Impact of differing glucose‐lowering regimens on the pattern of association between glucose control and survival

Aims

To characterize survival in relation to achieved glycated haemoglobin (HbA1c) level within alternative glucose‐lowering regimens with differing risks of hypoglycaemia.

Methods

Data were extracted from the UK Clinical Practice Research Datalink and the corresponding Hospital Episode Statistics. Patients with type 2 diabetes prescribed glucose‐lowering therapy in monotherapy or dual therapy with metformin between 2004 and 2013 were identified. Risk of all‐cause mortality within treatment cohorts was evaluated using the Cox proportional hazards model, introducing mean HbA1c as a quarterly updated, time‐dependent covariable.

Results

There were 6646 deaths in a total follow‐up period of 374 591 years. Survival for lower (<7%) vs moderate HbA1c levels (≥7%, <8.5%) differed by cohort: metformin, adjusted hazard ratio (aHR) 1.03 (95% confidence interval [CI] 0.95‐1.12); sulphonylurea, aHR 1.11 (95% CI 0.99‐1.25); insulin, aHR 1.47 (95% CI 1.25‐1.72); combined regimens with low hypoglycaemia risk, aHR 1.02 (95% CI 0.94‐1.10); and combined regimens with higher hypoglycaemia risk excluding insulin, aHR 1.24 (95% CI 1.13‐1.35) and including insulin, aHR 1.28 (95% CI 1.18‐1.37). Higher HbA1c levels were associated with increased mortality in regimens with low hypoglycaemia risk. Post hoc analysis by HbA1c deciles revealed an elevated risk of all‐cause mortality for the lowest deciles across all cohorts, but particularly in those regimens associated with hypoglycaemia. High HbA1c was associated with no difference, or a small increase in mortality risk in regimens with increased risk of hypoglycaemia.

Conclusions

The pattern of mortality risk across the range of HbA1c differed by glucose‐lowering regimen. Lower HbA1c was associated with increased mortality risk compared with moderate control, especially in those regimens associated with hypoglycaemia. High levels of HbA1c were associated with the expected elevated mortality risk in regimens with low hypoglycaemia risk.     

Sulfonylureas as Initial Treatment for Type 2 Diabetes and the Risk of Severe Hypoglycemia

Purpose

The magnitude of the risk of severe hypoglycemia associated with sulfonylureas as the initial treatment for type 2 diabetes in the real-world setting is unknown. We assessed the risk of severe hypoglycemia associated with initiating monotherapy with sulfonylurea compared with metformin for the treatment of type 2 diabetes.

Association of sulfonylureas with the risk of dementia: A population-based cohort study

Background

Sulfonylureas are oral glucose-lowering medications positioned as a second-line therapy for type 2 diabetes. Evidence relating them to cognitive decline has been mixed. The objective was to determine whether sulfonylurea use was associated with a differential risk of dementia compared with dipeptidyl peptidase-4 (DPP4) inhibitor use.

Methods

Using administrative data from residents in Ontario, Canada, adults aged ≥66 years who were new users of a sulfonylurea or a DPP4 inhibitor from June 14, 2011, to March 31, 2021 entered this population-based retrospective cohort study. Dementia was ascertained using a validated algorithm for Alzheimer's disease and related dementias. Propensity-score weighted Cox proportional hazards models were used to obtain adjusted hazard ratios (aHR) and confidence intervals (CI) for time to incident dementia. The observation window started at 1 year after cohort entry to mitigate protopathic bias due to delayed diagnosis. The primary analysis used an intention-to-treat exposure definition. A separate propensity-score weighted analysis was conducted to explore within-class differences in dementia risk among sulfonylurea new users selected from the primary cohort.

Results

Among 107,806 DPP4 inhibitor new users and 37,030 sulfonylurea new users, sulfonylureas compared with DPP4 inhibitors were associated with a higher risk of dementia (18.4/1000 person-years; aHR [95% CI] = 1.09 [1.04–1.15]) over a mean follow-up of 4.82 years from cohort entry. Glyburide compared to gliclazide exhibited a higher dementia risk (aHR [95% CI] = 1.17 [1.03–1.32]).

