Comparative analysis of hospitalization risk for incident heart failure in non-Hispanic Black versus non-Hispanic White individuals with type 2 diabetes on empagliflozin (Empa-AA): Insights from real-world data.

AIM: There are limited data to evaluate hospitalization for heart failure (hHF) in non-Hispanic Black (hereafter Black) or non-Hispanic White (hereafter White) individuals without previous hHF. Our goal was to evaluate the risk of hHF among Black versus White patients with type 2 diabetes (T2DM) who were initially prescribed empagliflozin using real-world data. METHODS: This multicentre retrospective cohort study included participants aged ≥18 years who had T2DM, were either Black or White, had no previous hHF, and were prescribed empagliflozin between August 2014 and December 2019. Our primary outcome was time to first hHF after the initial prescription of empagliflozin. A propensity-score (PS)-weighted analysis was performed to balance characteristics by race. The inverse probability treatment weighting method based on PS was used to make treatment comparisons. To compare Black with White, a PS-weighted Cox's cause-specific hazards model was used. RESULTS: In total, 8789 participants were eligible for inclusion (Black = 3216 vs. White = 5573). The Black cohort was significantly younger, had a higher proportion of females, and had a higher prevalence of chronic kidney disease, hypertension and diabetic retinopathy, while the White cohort had a higher prevalence of coronary artery disease. After adjustment for confounding factors such as age, gender, coronary artery disease, hypertension and diabetic retinopathy, the hazard ratio for first-time hHF was not significantly different between the two racial groups [hazard ratio (95% confidence interval) = 1.09 (0.84-1.42), p = .52]. CONCLUSION: This study showed no significant difference in incident hHF among Black versus White individuals with T2DM following a prescription for empagliflozin.

Diabetes-Related Microvascular Complications - A Practical Approach.

Diabetes-related microvascular complications include diabetic neuropathy (eg, diabetic symmetric polyneuropathy (DSPN), cardiac autonomic neuropathy, gastroparesis, enteropathy, erectile dysfunction, female sexual dysfunction, and hypoglycemia unawareness), diabetic kidney disease (DKD), and diabetes-related eye disease (eg, diabetic retinopathy (DR) and cataract). Both diabetes duration and degree of glycemic control strongly correlate with the development of microvascular complications. The development of diabetes-related microvascular complications interferes with the patient's quality of life and poses higher health system costs. This article will discuss a practical approach to effectively minimize/delay and manage the most common diabetes-related microvascular (DSPN, DKD, and DR).

Cardiovascular benefits of GLP-1RA and SGLT-2i in women with type 2 diabetes.

Given the CV benefit noted in the CVOTs, GLP-1RAs and SGLT-2is are given preference in T2DM guidelines. While guidelines do not report potential gender difference, those differences exist. On restricting the CVOTs results to women with increased CV risk or established ASCVD, GLP-1RAs significantly reduced MACE while SGLT-2is resulted in a non-significant reduction.

The benefit of GLP-1RA in different age groups in the cardiovascular outcome trials.

There may be hesitancy in prescribing GLP-1RA in older adults. On pooling results from the CVOTs comparing GLP-1RA to placebo, there was a significantly lower incidence of MACE favoring GLP-1RA in both younger and older adults. GLP-1RA should be considered in high risk patients regardless of age.

Sodium-glucose co-transporter-2 inhibitors and atrial fibrillation in the cardiovascular and renal outcome trials.

