The influence of glucose-lowering therapies on cancer risk in type 2 diabetes

Aims/hypothesis  The risk of developing a range of solid tumours is increased in type 2 diabetes, and may be influenced by glucose-lowering therapies. We examined the risk of development of solid tumours in relation to treatment with oral agents, human insulin and insulin analogues. Methods  This was a retrospective cohort study of people treated in UK general practices. Those included in the analysis developed diabetes >40 years of age, and started treatment with oral agents or insulin after 2000. A total of 62,809 patients were divided into four groups according to whether they received monotherapy with metformin or sulfonylurea, combined therapy (metformin plus sulfonylurea), or insulin. Insulin users were grouped according to treatment with insulin glargine, long-acting human insulin, biphasic analogue and human biphasic insulin. The outcome measures were progression to any solid tumour, or cancer of the breast, colon, pancreas or prostate. Confounding factors were accounted for using Cox proportional hazards models. Results  Metformin monotherapy carried the lowest risk of cancer. In comparison, the adjusted HR was 1.08 (95% CI 0.96–1.21) for metformin plus sulfonylurea, 1.36 (95% CI 1.19–1.54) for sulfonylurea monotherapy, and 1.42 (95% CI 1.27–1.60) for insulin-based regimens. Adding metformin to insulin reduced progression to cancer (HR 0.54, 95% CI 0.43–0.66). The risk for those on basal human insulin alone vs insulin glargine alone was 1.24 (95% CI 0.90–1.70). Compared with metformin, insulin therapy increased the risk of colorectal (HR 1.69, 95% CI 1.23–2.33) or pancreatic cancer (HR 4.63, 95% CI 2.64–8.10), but did not influence the risk of breast or prostate cancer. Sulfonylureas were associated with a similar pattern of risk as insulin. Conclusions/interpretation  Those on insulin or insulin secretagogues were more likely to develop solid cancers than those on metformin, and combination with metformin abolished most of this excess risk. Metformin use was associated with lower risk of cancer of the colon or pancreas, but did not affect the risk of breast or prostate cancer. Use of insulin analogues was not associated with increased cancer risk as compared with human insulin.     

Impact of glucose-lowering therapies on risk of stroke in type 2 diabetes

Patients with type 2 diabetes (T2D) have an increased risk of stroke compared with people without diabetes. However, the effects of glucose-lowering drugs on risk of ischaemic stroke in T2D have been less extensively investigated than in coronary heart disease. Some evidence, including the UKPDS, has suggested a reduced risk of stroke with metformin, although the number of studies is limited. Inhibition of the K_ATP channels increases ischaemic brain lesions in animals. This is in agreement with a recent meta-analysis showing an increased risk of stroke with sulphonylureas vs. various comparators as both mono- and combination therapy. Pioglitazone can prevent recurrence of stroke in patients with previous stroke, as already shown in PROactive, although results are less clear for first strokes. As for DPP-4 inhibitors, there was a non-significant trend towards benefit for stroke, whereas a possible increased risk of stroke with SGLT2 inhibitors—and in particular, empagliflozin in the EMPA-REG OUTCOME trial—has been suggested and requires clarification. Experimental results support a potential protective effect of GLP-1 receptor agonists against stroke that has, at least in part, been translated to clinical benefits in T2D patients in the LEADER and SUSTAIN-6 trials. Further interventional studies are now warranted to confirm the effects of glucose-lowering agents on risk of stroke in patients with T2D. In summary, the effects of antidiabetic drugs on risk of stroke appear to be heterogeneous, with some therapies (pioglitazone, GLP-1 receptor agonists) conferring possible protection against ischaemic stroke, other classes showing a neutral impact (DPP-4 inhibitors, insulin) and some glucose-lowering agents being associated with an increased risk of stroke (sulphonylureas, possibly SGLT2 inhibitors, high-dose insulin in the presence of insulin resistance).     

Effect of new glucose-lowering drugs on stroke in patients with type 2 diabetes: A systematic review and Meta-analysis

AimsPeople with diabetes tend to face a higher risk of stroke. Randomized controlled trials (RCTs) have demonstrated the different outcomes of new glucose-lowering drugs marketed in recent years on cardiovascular outcome events. The effects of glucagon-like peptide-1 (GLP-1) agonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors on stroke risk were evaluated in published RCTs.MethodsA search of Embase, Cochrane Library, and PubMed databases identified studies with stroke as an outcome event up to 3 December 2021. Risk ratios for stroke outcomes were analyzed using a fixed-effects model. I² was used to assess the heterogeneity of the study.Results19 RCTs with 155,027 participants with type 2 diabetes were identified. Pooled analysis showed that compared to placebo, GLP-1 agonists reduced non-fatal stroke by 15 % (RR = 0.85, 95%CI 0.77–0.94, P = 0.002, I² = 0 %) and total stroke (RR = 0.84, 95%CI 0.77–0.93, P = 0.000, I² = 0 %) by 16 %. SGLT-2 inhibitors and DPP-4 inhibitors were not significantly associated with lower stroke risk.ConclusionsThis meta-analysis indicates that GLP-1 agonists have potential benefits for stroke. However, further studies are needed if GLP-1 agonists are to be used to reduce the risk of stroke in patients with type 2 diabetes. More research is also needed to investigate the effects of new glucose-lowering drugs on different stroke subtypes.Systematic review registrationThis protocol was registered on the International Prospective Register of Systematic Reviews (https://www.crd.york.ac.uk/PROSPERO/; registration number: CRD42022326382).     