Conclusion

New use of a sulfonylurea especially glyburide was associated with a higher dementia risk compared with new use of a DPP4 inhibitor in older adults with diabetes.     

Mortality among veterans with type 2 diabetes initiating metformin, sulfonylurea or rosiglitazone monotherapy

Aims/hypotheses

Despite oral hypoglycaemic medications being the most commonly used pharmacological treatments for type 2 diabetes, research is limited on their comparative safety, particularly their effects on overall mortality. We compared mortality risk with monotherapy initiation of four oral hypoglycaemic medications in a nationwide cohort of US veterans with type 2 diabetes.

Methods

We identified new users of oral hypoglycaemic medication monotherapy between 2004 and 2009 who received care for at least 1 year from the Veterans Health Administration. Patients were followed until initial monotherapy discontinuation, addition of another diabetes pharmacotherapy, death or end of follow-up. Mortality HRs were estimated using Cox regression adjusted for potential confounding factors.

Results

Among new users of metformin, sulfonylureas and rosiglitazone (185,360 men, 7,812 women), 4,256 (2.2%) died during follow-up. Average duration of medication use ranged from 1.4 to 1.7 years. Significantly higher mortality risk was seen for glibenclamide (known as glyburide in the USA and Canada) (HR 1.38, 95% CI 1.27, 1.50) or glipizide (HR 1.55, 95% CI 1.43, 1.67) compared with metformin monotherapy, and for glipizide compared with rosiglitazone (HR 1.27, 95% CI 1.01, 1.59) or glibenclamide monotherapy (HR 1.12, 95% CI 1.02, 1.23). A significant sex–rosiglitazone interaction was seen (p?=?0.034) compared with metformin monotherapy, with women having a higher HR (HR 4.36, 95% CI 1.34, 14.20) than men (HR 1.19, 95% CI 0.95, 1.49).

Conclusions/interpretations

Significantly higher mortality was associated with glibenclamide, glipizide and rosiglitazone use compared with metformin, and with glipizide use compared with rosiglitazone or glibenclamide. The potential for residual confounding by indication should be considered in interpreting these results.     

Mortality risk with sulphonylureas compared to metformin

Current clinical guidelines in the USA and the UK recommend first‐line glucose‐lowering treatment with metformin monotherapy for glucose control in type 2 diabetes, where not contraindicated. Consequently, the proportion of people treated with sulphonylureas is decreasing. The purpose of this commentary is to discuss the risks and benefits associated with sulphonylurea monotherapy versus metformin monotherapy and the evidence that, in comparison with metformin, sulphonylureas cause increased harm to people with type 2 diabetes.     

Mortality Associated with Metformin Versus Sulfonylurea Initiation: A Cohort Study of Veterans with Diabetes and Chronic Kidney Disease

Background

For patients with type 2 diabetes and chronic kidney disease (CKD), high-quality evidence about the relative benefits and harms of oral glucose-lowering drugs is limited.

Objective

To evaluate whether mortality risk differs after the initiation of monotherapy with either metformin or a sulfonylurea in Veterans with type 2 diabetes and CKD.

Design

Observational, national cohort study in the Veterans Health Administration (VHA).

Participants

Veterans who received care from the VHA for at least 1 year prior to initiating monotherapy treatment for type 2 diabetes with either metformin or a sulfonylurea between 2004 and 2009.

Main Measures

Metformin and sulfonylurea use was assessed from VHA electronic pharmacy records. The CKD-EPI equation was used to estimate glomerular filtration rate (eGFR). The outcome of death from January 1, 2004, through December 31, 2009, was assessed from VHA Vital Status files.

Key Results

Among 175,296 new users of metformin or a sulfonylurea monotherapy, 5121 deaths were observed. In primary analyses adjusted for all measured potential confounding factors, metformin monotherapy was associated with a lower mortality hazard ratio (HR) compared with sulfonylurea monotherapy across all ranges of eGFR evaluated (HR ranging from 0.59 to 0.80). A secondary analysis of mortality risk differences favored metformin across all eGFR ranges; the greatest risk difference was observed in the eGFR category 30–44 mL/min/1.73m² (12.1 fewer deaths/1000 person-years, 95% CI 5.2–19.0).

