2023 UPDATE: Luso-Brazilian evidence-based guideline for the management of antidiabetic therapy in type 2 diabetes.

BACKGROUND: The management of antidiabetic therapy in people with type 2 diabetes (T2D) has evolved beyond glycemic control. In this context, Brazil and Portugal defined a joint panel of four leading diabetes societies to update the guideline published in 2020. METHODS: The panelists searched MEDLINE (via PubMed) for the best evidence from clinical studies on treating T2D and its cardiorenal complications. The panel searched for evidence on antidiabetic therapy in people with T2D without cardiorenal disease and in patients with T2D and atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), or diabetic kidney disease (DKD). The degree of recommendation and the level of evidence were determined using predefined criteria. RESULTS AND CONCLUSIONS: All people with T2D need to have their cardiovascular (CV) risk status stratified and HbA1c, BMI, and eGFR assessed before defining therapy. An HbA1c target of less than 7% is adequate for most adults, and a more flexible target (up to 8%) should be considered in frail older people. Non-pharmacological approaches are recommended during all phases of treatment. In treatment naïve T2D individuals without cardiorenal complications, metformin is the agent of choice when HbA1c is 7.5% or below. When HbA1c is above 7.5% to 9%, starting with dual therapy is recommended, and triple therapy may be considered. When HbA1c is above 9%, starting with dual therapyt is recommended, and triple therapy should be considered. Antidiabetic drugs with proven CV benefit (AD1) are recommended to reduce CV events if the patient is at high or very high CV risk, and antidiabetic agents with proven efficacy in weight reduction should be considered when obesity is present. If HbA1c remains above target, intensification is recommended with triple, quadruple therapy, or even insulin-based therapy. In people with T2D and established ASCVD, AD1 agents (SGLT2 inhibitors or GLP-1 RA with proven CV benefit) are initially recommended to reduce CV outcomes, and metformin or a second AD1 may be necessary to improve glycemic control if HbA1c is above the target. In T2D with HF, SGLT2 inhibitors are recommended to reduce HF hospitalizations and mortality and to improve HbA1c. In patients with DKD, SGLT2 inhibitors in combination with metformin are recommended when eGFR is above 30 mL/min/1.73 m2. SGLT2 inhibitors can be continued until end-stage kidney disease.

Drug-drug interactions and inappropriate medicines impact on glycemic control and kidney function in older adults with diabetes-attending specialty care institution.

PURPOSE: To describe and assess the impact of polypharmacy, and its potential adverse reactions; serious clinically relevant drug-drug interactions (DDIs) and inappropriate medicines (PIMs) on glycemic target, and kidney function in a sample of older adults with type 2 diabetes (T2D). METHODS: Cross-sectional study was performed in a real-world database including 444 elderly people with T2D from the Portuguese Diabetes Association, aged ≥ 65 years, and registered in 2018. DDIs were analyzed using Micromedex drug-interaction platform and PIMs identified using STOPP criteria version-2. RESULTS: Polypharmacy was identified in 43.6% of patients. This group of patients has shown to be more females (50 vs. 39.6%, P=0.0208), higher HbA1c targets (P=0.0275), longer diabetes duration (66.4 vs. 54.4%, P=0.0019), more hypertensive (87 vs. 62.9%, P<0.0001), using more insulin (38.1 vs. 26%, P=0.0062), sulfonylureas (37.1 vs. 15.6%, P<0.0001), GLP-1 receptor-agonists (9.7 vs. 3.6%, P=0.0077), metformin-DPP-4 inhibitors (41.2 vs. 29.2%, P=0.0081), and SGLT2 inhibitors (19 vs. 9.6%, P=0.0040). A total of 8.7% of patients had potentially serious clinically relevant DDIs, mainly due to interacting medicine pairs dexamethasone and fluoroquinolones. Furthermore, 23.4% had PIMs, and cardiovascular medicines accounted for largest therapeutic group associated. Polypharmacy found to be associated with twofold greater odds of having HbA1c ≤8%, whereas PIMs associated with 2.5-fold greater odds of having HbA1c ≤9%, and 5.5-folds greater odds of having severe kidney function. CONCLUSIONS: These findings suggested that there is a potential association between polypharmacy and PIMs and altered glycemic control, and PIMs with the deterioration of kidney function.

Polypharmacy, potentially serious clinically relevant drug-drug interactions, and inappropriate medicines in elderly people with type 2 diabetes and their impact on quality of life.

