per 1000 person-years for the middle-income group, and 0.28 cases per 1000 person-years for the high-income group. Children and adolescents from very-low-income (aHR, 1.55; 95% CI, 1.41-1.71), low-income (aHR, 1.34; 95% CI, 1.27-1.41), and middle-income (aHR, 1.27; 95% CI, 1.20-1.34) families had a significantly higher hazard of youth-onset type 2 diabetes than those from high-income families. Children and adolescents from very-low-income (aHR, 2.18; 95% CI, 1.97-2.41), low-income (aHR, 1.51; 95% CI, 1.42-1.60), and middle-income (aHR, 1.22; 95% CI, 1.14-1.31) families also had a significantly higher hazard of all-cause mortality than those from high-income families. Children and adolescents who were older, female, and obese and had dyslipidemia, gout, or psychiatric disorders had a significantly higher risk of youth-onset type 2 diabetes than children without those characteristics. Conclusions and Relevance: This population-based cohort study showed that children and adolescents from very-low-income to middle-income families had a higher hazard of youth-onset type 2 diabetes and mortality than those from high-income families. Further research to reveal the factors underlying this association may improve the accuracy of identifying individuals at greatest risk for developing type 2 diabetes in youth.

Glucagon-like Peptide-1 Receptor Agonist Use in Patients With Liver Cirrhosis and Type 2 Diabetes.

BACKGROUND AND AIMS: Liver cirrhosis is often associated with type 2 diabetes (T2D), but research on treatment of T2D in cirrhotic patients is scarce. We investigated the long-term outcomes of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with T2D and cirrhosis. METHODS: Using propensity score matching, we selected 467 matched pairs of GLP-1 RA users and nonusers from the National Health Insurance Research Database of Taiwan from January 1, 2008, to December 31, 2019. Multivariable-adjusted Cox proportional hazards models were used to compare the outcomes between GLP-1 RA users and nonusers. RESULTS: The mean follow-up time was 3.28 and 3.06 years for GLP-1 RA users and nonusers, respectively. The rates of death were 27.46 and 55.90 per 1000 person-years for GLP-1 RA users and nonusers, respectively. The multivariable-adjusted models showed that GLP-1 RA users had lower risks of mortality (adjusted hazard ratio [aHR], 0.47; 95% confidence interval [CI], 0.32-0.69), cardiovascular events (aHR, 0.6; 95% CI, 0.41-0.87), decompensated cirrhosis (aHR, 0.7; 95% CI, 0.49-0.99), hepatic encephalopathy (aHR, 0.59; 95% CI, 0.36-0.97), and liver failure (aHR, 0.54; 95% CI, 0.34-0.85) than nonusers. A longer cumulative duration of GLP-1 RA use had a lower risk of these outcomes than GLP-1 RA nonuse. CONCLUSIONS: This population-based cohort study showed that GLP-1 RA users exhibited a significantly lower risk of death, cardiovascular events, decompensated cirrhosis, hepatic encephalopathy, and liver failure in patients with T2D and compensated liver cirrhosis. Additional studies are needed to confirm our results.

Is a low-carbohydrate, high-fat diet feasible for people with type 2 diabetes and nonalcoholic fatty liver disease?

More rigorous studies are needed to obtain robust and consistent results to provide helpful and feasible dietary recommendations for patients with type 2 diabetes and nonalcoholic fatty liver disease.

Respiratory Outcomes of Insulin Use in Patients with COPD: A Nationwide Population-Based Cohort Study.

Acute exacerbations of chronic obstructive pulmonary disease (COPD) with severe hyperglycemia may require insulin to lower glucose levels in people with coexisting type 2 diabetes (T2D) and COPD. We conducted this study to examine the risk of hospitalization for COPD, pneumonia, ventilator use, lung cancer, hypoglycemia, and mortality with and without insulin use in people with T2D and COPD. We adopted propensity-score-matching to identify 2370 paired insulin users and non-users from Taiwan's National Health Insurance Research Database between 1 January 2000 and 31 December 2018. Cox proportional hazards models and the Kaplan-Meier method were utilized to compare the risk of outcomes between study and control groups. The mean follow-up for insulin users and non-users was 6.65 and 6.37 years. Compared with no insulin use, insulin use was associated with a significantly increased risk of hospitalization for COPD (aHR 1.7), bacterial pneumonia (aHR 2.42), non-invasive positive pressure ventilation (aHR 5.05), invasive mechanical ventilation (aHR 2.72), and severe hypoglycemia (aHR 4.71), but with no significant difference in the risk of death. This nationwide cohort study showed that patients with T2D and COPD requiring insulin therapy may have an increased risk of acute COPD exacerbations, pneumonia, ventilator use, and severe hypoglycemia without a significant increase in the risk of death.