Conclusions

Initiation of metformin versus a sulfonylurea among individuals with type 2 diabetes and CKD was associated with a substantial reduction in mortality, in terms of both relative and absolute risk reduction. The largest absolute risk reduction was observed among individuals with moderately–severely reduced eGFR (30–44 mL/min/1.73m²).

     

Long-acting insulin analogues and the risk of diabetic retinopathy among patients with type 2 diabetes: A population-based cohort study

Aim

To determine whether the use of long-acting insulin analogues is associated with an increased risk of incident diabetic retinopathy (DR) among patients with type 2 diabetes.

Methods

Using data from the Clinical Practice Research Datalink Aurum, this retrospective, population-based cohort study included patients with type 2 diabetes who initiated a long-acting insulin analogue (glargine, detemir, degludec) or Neutral Protamine Hagedorn (NPH) insulin. The primary outcome was incident DR. We used Cox proportional hazards models with inverse probability of treatment weighting to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident DR with insulin analogues versus NPH insulin.

Results

There were 66 280 new users of long-acting insulin analogues and 66 173 new users of NPH insulin. The incidence rate of DR was 101.7 per 1000 person-years (95% CI, 98.7-104.8) for insulin analogues and 93.2 (95% CI, 90.0-96.5) per 1000 person-years for NPH insulin. Compared with the current use of NPH insulin, insulin analogues were not associated with the risk of incident DR (HR 1.04, 95% CI, 0.99-1.09). The adjusted HRs were 0.84 (95% CI, 0.66-1.07) for proliferative DR and 1.02 (95% CI, 0.97-1.08) for non-proliferative DR.

Conclusions

Compared with NPH insulin, long-acting insulin analogues were not associated with the risk of incident DR among patients with type 2 diabetes. This finding provides important reassurance regarding the safety of long-acting insulin analogues with respect to incident DR.     

Reduced cardiovascular morbidity and mortality associated with metformin use in subjects with Type 2 diabetes.

AIM: Metformin therapy reduces microvascular complications in Type 2 diabetes; questions remain, however, regarding its impact on macrovascular events. This study examined metformin use in relation to risk of cardiovascular-related hospitalization and mortality. METHODS: We conducted a retrospective cohort analysis, using Saskatchewan Health administrative databases to identify new users of oral antidiabetic drugs. Subject groups were defined by medication use during 1991-1999: sulphonylurea monotherapy, metformin monotherapy, or combination therapy. Deaths and non-fatal hospitalizations recorded during the study period were identified as cardiovascular-related from ICD-9 codes. The main outcome was a composite of first non-fatal hospitalization or death. Standard multivariate techniques, including propensity scores, were used to adjust for potential confounding. Multivariate Cox proportional hazard models were used to examine the relationship between metformin use and the composite endpoint. RESULTS: Metformin monotherapy was associated with a lower risk of the composite endpoint (adjusted hazard ratio 0.81; 95% confidence interval 0.68, 0.97) compared with sulphonylurea monotherapy. Combination therapy with meformin and a sulphonylurea was associated with lower mortality, but had similar hospitalization rates, to sulphonylurea monotherapy. CONCLUSIONS: Metformin monotherapy was associated with a lower risk of cardiovascular-related morbidity and mortality, and combination metformin and sulphonylurea therapy was associated with a reduced risk of fatal cardiovascular events, when compared with sulphonylurea monotherapy.     