Dapagliflozin is a sodium-glucose co-transporter-2 (SGLT2) inhibitor that has recently been shown to reduce the incidence of reported episodes of atrial fibrillation (AF)/atrial flutter in the DECLARE-TIMI 58 trial. This raises the question regarding whether SGLT2 inhibitors can reduce the incidence of AF in a high-risk population. We searched for trials comparing SGLT2 inhibitors to placebo in high-risk individuals with or without diabetes (ie, cardiovascular and renal outcome trials) and that reported the incidence of AF as a serious adverse event. The EMPA-REG OUTCOME trial, CANVAS, CANVAS-R, the DECLARE-TIMI 58 trial, CREDENCE, DAPA-HF, VERTIS-CV and DAPA-CKD were included. The incidence of AF, reported as a serious adverse event, was 0.9% in individuals who received an SGLT2 inhibitor compared to 1.1% in those who received placebo. Pooled results showed a significantly lower incidence of AF in individuals with and without diabetes (relative risk 0.79, 95% confidence interval 0.67,0.93). This review suggests that there is a significantly lower risk of incident AF for individuals on SGLT2 inhibitors versus placebo. While there was a statistically significant lower incidence of AF, reported as a serious adverse event, more research is needed to evaluate its clinical significance.

Should Baseline Hemoglobin A1c or Dose of SGLT-2i Guide Treatment With SGLT-2i Versus DPP-4i in People With Type 2 Diabetes? A Meta-Analysis and Systematic Review.

Our aim was to explore whether the baseline hemoglobin A1c or the dose of sodium glucose cotransporter-2 inhibitor (SGLT-2i) chosen better predicted the efficacy of SGLT-2i versus dipeptidyl peptidase-4 inhibitor (DPP-4i) in type 2 diabetes. We searched for randomized trials that compared SGLT-2i with DPP-4i in type 2 diabetes and reported a change in hemoglobin A1c over time. We created 2 separate analyses (one based on baseline hemoglobin A1c and the other according to US Food and Drug Administration [FDA]-approved SGLT-2i dose). Thirteen trials were included. In the analysis according to baseline hemoglobin A1c , there was a significantly greater reduction in hemoglobin A1c when baseline hemoglobin A1c was ≥8.5%, favoring SGLT-2i over DPP-4i but not when baseline hemoglobin A1c was <8.5% (mean difference [95%CI], -0.36% [-0.53% to -0.18%] and 0.04% [-0.09% to 0.17%], respectively). On restricting the analysis to trials stratifying hemoglobin A1c to <8.0% or ≥8.0%, results did not change. In the analysis based on FDA-approved SGLT-2i doses, higher SGLT-2i doses caused a significantly greater hemoglobin A1c reduction at ≤26 and ≥52 weeks compared with the highest DPP-4i doses (mean difference [95%CI], -0.11% [-0.18% to -0.04%] and -0.24% [-0.34% to -0.15%], respectively). Lower SGLT-2i doses caused a significantly greater hemoglobin A1c reduction at ≥52 weeks but not at ≤26 weeks compared with the highest DPP-4i doses (mean difference [95%CI], -0.12% [-0.23% to -0.02%] and 0.01% [-0.05% to 0.07%], respectively). In people with type 2 diabetes and a baseline hemoglobin A1c ≥ 8.0%, SGLT-2i produced significantly greater reductions in hemoglobin A1c compared with DPP-4i and may be preferred. SGLT-2i dose titration to a higher FDA-approved dose is recommended in suitable patients.

Transitioning to non-insulin therapy in a patient receiving high dose insulin.

In people with type 2 diabetes with evidence of obesity-related insulin resistance, use of insulin to treat hyperglycemia has not been shown to reduce macrovascular complications, despite widespread use for many years. However, newer classes of diabetes medications, designed to address the prevalent pathophysiologic defect of type 2 diabetes, have emerged. Consequently, in many patients, reduction of insulin doses or even total elimination is possible after the addition of these newer agents. The authors suggest a cautious approach in which people with type 2 diabetes and established cardiovascular disease who are on high insulin doses (>1.0 unit/kg/day) be treated with diabetes medications that showed evidence of cardiovascular benefit (such as glucagon-like peptide-1 receptor agonists [GLP-1RAs]), on whom close monitoring is crucial because they may be at particular risk for developing hypoglycemia. This approach can be labor intensive and may be challenging for busy primary care providers for who may have limited time to evaluate and follow the patient. The authors present a case report of adding a GLP-1RA to high insulin doses. If the hemoglobin A1c is <8.0% when GLP-1RA is added, insulin doses should be reduced by 20%. Patients should be monitored at least every 4 weeks initially until it is confirmed there is no hypoglycemia risk. If glycemic targets (defined as fasting or preprandial glucose level between 80 and 130 mg/dl) are consistently achieved, providers may consider proactively reducing insulin doses by 10-20% to avoid hypoglycemia. The authors recommend creating appropriate goals and expectation before initiating this process.