Impact of individual microvascular disease on the risks of macrovascular complications in type 2 diabetes: a nationwide population-based cohort study.

BACKGROUND: This study compared the risks of cardiovascular morbidity and mortality between patients with type 2 diabetes (T2D) with and without microvascular diseases, and between matched patients with microvascular diseases. METHODS: We identified newly diagnosed type 2 diabetes patients from National Health Insurance Research Database in Taiwan from January 1, 2008, to December 31, 2019. Propensity score matching was applied to construct matched pairs of patients with diabetic kidney disease, retinopathy, or neuropathy. Multivariable Cox proportional-hazard models were adopted to compare the risks of cardiovascular morbidity and mortality. RESULTS: Patients with microvascular disease had a significantly higher risk of cardiovascular morbidities and mortality than those without microvascular disease. Among the matched cohorts, patients with diabetic retinopathy had a significantly higher risk of stroke development than those with diabetic kidney disease (aHR 1.11, 95%CI 1.03-1.2). Diabetic neuropathy showed a significantly higher risk of stroke development than diabetic kidney disease (aHR 1.17, 95%CI 1.1-1.25) and diabetic retinopathy (aHR 1.12, 95%CI 1.03-1.21). Diabetic retinopathy had a significantly higher risk of incident heart failure than diabetic kidney disease (aHR 1.43, 95%CI 1.3-1.57), and diabetic neuropathy had a significantly lower risk of incident heart failure than diabetic retinopathy (aHR 0.79, 95%CI 0.71-0.87). CONCLUSIONS: T2D patients with microvascular disease have a significantly higher risk of cardiovascular morbidities and mortality than those without microvascular disease. In the matched cohorts, diabetic neuropathy was significantly associated with stroke development, and diabetic retinopathy had a significant association with heart failure compared to other microvascular diseases.

Metformin use before COVID-19 vaccination and the risks of COVID-19 incidence, medical utilization, and all-cause mortality in patients with type 2 diabetes mellitus.

AIMS: We designed this study to determine whether metformin use before COVID-19 vaccination influences the risk of COVID-19 infection, medical utilization, and mortality. METHODS: We used the US collaborative network of TriNetX to identify 123,709 patients with type 2 diabetes mellitus fully vaccinated against COVID-19 between January 1, 2020, and November 22, 2022. The study selected 20,894 pairs of metformin users and nonusers by propensity score matching. The Kaplan-Meier method and Cox proportional hazards models were used to compare the risks of COVID-19 infection, medical utilization, and mortality between the study and control groups. RESULTS: No significant difference was noted between metformin users and nonusers in the risk of COVID-19 incidence (aHR = 1.02, 95% CI = 0.94-1.10). Compared to the control cohort, the metformin cohort exhibited a significantly lower risk of hospitalization (aHR = 0.85, 95% CI = 0.81-0.89), critical care services (aHR = 0.81, 95% CI = 0.70-0.94), mechanical ventilation (aHR = 0.75, 95% CI = 0.60-0.95), and mortality (aHR = 0.75, 95% CI = 0.63-0.89). The subgroup analyses and sensitivity analysis showed similar results. CONCLUSION: The present study showed that metformin use before COVID-19 vaccination could not reduce COVID-19 incidence; however, it was associated with significantly lower risks of hospitalization, intensive care service, mechanical ventilation, and mortality in fully vaccinated type 2 diabetes mellitus patients.

Thiazolidinediones lower the risk of pneumonia in patients with type 2 diabetes.

Introduction: We conducted this study to compare the risk of pneumonia between thiazolidinedione (TZD) use and nonuse in persons with type 2 diabetes (T2D). Methods: We identified 46,763 propensity-score matched TZD users and nonusers from Taiwan's National Health Insurance Research Database between January 1, 2000, and December 31, 2017. The Cox proportional hazards models were used for comparing the risk of morbidity and mortality associated with pneumonias. Results: Compared with the nonuse of TZDs, the adjusted hazard ratios (95% CI) for TZD use in hospitalization for all-cause pneumonia, bacterial pneumonia, invasive mechanical ventilation, and death due to pneumonia were 0.92 (0.88-0.95), 0.95 (0.91-0.99), 0.80 (0.77-0.83), and 0.73 (0.64-0.82), respectively. The subgroup analysis revealed that pioglitazone, not rosiglitazone, was associated with a significantly lower risk of hospitalization for all-cause pneumonia [0.85 (0.82-0.89)]. Longer cumulative duration and higher cumulative dose of pioglitazone were associated with further lower adjusted hazard ratios in these outcomes compared to no-use of TZDs. Discussion: This cohort study demonstrated that TZD use was associated with significantly lower risks of hospitalization for pneumonia, invasive mechanical ventilation, and death due to pneumonia in patients with T2D. Higher cumulative duration and dose of pioglitazone were associated with a further lower risk of outcomes.