老年2型糖尿病患者糖尿病肾病危险因素分析

糖尿病肾病（DN）可进展为终末期肾病（ESRD）。在所有老年ESRD患者中41％为DN所致，75岁以上者比例更高。本文对60岁以上568例2型糖尿病患者的临床资料及生化指标进行了分析，探讨DN的危险因素。     

Improvement of liver function parameters in patients with type 2 diabetes treated with thiazolidinediones

To increase our understanding of the effect of thiazolidinediones, a new class of antidiabetic drugs, on liver function as well as glycemic control, we investigated liver function before, during, and after treatment with troglitazone and pioglitazone. A total of 32 patients with type 2 diabetes were studied. Glycemic control and liver function were measured before, during, and after 4 to 12 weeks of treatment with troglitazone or pioglitazone. Glycemic control was assessed by fasting levels of plasma glucose, hemoglobin A 1c , and serum insulin, and liver function was assessed by asparatate aminotransferase (AST), alanine aminotransferase (ALT), and gamma -glutamyl transpeptidase ( gamma-GTP). Homeostasis model assessment for insulin resistance was used as an index of insulin resistance. During treatment with troglitazone, fasting plasma glucose and hemoglobin A 1c levels and homeostasis model assessment for insulin resistance were significantly decreased. Serum AST, ALT, and gamma-GTP levels were significantly decreased during treatment (AST, -17.4%; ALT, -27.2%; gamma-GTP, -47.9%) and returned to pretreatment levels after 4 weeks of withdrawal of the drug. A similar tendency was observed during treatment with pioglitazone (AST, -4.7%; ALT, -16.4%; gamma-GTP, -30.8%). These data suggest that, in contrast to the deterioration of liver function reported in a small subset of patients treated with troglitazone, treatment with thiazolidinediones was associated with a decrease in serum transaminases in most patients. The improvement in liver function parameters known to be associated with fatty liver in the present study, together with an improvement in fatty liver reported for another class of insulin sensitizers, biguanides, suggests that thiazolidinediones may have a beneficial effect on fatty liver.     

Alcohol consumption and risk of type 2 diabetes mellitus among US male physicians

OBJECTIVE: To examine the association between low to moderate alcohol consumption and the incidence of type 2 diabetes mellitus (DM) in men. DESIGN: Prospective cohort study. SUBJECTS AND METHODS: Over an average period of 12.1 years, we evaluated 20 951 participants in the Physicians' Health Study between ages 40 and 84 years who were free of cardiovascular disease, cancer, and diabetes and provided data on alcohol consumption at baseline. MAIN OUTCOME MEASURE: Type 2 DM diagnosed after randomization. RESULTS: Among 20 951 physicians, 766 cases of incident DM were reported over an average follow-up period of 12.1 years. After adjustment for age, randomized treatment assignment, smoking, physical activity, and body mass index, the relative risk estimates and 95% confidence intervals for those reporting alcohol use of rarely/ never, 1 to 3 drinks per month, 1 drink per week, 2 to 4 drinks per week, 5 to 6 drinks per week, and 1 or more drinks per day were 1.00 (referent), 1.03 (0.80-1.33), 0.89 (0.70-1.14), 0.74 (0.59-0.93), 0.67 (0.51-0.89), and 0.57 (0.45-0.73), respectively (linear trend, P<.001). Additional adjustment for baseline history of hypertension, high cholesterol level, or parental history of myocardial infarction or family history of diabetes (data collected at 9 years) did not materially alter the results. These associations persisted in analyses stratified by age, smoking status, body mass index, physical activity, and family history of DM. CONCLUSION: These data indicate that apparently healthy men who self-select for light to moderate alcohol consumption have a decreased subsequent risk of type 2 DM.     

Fournier's gangrene in patients with type 2 diabetes using second-line antidiabetic medications

Cases of a rare but serious infection called Fournier's gangrene have been reported with sodium-glucose co-transporter-2 inhibitors (SGLT-2i). To evaluate the safety signal in a population of patients with type 2 diabetes, we used administrative claims data from Horizon Blue Cross Blue Shield of New Jersey from 2014 through 2017 to estimate incidence rates of Fournier's gangrene or necrotizing fasciitis of the perineum among patients treated with a second-line antidiabetic drug. We found very low incidence rates of Fournier's gangrene or necrotizing fasciitis. While we found no indication of an increased risk among SGLT-2i users compared with similar patients treated with other second-line antidiabetic medications, the small number of events yielded wide confidence intervals.     