Insulin therapy in patients with type 2 diabetes and high insulin resistance is associated with increased risk of complications and mortality.

Objective: To investigate the relationship between insulin use and clinical outcomes in patients with type 2 diabetes stratified by level of insulin resistance (IR).Methods: Cross sectional analysis of the NHANES database from 2001 to 2010. Sample was comprised of 3,124 individuals with diabetes, representing a US population of 16,713,593. Insulin use was self-reported. Fasting glucose and insulin levels were used to assess IR by HOMA-IR determination. Subjects were allocated within High or Low HOMA-IR groups based on the sample median. Outcome variables were mortality, major adverse cardiovascular events (MACE), and diabetic kidney disease (DKD). Logistic regression adjusting for covariates including glycemic control and comorbidities were performed.Results: In the adjusted model, insulin use was significantly associated with increased risk of mortality (OR: 2.39, 95% CI: 1.136-5.010) having a MACE (OR: 2.45, 95% CI: 1.137-4.550), and developing DKD (OR: 1.89, 95% CI: 1.119-3.198) in the high HOMA-IR group. The association between insulin use and the outcome variables was not statistically significant in patients within the low HOMA-IR group.Conclusions: Insulin use was associated with increased risk of mortality, MACE, and DKD in patients within the high IR group, but the association was not significant within the low IR group. Our findings indicate that insulin therapy could be less beneficial in patients with high IR. Prospective studies are needed to identify subsets of individuals with type 2 diabetes who would benefit the most from insulin therapy, and for which patients, insulin should be avoided.

Do GLP-1RAs and SGLT-2is reduce cardiovascular events in black patients with type 2 diabetes? A systematic review and meta-analysis.

AIMS: While recent cardiovascular safety trials (CVST) concerning newer diabetes medications included mostly white participants, results are being generalized to all races in recent guidelines. This raises a controversial question regarding the appropriateness of applying CVST data to black patients with type 2 diabetes. MATERIALS AND METHODS: We searched for randomized trials comparing diabetes medications to placebo in type 2 diabetes and investigated three- or four-point major adverse cardiovascular events (MACE). Data concerning black patients were then extracted. As the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) updated their recommendations for patients with established cardiovascular risk based on the CVST showing cardiovascular benefit, we performed a sensitivity analysis by including those trials only. RESULTS: A total of 11 trials were included, investigating a glucagon-like peptide-1 receptor agonist (GLP-1RA) in five, a sodium-glucose co-transporter-2 inhibitor (SGLT-2i) in two and dipeptidyl peptidase-4 inhibitors (DPP-4i) in four. Of the 102 416 participants enrolled in the included trials, only 4601 were black (4.5%). Pooled results showed no significant difference in the incidence of MACE among diabetes medications (GLP-1RA, SGLT-2i or DPP-4i) and placebo in black patients with type 2 diabetes (relative risk [RR] [95% CI], 0.94 [0.77,1.16]). Restricting the analysis to different classes of diabetes medication, the results remained non-significant. Restricting the analysis to CVST with significant outcomes, the results remained non-significant (RR [95% CI], 0.97 [0.68,1.39]). CONCLUSIONS: Given that black patients with type 2 diabetes were not well represented in CVSTs and such trials were underpowered to evaluate racial differences, it remains unclear whether GLP-1RAs or SGLT-2is would reduce cardiovascular risk in such patients, and additional studies targeting black patients are urgently needed.