Insulin therapy and colorectal cancer risk among type 2 diabetes mellitus patients

BACKGROUND & AIMS: Endogenous hyperinsulinemia in the context of type 2 diabetes mellitus is potentially associated with an increased risk of colorectal cancer. We aimed to determine whether insulin therapy might increase the risk of colorectal cancer among type 2 diabetes mellitus patients. METHODS: We conducted a retrospective cohort study among all patients with a diagnosis of type 2 diabetes mellitus in the General Practice Research Database from the United Kingdom. We excluded patients with <3 years of colorectal cancer-free database follow-up after the diabetes diagnosis as well as those insulin users who developed colorectal cancer after <1 year of insulin therapy. The remaining insulin users and the noninsulin-using type 2 diabetic patients were followed for the occurrence of colorectal cancer. Hazard ratios (HR) were determined in Cox proportional hazard analysis. A nested case-control study was conducted to perform multivariable analysis and to determine a duration-response effect. RESULTS: The incidence of colorectal cancer in insulin users (n = 3160) was 197 per 100,000 person-years, compared with 124 per 100,000 person-years in type 2 diabetes mellitus patients not receiving insulin (n = 21,758). The age- and sex-adjusted HR of colorectal cancer associated with > or =1 year of insulin use was 2.1 (95% CI: 1.2-3.4, P = 0.005). The positive association strengthened after adjusting for potential confounders. The multivariable odds ratio associated with each incremental year of insulin therapy was 1.21 (95% CI: 1.03-1.42, P = 0.02). CONCLUSIONS: Chronic insulin therapy significantly increases the risk of colorectal cancer among type 2 diabetes mellitus patients.     

The use of metformin,insulin, sulphonylureas,and thiazolidinediones and the risk of fracture: Systematic review and meta‐analysis of observational studies

Certain glucose‐lowering medications have been implicated in the risk of fracture. While there is convincing evidence from randomized controlled trials (RCTs) that thiazolidinedione use is associated with a higher risk of fracture, the effects of metformin, insulin, and sulphonylureas on the risk of fracture remain equivocal because these medications are not generally investigated in RCTs. A meta‐analysis of observational studies to provide further insights into the association between the use of metformin, insulin, sulphonylureas, or thiazolidinediones and the risk of fracture was performed. PubMed and Web of Science databases were searched to identify relevant observational studies. A random effects model was used to estimate the summary relative risks (RRs) with 95% confidence intervals (CIs). The use of insulin (RR 1.49, 95% CI 1.29, 1.73; n = 23 studies), sulphonylureas (RR 1.30, 95% CI 1.18, 1.43; n = 10), and thiazolidinediones (RR 1.24, 95% CI 1.13, 1.35; n = 14) was associated with an increased risk of fracture, whereas the use of metformin was associated with a reduced risk of fracture (RR 0.86, 95% CI 0.75, 0.99; n = 12). Regarding types of thiazolidinediones, both pioglitazone (RR 1.38, 95% CI 1.23, 1.54; n = 5) and rosiglitazone (RR 1.34, 95% CI 1.14, 1.58; n = 5) were positively associated with the risk of fracture. In summary, there is compelling evidence to discourage the use of thiazolidinediones in individuals with an increased risk of fracture, whereas metformin appears to have a good safety profile for the risk of fracture. The reduced risk of fracture with metformin could possibly be due to the reduced overall risk of fracture among metformin users, as this medication is typically prescribed in the early stages of type 2 diabetes mellitus. The use of insulin or sulphonylureas may increase fracture risk; this risk is most likely attributed to an increased risk of hypoglycaemia‐induced falls. Further confirmation by additional RCTs is required to determine whether the observed association between the use of metformin, insulin, or sulphonylureas and the risk of fracture is due to treatment with these medications or confounding factors.     

Nontuberculosis Mycobacterium Disease is a Risk Factor for Chronic Obstructive Pulmonary Disease: A Nationwide Cohort Study

Background

The aim of this study was to evaluate the association between chronic obstructive pulmonary disease (COPD) and nontuberculosis mycobacterium (NTM) disease.

Methods

We used data from the National Health Insurance Research Database of Taiwan in this study. The NTM cohort contained 3,005 patients, and each case was randomly frequency matched by age, sex, income, occupation, and index year with four people from the general population without NTM infections. Multivariate Cox proportional hazards regression was used to calculate adjusted hazard ratios (aHR) of COPD in the NTM cohort compared with the non-NTM cohort.