Effect of thiazolidinediones on glucose and fatty acid metabolism in patients with type 2 diabetes

The current study aimed to compare the effects of treatment (2 months) with thiazolidinediones (TZDs) and placebo on glucose and fat metabolism in patients with type 2 diabetes (T2DM) in a crossover design. Eight patients received placebo (2 months) followed by TZD (2 months). Two-stage (1.5 and 6.0 pmol/kg min) hyperinsulinemic-euglycemic clamps were performed in all 8 patients pre- and post-placebo and post-TZD (post-placebo = pre-TZD). We determined rates of glucose disappearance (G(Rd)), glycolysis (GLS), glycogen synthesis (GS) (all with 3-(3)H glucose), carbohydrate (CHO) oxidation (indirect calorimetry), endogenous glucose production (EGP), free fatty acid (FFA) release ((2)H(5) glycerol), and oxidation (indirect calorimetry) and re-esterification, as well as plasma adiponectin and leptin concentrations, and fat cell size and number (determined in upper thigh biopsy samples). Placebo treatment had no effects on any of the measured parameters. TZD treatment improved insulin-stimulated glucose uptake (ISGU) from 17.1 to 26.4 micromol/kg min (P <.01) and insulin-stimulated GS from 4.8 to 13.4 micromol/kg min (P < 0.03), potentiated insulin-induced suppression of lipolysis from 4.3 to 2.3 micromol/kg min (P <.03) and FFA re-esterification from 1.9 to 1.0 micromol/kg min (P <.02), increased plasma adiponectin levels from 2.7 to 7.2 microg/mL (P <.05), and decreased plasma leptin levels from 30.8 to 23.4 ng/mL (P <.02). In addition, TZD tended to increase the number of small adipocytes (<50 microm) in subcutaneous adipose tissue. We conclude that TZDs have multiple actions and that many, but perhaps not all, can be accounted for by their action on adipose tissue.     

Overtreatment and associated risk factors among multimorbid older patients with diabetes

Background

In multimorbid older patients with type 2 diabetes mellitus (T2DM), the intensity of glucose-lowering medication (GLM) should be focused on attaining a suitable level of glycated hemoglobin (HbA_1c) while avoiding side effects. We aimed at identifying patients with overtreatment of T2DM as well as associated risk factors.

Methods

In a secondary analysis of a multicenter study of multimorbid older patients, we evaluated HbA_1c levels among patients with T2DM. Patients were aged ≥70 years, with multimorbidity (≥3 chronic diagnoses) and polypharmacy (≥5 chronic medications), enrolled in four university medical centers across Europe (Belgium, Ireland, Netherlands, and Switzerland). We defined overtreatment as HbA_1c < 7.5% with ≥1 GLM other than metformin, as suggested by Choosing Wisely and used prevalence ratios (PRs) to evaluate risk factors of overtreatment in age- and sex-adjusted analyses.

Results

Among the 564 patients with T2DM (median age 78 years, 39% women), mean ± standard deviation HbA_1c was 7.2 ± 1.2%. Metformin (prevalence 51%) was the most frequently prescribed GLM and 199 (35%) patients were overtreated. The presence of severe renal impairment (PR 1.36, 1.21–1.53) and outpatient physician (other than general practitioner [GP], i.e. specialist) or emergency department visits (PR 1.22, 1.03–1.46 for 1–2 visits, and PR 1.35, 1.19–1.54 for ≥3 visits versus no visits) were associated with overtreatment. These factors remained associated with overtreatment in multivariable analyses.

Conclusions

In this multicountry study of multimorbid older patients with T2DM, more than one third were overtreated, highlighting the high prevalence of this problem. Careful balancing of benefits and risks in the choice of GLM may improve patient care, especially in the context of comorbidities such as severe renal impairment, and frequent non-GP healthcare contacts.     

2型糖尿病患者噻唑烷二酮类药物疗效差异性的分析

临床研究表明,2型糖尿病患者噻唑烷二酮类药物疗效具有差异性,其差异性的原因可能与过氧化物酶体增殖物活化受体γ(PPARγ)、PPARγ协同刺激因子、脂联素、解耦联蛋白2、β3肾上腺素能受体基因、视黄醇结合蛋白4、细胞色素酶、脂素基因1等基因多态性相关,但是目前尚无一致性结论.目前国内、外关于PPARγ、PPARγ共激活因子、脂联素基因多态性与2型糖尿病患者噻唑烷二酮类药物疗效差异性的研究较多.     

老年2型糖尿病不同降糖药物应用及特点

老年糖尿病患者的生理学特点,决定了他们在选择治疗药物时有其自身的特点。二甲双胍是首选的一线降糖药物;二代磺脲类药物较一代药物更为安全,在老年人中应用广泛;α 葡萄糖苷酶抑制剂和非磺脲类促泌剂有利于降低餐后血糖;老年人应用胰岛素应注意避免低血糖事件。新的降糖药物肠促胰素样物质更为安全,能减少低血糖等不良反应。老年患者的治疗应循序渐进,治疗目标需适度放宽。