Re-examining insulin compared to non-insulin therapies for type 2 diabetes: when in the disease trajectory is insulin preferable?

In patients with type 2 diabetes secondary to excess nutrients and energy balance, relative - not absolute - insulin deficiency plays a key role in disease development and progression. Although patients with type 2 diabetes who have features of insulin resistance would usually have hyperinsulinemia, insulin therapy remains recommended by guidelines particularly when patients fail to achieve glycemic goals. This approach does not prevent complications particularly macrovascular complications. This raises a controversial question regarding the benefit of using exogenous insulin for glycemic control in patients with type 2 diabetes who have features of insulin resistance. To address this concern, the authors performed a literature search looking for either randomized trials or meta-analyses directly comparing exogenous insulin to non-insulin therapy in the treatment of patients with type 2 diabetes. Our main outcomes of interest were effect on glycemic control and insulin resistance at various time points in the usual trajectory of type 2 diabetes. In trials investigating early short-term initiation of intensive insulin therapy, insulin therapy was beneficial in rapidly achieving glycemic control and reversing glucotoxicity. Following the initial 2 weeks to 3 months of adequate glycemic control in patients on intensive insulin therapy, there is little evidence that continuing insulin therapy provides greater glycemic control or improves insulin resistance beyond what can be achieved with other therapies. In conclusion, long-term insulin use appears neutral if not potentially harmful with respect to insulin resistance and cardiovascular outcomes. While this review has limitations and should be dealt cautiously, it raises questions regarding the benefit of insulin in patients with type 2 diabetes with features of insulin resistance. Further research is needed to confirm these findings.

The efficacy and safety of DPP4 inhibitors compared to sulfonylureas as add-on therapy to metformin in patients with Type 2 diabetes: A systematic review and meta-analysis.

There is no consensus on the selection of specific drug therapies when metformin fails in Type 2 diabetes (T2D). This meta-analysis was performed to determine the efficacy and safety of Dipeptidyl peptidase-4 inhibitors (DPP4-I) compared to sulfonylurea (SU) as add-on therapy to metformin in inadequately controlled T2D patients. We searched MEDLINE, CENTRAL, EMBASE, and CINAHL for randomized trials comparing DPP4-I to SU as add-on therapy to metformin and reported a change in hemoglobin A1c (HbA1c). Sixteen articles were included. There was a significantly greater reduction in HbA1c from baseline to 12 weeks with SU versus DPP4-I (MD[95% CI]=0.21%(2 mmol/mol) [0.06, 0.35]) but no significant difference at 52 and 104 weeks (MD[95% CI]=0.06%(-1 mmol/mol) [-0.03, 0.15] and 0.02%(-1 mmol/mol) [-0.13,0.18] respectively). SU was associated with weight gain and DPP4-I with weight loss at all time-points. The incidence of hypoglycemia at 12, 52, and 104 weeks was significantly greater with SU (20%, 24%, and 27% respectively) compared to DPP4-I (6%, 3%, and 4% respectively). The proportion of patients with HbA1c<7%(53 mmol/mol) without hypoglycemia was significantly higher at 52 and 104 weeks among patients on DPP4-I (RR[95% CI]=1.20 [1.05, 1.37] and 1.53 [1.16, 2.02] respectively). There was no significant difference between the two groups in the incidence of other side effects. While both SU and DPP4-I can be considered as options for add-on therapy to metformin in inadequately controlled T2D, SU results in a significantly increased risk of hypoglycemia and weight gain. By contrast, DPP4-I produce 0.4-0.6% (4-7 mmol/mol) reduction in HbA1c, lower risk of hypoglycemia, and weight loss.

Nicotine for postoperative analgesia: a systematic review and meta-analysis.