Results

The incidence of COPD was 3.08-fold higher (21.75 vs. 6.11 per 1,000 person-years) in the NTM cohort than in the non-NTM cohort. The aHR of COPD comparing the NTM cohort with the non-NTM cohort was 3.57 (95 % CI 2.56–4.97) for women and 2.89 (95 % CI 2.31–3.61) for men. The aHR of COPD was higher in the patients with NTM infection and a comorbidity such as bronchopneumonia, pneumonia, diabetes, asthma, and heart disease. The Mycobacterium avium-intracellulare complex group (MAC) and the non-MAC group were isolated in the NTM cohort. The MAC group had a higher aHR of COPD than the non-NTM cohort (aHR = 3.72, 95 % CI 2.94–4.72). The cumulative incidence of COPD in the NTM cohort was higher than in the non-NTM cohort (P < 0.0001, log rank test).

Conclusions

Physicians should be aware of indolent NTM disease that increases the risk of COPD.     

Sulfonylureas as second line therapy for type 2 diabetes among veterans: Results from a National Longitudinal Cohort Study

AimsTo assess if switching to or adding sulfonylureas increases major adverse cardiovascular events (MACE) or severe hypoglycemia versus remaining on metformin alone.Materials and MethodsThis was a retrospective, longitudinal cohort utilizing United States Veterans Health Administration and Medicare data. Veterans with type 2 diabetes on metformin monotherapy between 2004 and 2006 were identified. Follow-up occurred through 2016. Those treated with either metformin plus a second-generation sulfonylurea (N = 45,305) or converted from metformin to a second-generation sulfonylurea (N = 2813) were compared to those receiving metformin monotherapy (N = 65,550). Hazard ratios (HR) and 95%CI from longitudinal competing risk Cox models were used to measure the association between sulfonylureas and outcomes.ResultsSwitching to or adding a sulfonylurea to metformin was associated with 3 times the risk of severe hypoglycemia versus metformin monotherapy (HR:3.44, 95% CI: 3.06,3.85 and HR: 3.08, 95% CI: 2.77,3.42, respectively). Switching to or adding a sulfonylurea to metformin was associated with a 7–19% higher risk of MACE versus metformin monotherapy (HR: 1.07, 95% CI: 1.00,1.14 and HR: 1.19, 95% CI: 1.13,1.25, respectively).ConclusionsSwitching to and adding second-generation sulfonylureas was associated an increase in severe hypoglycemia and MACE versus remaining on metformin alone. In an era where guidelines recommend diabetes therapies based on compelling indications, safety outcomes should be a key consideration when selecting therapy.     

Metformin‐associated risk of acute dialysis in patients with type 2 diabetes: A nationwide cohort study

Recent guidelines governing anti‐diabetic medications increasingly advocate metformin as first‐line therapy in all patients with type 2 diabetes. However, metformin could be associated with increased risk of acute kidney injury (AKI), acute dialysis and lactate acidosis in marginal patients. In a retrospective nationwide cohort study, a total of 168 443 drug‐naïve patients with type 2 diabetes ≥50 years, initiating treatment with either metformin or sulphonyl in Denmark between 2000 and 2012 were included in this study (70.7% initiated treatment with metformin); calculation of 1‐year risk of acute dialysis was based on g‐standardization of cause‐specific Cox regression models for acute dialysis, end‐stage renal disease and death. One‐year risks of acute dialysis were 92.4 per 100 000 (95% CI, 67.1‐121.3) and 142.7 per 100 000 (95% CI, 118.3‐168.0) for sulphonylurea and metformin, respectively. The metformin‐associated 1‐year risk of acute dialysis was increased by 50.3 per 100 000 (95% CI, 7.9‐88.6), corresponding to a risk ratio of 1.53 (95% CI, 1.06‐2.23), and a number needed to harm of 1988, thus providing evidence of potential concerns pertaining to the increasing use of metformin.     