The aim of the study is to investigate the patterns of polypharmacy, clinical-relevant drug-drug interactions (DDIs), and potentially inappropriate medicines (PIMs), and whether polypharmacy, potential serious clinically-relevant DDIs, or PIMs can be associated with low quality of life (QoL) index scores of older adults with type 2 diabetes (T2D). A cross-sectional study was conducted using data of 670 elderly T2D sub-cohort from a nationwide pharmacy-based intensive monitoring study of inception cohort of T2D in Portugal. 72.09% were found on polypharmacy (≥5 medicines). Participants on polypharmacy were mostly females (P = .0115); more obese (P = .0131); have more comorbid conditions (P < .0001); more diabetes complications (P < .0001); and use more of glucose lowering drugs (P = .0326); insulin (P < .0001); chronic medicines (P < .0001); and have higher diabetes duration (P = .0088) than those without polypharmacy. 10.59% of the participants were found to have potential serious clinically relevant DDIs. The most frequent drug-combinations were angiotensin-converting enzyme (ACE) inhibitors with angiotensin-receptor blockers (ARBs), aspirin with Selective serotonin reuptake inhibitors (SSRIs), and clopidogrel with calcium channel blockers. PIMs are found in 36.11% of the participants. The most common PIMs were benzodiazepines, long-acting sulfonylureas, and iron overdose. The adjusted multivariate models show that Polypharmacy, PIMs, and potential serious clinically relevant DDIs were associated with lower QoL index scores (OR 1.80 95% CI 1.15-2.82), (OR 1.57 95% CI 1.07-2.28), and (OR 1.34 95% CI 0.73-2.48) respectively. The study shows that polypharmacy, potential serious clinical-relevant DDIs, and PIMs may correlate with risk of reduced health related QoL outcome of older adults with T2D.

Portuguese-Brazilian evidence-based guideline on the management of hyperglycemia in type 2 diabetes mellitus.

BACKGROUND: In current management of type 2 diabetes (T2DM), cardiovascular and renal prevention have become important targets to be achieved. In this context, a joint panel of four endocrinology societies from Brazil and Portugal was established to develop an evidence-based guideline for treatment of hyperglycemia in T2DM. METHODS: MEDLINE (via PubMed) was searched for randomized clinical trials, meta-analyses, and observational studies related to diabetes treatment. When there was insufficient high-quality evidence, expert opinion was sought. Updated positions on treatment of T2DM patients with heart failure (HF), atherosclerotic CV disease (ASCVD), chronic kidney disease (CKD), and patients with no vascular complications were developed. The degree of recommendation and the level of evidence were determined using predefined criteria. RESULTS AND CONCLUSIONS: In non-pregnant adults, the recommended HbA1c target is below 7%. Higher levels are recommended in frail older adults and patients at higher risk of hypoglycemia. Lifestyle modification is recommended at all phases of treatment. Metformin is the first choice when HbA1c is 6.5-7.5%. When HbA1c is 7.5-9.0%, dual therapy with metformin plus an SGLT2i and/or GLP-1RA (first-line antidiabetic agents, AD1) is recommended due to cardiovascular and renal benefits. If an AD1 is unaffordable, other antidiabetic drugs (AD) may be used. Triple or quadruple therapy should be considered when HbA1c remains above target. In patients with clinical or subclinical atherosclerosis, the combination of one AD1 plus metformin is the recommended first-line therapy to reduce cardiovascular events and improve blood glucose control. In stable heart failure with low ejection fraction (< 40%) and glomerular filtration rate (eGFR) > 30 mL/min/1.73 m2, metformin plus an SGLT-2i is recommended to reduce cardiovascular mortality and heart failure hospitalizations and improve blood glucose control. In patients with diabetes-associated chronic kidney disease (CKD) (eGFR 30-60 mL/min/1.73 m2 or eGFR 30-90 mL/min/1.73 m2 with albuminuria > 30 mg/g), the combination of metformin and an SGLT2i is recommended to attenuate loss of renal function, reduce albuminuria and improve blood glucose control. In patients with severe renal failure, insulin-based therapy is recommended to improve blood glucose control. Alternatively, GLP-1RA, DPP4i, gliclazide MR and pioglitazone may be considered to reduce albuminuria. In conclusion, the current evidence supports individualizing anti-hyperglycemic treatment for T2DM.

The association between polypharmacy and adverse health consequences in elderly type 2 diabetes mellitus patients; a systematic review and meta-analysis.

AIM: To summarize the existing literature concerning the association between polypharmacy and adverse health consequences in elderly patients with type 2 diabetes mellitus. METHODS: We searched four literature databases (PubMed/Medline, ScienceDirect and Web of Science) through April 2019. We included all studies that addressed the association between polypharmacy and all-cause of mortality, glycemic control, macrovacular complications, hospitalization, potentially inappropriate medicines, drug-drug interactions and fall. A statistical program OpenMeta [Analyst] was used. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with a random effects model. I2 statistics was performed to assess heterogeneity. RESULTS: Out of sixteen studies, three studies were used for meta-analysis. A statistically significant association was found between polypharmacy and all-cause mortality (OR = 1.622, 95% CI (1.606-1.637) P < 0.001), and myocardial infarction (OR = 1.962, 95% CI (1.942-1.982), P < 0.001. Non-statistically significant association with evidence of moderate heterogeneity was found between polypharmacy and stroke (OR = 1.335; 95% CI (0.532-3.346), P = 0.538, I2 = 45%), and hospitalization (OR = 1.723; 95% CI (0.983-3.021), P = 0.057, I2 = 57%). CONCLUSIONS: Pooled risk estimates reveal that polypharmacy is associated with increased all-cause mortality, macrovacular complications and hospitalization using categorical definitions. These findings assert the need for interventions that optimize the balance of benefits and harms in medicines prescribing.