BACKGROUND: The perioperative adminstration of nicotine has been investigated as an analgesic adjunct and a possible modality to prevent postoperative nausea and vomiting (PONV). We performed this systematic review to assess the impact of perioperative administration of nicotine on postoperative pain and PONV. METHODS: A literature search of MEDLINE, CENTRAL, EMBASE, and CINAHL was done for randomized controlled trials that investigated the effects of nicotine compared with placebo regarding postoperative pain and/or PONV in patients undergoing surgery under general anesthesia. A random effects model was used for analysis. The primary end points were cumulative analgesic consumption and pain scores at 24 hours after surgery. RESULTS: Nine studies (662 patients) were included. Nicotine was administered as a transdermal patch in 6 studies and as a nasal spray in 3. Four studies recruited only women while 7 recruited only nonsmokers. Perioperative nicotine administration was associated with a reduction in cumulative opioid consumption at 24 hours compared with control (mean difference = -4.85 mg morphine equivalents, 95% confidence interval [CI], = -9.40 to -0.30, P = 0.04). Pain scores were neither clinically nor statistically reduced. Nicotine was associated with a significantly higher incidence of postoperative nausea (relative risk = 1.26, 95% CI, = 1.05 to 1.52) and need for rescue antiemetics (relative risk = 1.54, 95% CI, = 1.37 to 1.74) during the first postoperative hour and significantly higher postoperative nausea at 24 hours (relative risk = 1.14, 95% CI, = 1.02 to 1.28). The 24 hours opioid sparing was only seen in nonsmokers. When excluding 1 study with high risk of bias, nicotine was still associated with more postoperative nausea at 24 hours (relative risk = 1.15, 95% CI, = 1.05 to 1.25). CONCLUSIONS: This systematic review suggests that perioperative nicotine administration was associated with a statistically significant reduction in cumulative opioid consumption at 24 hours and a statistically insignificant reduction in pain scores at 24 hours. Perioperative nicotine was also associated with an increased incidence of postoperative nausea in patients undergoing surgery under general anesthesia. The opioid-sparing effect seemed to be limited to nonsmokers. Current data do not support a role for nicotine in perioperative analgesia.

Transversus abdominis plane block for analgesia after Cesarean delivery: a systematic review and meta-analysis.

PURPOSE: To assess the efficacy of transversus abdominis plane (TAP) block in improving analgesia following Cesarean delivery (CD). SOURCE: We searched MEDLINE, CENTRAL, EMBASE, and CINAHL for randomized controlled trials that assessed the efficacy of TAP block following CD and reported on postoperative pain scores and/or opioid consumption. Studies were combined according to the use or non-use of intrathecal morphine (ITM). Another analysis was performed for studies comparing TAP block with ITM. PRINCIPAL FINDINGS: Nine studies were included. Transversus abdominis plane block significantly reduced opioid consumption (mg morphine equivalents) after Cesarean delivery at six hours (mean difference [MD] -10.18; 95% confidence interval [CI] -13.03 to -7.34), at 12 hr (MD -13.83; 95% CI -22.77 to -4.89), and at 24 hr (MD -20.23; 95% CI -33.69 to -6.77). The TAP block also reduced pain scores for up to 12 hr and nausea in patients who did not receive ITM. When added to ITM, TAP block produced a small reduction in pain scores on movement in the first six hours (MD -0.82, 95% CI -1.52 to -0.11). When compared with ITM, pain scores on movement and opioid consumption at 24 hr were lower (MD 0.98; 95% CI 0.06 to 1.91 and MD 8.42 mg; 95% CI 1.74 to 15.10, respectively), and time to first rescue analgesic was longer with ITM (8 hr vs 4 hr), although opioid-related side effects were more common. CONCLUSION: Transversus abdominis plane block significantly improved postoperative analgesia in women undergoing CD who did not receive ITM but showed no improvement in those who received ITM. Intrathecal morphine was associated with improved analgesia compared with TAP block alone at the expense of an increased incidence of side effects.