The risk of heart failure in patients with type 2 diabetes treated with oral agent monotherapy

AIM: To determine if the risk of developing heart failure (HF) is associated with the use of sulfonylurea or metformin in patients with diabetes. METHODS: Retrospective cohort study of all adults without HF newly treated with oral antidiabetic drugs in Saskatchewan, Canada between 1991 and 1999. RESULTS: Of 5,631 diabetic subjects (mean age 66+/-13 years) newly treated with a single oral agent and followed for 4.7 (+/-2.2) years, 981 developed HF (4.1 cases per 100 patient years). The incidence of HF was greater in patients using sulfonylurea monotherapy (4.4 cases per 100 treatment years) than those taking metformin monotherapy (3.3 cases per 100 years), and users of high-dose sulfonylureas were more likely to develop incident HF than users of high-dose metformin (adjusted HR 1.24, 95% CI 1.01-1.54). Users of high-dose sulfonylureas were also more likely to develop HF (HR 1.38, 95% CI 1.20-1.60) than users of low-dose sulfonylureas; no such association existed for metformin users (HR 1.06, 95% CI 0.81-1.41). CONCLUSIONS: Users of higher doses of sulfonylurea exhibited a greater risk of developing HF. Clinicians should carefully weigh the need for high-dose sulfonylurea therapy in diabetic subjects with, or at high risk of, HF.     

Sulphonylurea–metformin combination therapy,cardiovascular disease and all‐cause mortality: the Fremantle Diabetes Study

Aim: To determine whether combination of metformin–sulphonylurea is associated with an increased risk of cardiovascular disease (CVD) and mortality in an urban community‐based cohort of type 2 patients. Methods: We studied 1271 (98.2%) of 1294 type 2 participants in the observational Fremantle Diabetes Study (mean age 64.2 years, 48.8% males) who had detailed diabetes‐specific therapy recorded at baseline and complete follow‐up data. Mortality and hospital discharge data were collected over 13 174 patient‐years (mean ± SD: 10.4 ± 3.9 years). Cox proportional hazards modelling was used to determine whether baseline diabetes treatments were independently associated with cardiovascular mortality, hospitalization for/death from CVD or all‐cause mortality after adjustment for other explanatory variables. Results: During follow‐up, 523 deaths occurred (41.1%) of which 269 (51.4%) were attributed to CVD. Hospitalization for CVD as principal diagnosis occurred at least once for 481 (37.8%) participants. In Kaplan–Meier analyses, there were significant differences in cardiovascular mortality, hospitalization for/death from CVD and all‐cause mortality between diabetes therapy groups (p < 0.001). Compared with diet and metformin monotherapy, those treated with metformin–sulphonylurea had higher cardiovascular and all‐cause mortality (p ≤ 0.024). Insulin users had significantly higher cardiovascular mortality, hospitalization for/death from CVD and all‐cause mortality than those on combination therapy (p ≤ 0.016). After adjustment for significant variables in the most parsimonious models, diabetes treatment was not independently associated with any of the three study endpoints (p ≥ 0.49). Conclusions: Combination metformin–sulphonylurea appears as safe as other blood glucose‐lowering therapies used for type 2 diabetes.     

Relative fracture risk in patients with diabetes mellitus, and the impact of insulin and oral antidiabetic medication on relative fracture risk

Aims/hypothesis We studied the association between fractures and type 1 and type 2 diabetes mellitus.Methods In this case-control study, all subjects diagnosed with a fracture (n=124,655) in Denmark served as cases, and for each case three control subjects (n=373,962) matched for sex and age were retrieved from the general population.Results Type 1 and type 2 diabetes were associated with an increased risk (1) of any fracture (odds ratio [OR]=1.3, 95% CI: 1.2–1.5 for type 1 diabetes and 1.2, 95% CI: 1.1–1.3 for type 2 diabetes after adjustment for confounders) and (2) of hip fractures (OR=1.7, 95% CI: 1.3–2.2 for type 1 diabetes, and 1.4, 95% CI: 1.2–1.6 for type 2 diabetes). Furthermore, type 2 diabetes was associated with a significant increase in forearm fractures (OR=1.2, 95% CI: 1.0–1.5), and type 1 diabetes was associated with an increased risk of spine fractures (OR=2.5, 95% CI: 1.3–4.6), whereas type 2 diabetes was not. Use of metformin and sulphonylureas was associated with a significantly decreased risk of any fracture, whereas a non-significant trend towards decreased risk of any fracture was associated with the use of insulin. Except for a decrease in hip fractures with use of sulphonylureas, no change in fracture risk in the hip, spine or forearm was associated with the use of insulin or oral antidiabetic drugs.Conclusions/interpretation Type 1 and type 2 diabetes are associated with an increased risk of any fracture and hip fractures. The use of drugs to control diabetes may reduce the association between diabetes and fractures.     