First Incidence and Progression Study for Diabetic Retinopathy in Portugal, the RETINODIAB Study: Evaluation of the Screening Program for Lisbon Region.

PURPOSE: To estimate the 5-year incidence and progression of diabetic retinopathy (DR) among persons with type 2 diabetes mellitus (DM). DESIGN: Population-based, prospective, cohort study. PARTICIPANTS: The RETINODIAB (Study Group for Diabetic Retinopathy Screening) program was implemented in the Lisbon and Tagus Valley area between July 2009 and December 2014. A total of 109 543 readable screening examinations were performed and corresponded to 56 903 patients who attended the screening program at entry. A total of 30 641 patients (53.85%) had at least 1 further screening event within the study period and were included in the analysis. METHODS: Participants underwent two 45° nonstereoscopic retinal digital photographs per eye according to RETINODIAB protocol. All images were graded according to the International Clinical Diabetic Retinopathy Scale. Referable diabetic retinopathy (RDR) was defined for all patients graded as moderate nonproliferative DR (NPDR), severe NPDR, or proliferative DR (PDR), with or without maculopathy or mild NPDR with maculopathy. Nonparametric estimates of the annual and cumulative incidences were obtained by Turnbull's estimator. Associations between the potential risk factors and the time to onset/progression of retinopathy were assessed through a parametric survival analysis for interval-censored data. MAIN OUTCOME MEASURES: The authors estimated the onset and progression incidence rates of DR. RESULTS: Yearly incidence of any DR in patients without retinopathy at baseline was 4.60% (95% confidence interval [CI], 3.96-4.76) in the first year, decreasing to 3.87% (95% CI, 2.57-5.78) in the fifth year. In participants with mild NPDR at baseline, the progression rate to RDR in year 1 was 1.18% (95% CI, 0.96-1.33). Incidence of any DR and RDR and DR progression rate were associated with known duration of diabetes, age at diagnosis, and use of insulin treatment. CONCLUSIONS: This longitudinal epidemiologic study provides the first Portuguese incidence DR data in a large-scale population-based cohort of type 2 diabetes after a 5-year follow-up. Duration of diabetes, age at diagnosis, and insulin treatment were associated with increasing risk of incidence and progression of DR. A personalized schedule distribution of screening intervals according to the individual patient's profile should be implemented, with resulting benefits in terms of health costs.

First diabetic retinopathy prevalence study in Portugal: RETINODIAB Study--evaluation of the screening programme for Lisbon and Tagus Valley region.

BACKGROUND/AIMS: In Portugal, so far, there is no study or even accurate data on the prevalence of diabetic retinopathy (DR), based on a large representative sample and on a long-term follow-up. The objective of our study was to determine the prevalence of DR based on a national screening community-based programme. METHODS: A 5-year retrospective analysis of the RETINODIAB screening programme results was implemented in Lisbon and Tagus Valley area between July 2009 and October 2014. We estimated the prevalence of retinopathy for all patients with type 2 diabetes and studied the association between known risk factors and retinopathy emergence at their first screening. RESULTS: Throughout this period, from a total of 103 102 DR readable screening examinations, 52 739 corresponded to patients who attended RETINODIAB screening at entry. Globally, DR was detected in 8584 patients (16.3%). Of these, 5484 patients (10.4%) had mild non-proliferative (NP) DR, 1457 patients (2.8%) had moderate NPDR and 672 (1.3%) had severe NPDR. Finally, 971 patients (1.8%) had proliferative DR requiring urgent referral to an ophthalmologist. The presence of any DR, non-referable DR or referable DR was strongly associated with increasing duration of diabetes and earlier age at diagnosis. CONCLUSIONS: The prevalence rate of DR in our study (16.3%) was slightly lower than other published international data. The RETINODIAB network proved to be an effective screening programme as it improved DR screening in Lisbon and Tagus Valley surrounding area.

Ectopic cushing's syndrome caused by an 8 mm lung carcinoid localized by scintigram with the somatostatin analog111in-pentetreotide.

Small tumors producing adrenocorticophic hormone (ACTH) ectopically may be very difficult to locate. We describe a 57-year-old woman who presented with ectopic Cushing's syndrome as diagnosed by bilateral inferior petrosal sinus catheterization with corticotrophin-releasing hormone (CRH) test. Thoracic pentetreotide (a somatostatin analogue) revealed a small "hot spot" in the base of the left lung. This "hot spot" was constant throughout the procedure. A second thoracic CT scan with 3-mm cuts showed a small image in the area under suspicion, similar to vascular images found elsewhere in both lungs. At surgery, an 8-mm tumor was found and excised. Pathological examination revealed a carcinoid tumor immunoreactive for ACTH, beta-endorphin, bombesin, serotonin, and the α-subunit. One month after surgery, the patient was clinically well and had normal adrenal function. An111ln-pentetreotide scintiscan clearly identified a small ACTH-producing neuroendocrine tumor of the lung undetectable by plain chest radiography or CT scan.