Maternal autoimmune disease associated with a higher risk of offspring with type 1 diabetes: A nationwide mother-child cohort study in Taiwan.

AIM: The incidence of type 1 diabetes continues to increase. However, the strategies to prevent or reduce its occurrence are inadequate. Therefore, we attempted to investigate if mothers with autoimmune disease were more likely to have children with type 1 diabetes. METHODS: We identified 1,288,347 newborns from the Taiwan Maternal and Child Health Database between January 1, 2009, and December 31, 2016, and followed them up to December 31, 2019. We used a multivariable Cox regression model to compare the childhood-onset type 1 diabetes risk between children whose mother had or did not have an autoimmune disease. RESULTS: The multivariable model demonstrated significantly higher risks of type 1 diabetes in the children with maternal autoimmune disease (aHR 1.55, 95% CI 1.16-2.08), type 1 diabetes (aHR 11.33, 95% CI 4.62-27.77), Hashimoto's thyroiditis (aHR 3.73, 95% CI 1.70-8.15), and inflammatory bowel diseases (aHR 2.00, 95% CI 1.07-3.76). CONCLUSION: This nationwide mother and child cohort study showed a higher risk of type 1 diabetes in the children whose mothers had autoimmune disease, including Hashimoto's thyroiditis, and inflammatory bowel diseases.

The Risk of Severe Hypoglycemia and Mortality in Patients With Type 2 Diabetes and Discharged With Acute Liver Injury.

OBJECTIVE: To compare the risks of severe hypoglycemia and mortality between patients with type 2 diabetes (T2D) and discharged with and without acute liver injury. RESEARCH DESIGN AND METHODS: From 1 January 2000 to 31 December 2010, we identified patients with T2D and hospitalization for acute liver injury and hospitalization for other causes from the National Health Insurance Research Database of Taiwan. Multivariable-adjusted Cox proportional hazards models were used to compare the risks of severe hypoglycemia and mortality between the study and control groups. RESULTS: The incidence rates and adjusted hazard ratios (aHRs) for severe hypoglycemia within 90 days and 365 days after discharge were 12.28 and 5.59/1,000 person-years (aHR 1.92 [1.30-2.85]) and 7.35 and 2.9/1,000 person-years (aHR 1.98 [1.52-2.58]) for patients discharged with and without acute liver injury, respectively. The incidence rates and aHRs for mortality within 90 days and 365 days after discharge were 82.4 and 27.54/1,000 person-years (aHR 1.73 [1.46-2.05]) and 36.8 and 9.3/1,000 person-years (aHR 1.94 [1.69-2.24]) for patients discharged with and without acute liver injury, respectively. The subgroup analysis of hypoglycemia risk in patients discharged with acute liver injury revealed no significant interaction in risk factors of age, chronic kidney disease, and medications, except for sex difference, which has significant interaction. CONCLUSIONS: This cohort study demonstrated that patients with T2D and discharged with acute liver injury showed significantly higher risks of severe hypoglycemia and mortality within 90 days and 365 days after discharge than patients discharged with other causes.

Metformin use and the risks of herpes zoster and postherpetic neuralgia in patients with type 2 diabetes.

Herpes zoster and postherpetic neuralgia cause substantial pain in patients. Persons with type 2 diabetes (T2D) are prone to zoster infection and postherpetic neuralgia due to compromised immunity. We conducted this study to evaluate the risks of herpes zoster and postherpetic neuralgia between metformin users and nonusers. Propensity score matching was utilized to select 47 472 pairs of metformin users and nonusers from Taiwan's National Health Insurance Research Database between January 1, 2000, and December 31, 2017. The Cox proportional hazards models were used for comparing the risks of herpes zoster and postherpetic neuralgia between metformin users and nonusers in patients with T2D. Compared with no-use of metformin, the adjusted hazard ratios (95% confidence interval) for metformin use in herpes zoster and postherpetic neuralgia were 0.70 (0.66, 0.75) and 0.510 (0.39, 0.68), respectively. A higher cumulative dose of metformin had further lower risks of herpes zoster and postherpetic neuralgia than metformin no-use. This nationwide cohort study demonstrated that metformin use was associated with a significantly lower risk of herpes zoster and postherpetic neuralgia than metformin no-use. Moreover, a higher cumulative dose of metformin was associated with further lower risks of these outcomes.