Increase in overall mortality risk in patients with type 2 diabetes receiving glipizide, glyburide or glimepiride monotherapy versus metformin: a retrospective analysis

Aims: It remains uncertain if differences in mortality risk exist among the sulfonylureas, especially in patients with documented coronary artery disease (CAD). The purpose of this study was to assess the overall mortality risk of the individual sulfonylureas versus metformin in a large cohort of patients with type 2 diabetes. Methods: A retrospective cohort study was conducted using an academic health centre enterprise‐wide electronic health record (EHR) system to identify 23 915 patients with type 2 diabetes who initiated monotherapy with metformin (N = 12774), glipizide (N = 4325), glyburide (N = 4279) or glimepiride (N = 2537), ≥18 years of age, with and without a history of CAD, and not on insulin or a non‐insulin injectable at baseline. The patients were followed for mortality by documentation in the EHR and Social Security Death Index. Multivariable Cox models with propensity analysis were used to compare cohorts. Results: An increase in overall mortality risk was observed in the entire cohort with glipizide (HR 1.64; 95% CI 1.39–1.94), glyburide (HR 1.59; 95% CI 1.35–1.88), and glimepiride (HR 1.68; 95% CI 1.37–2.06) versus metformin; however, in those patients with documented CAD, a statistically significant increase in overall mortality risk was only found with glipizide (HR 1.41; 95% CI 1.07–1.87) and glyburide (HR 1.38; 95% CI 1.04–1.83) versus metformin. Conclusions: Glipizide, glyburide and glimepiride are associated with an increased risk of overall mortality versus metformin. Our results suggest that if a sulfonylurea is required to obtain glycaemic control, glimepiride may be the preferred sulfonylurea in those with underlying CAD.     

Glycaemic control and adverse events in patients with type 2 diabetes treated with metformin + sulphonylurea: a meta-analysis

Aim:  The aim of this study was to quantify the effect of a sulphonylurea on glycaemic control and the risk adverse events when incorporated into the treatment regimen of patients with type 2 diabetes inadequately controlled on metformin.
Methods:  A systematic review was carried out to identify randomized controlled trials of sulphonylurea therapy in patients with type 2 diabetes whose glycaemic control was inadequate after maximal treatment with metformin. Data on reductions in haemoglobin A_1C (HbA_1C), fasting plasma glucose (FPG) and risk of hypoglycaemic events were extracted from each study and pooled in meta-analyses. Data on weight change were also extracted and tabulated.
Results:  Six studies including 1364 patients were identified. Based on random effects meta-analysis, the pooled estimate of change in HbA_1C from baseline was 0.9% (95% CI 0.7–1.1, p = 0.00011 vs. baseline) and for change in FPG from baseline was 1.8 mmol/l (95% CI 1.1–2.5, p = 0.0026 vs. baseline). The odds of experiencing a hypoglycaemic event was significantly higher in sulphonylurea-treated patients than in those on comparator treatments (OR = 5.3, 95% CI 1.7–16.3, p = 0.03). Mean weight change ranged from +2.5 to −0.1 kg, depending on the comparator treatment.
Conclusions:  This analysis has demonstrated that, in patients with type 2 diabetes whose control is inadequate on metformin monotherapy, the magnitude of incremental HbA_1C reduction achieved by the addition of a sulphonylurea is unlikely to exceed 1%, even after titration to maximum tolerated doses. Additionally, clinically relevant side-effects such as symptomatic hypoglycaemia and weight gain may be experienced.