A meta-analysis reveals that the risk is present for most surgeries.

A published meta-analysis and systematic review reveals that diabetic patients are at an increased risk of having post-surgery surgical site infections for the majority of surgeries. The review included 94 published studies from 1985 to 2015. Of the studies, 91 were observational and 3 were randomized controlled trials. None of the studies differentiated between T1DM and T2DM.

The primary outcome the study looked at was surgical site infection (SSI), as defined by the Centers for Disease Control and Prevention surveillance criteria. The association between diabetes and SSI was an odds ratio of 1.53 (95% predictive interval [PI], 1.11-2.12, 57.2%). The results were not confounded by BMI, study design, or class of SSI. The review found that cardiac surgery had the highest association between diabetes and SSI with an odds ratio of 2.03 (95% PI, 1.13-4.05, P = 0.001), although the increased risk was present for the majority of surgery types, including spinal and breast-related surgeries. Overall, diabetic patients were about 50 percent more likely to have an SSI over nondiabetic patients.

Examining incidence of SSI is important because of the impact they have on healthcare. They are the most frequent cause of hospital-acquired infection and frequently lead to rehospitalization (for which the CMS can penalize hospitals). The annual healthcare cost of SSI’s is more than $3 billion. Previous studies have identified that hyperglycemia and diabetes are risk factors for SSI, but this meta-analysis proves that the risk is present for a wide variety of surgical procedure types. Therefore, clinicians for surgical patients with diabetes should begin to take important precautions for prevention of SSI, such as potentially establishing and maintaining euglycemia before and after surgery and appropriate prophylaxis treatment. Further research is necessary to establish the relationship between level of glycemic control and risk of SSI following surgery in diabetes patients. In addition, more studies are needed to distinguish what differences in risk exist based on the patient’s type of diabetes.

Practice Pearls:

• Diabetes in general is a risk factor for surgical site infection (SSI) post-surgery.
• This meta-analysis reveals that the risk appears to be highest for cardiovascular surgery patients with diabetes.
• Appropriate infection prophylaxis is extremely important for diabetic surgical patients in order to prevent these potentially costly and devastating infections.

Infection Control & Hospital Epidemiology, Available Martin ET, Kaye KS, Knott C, et al. Diabetes and Risk of Surgical Site Infection: A Systematic Review and Meta-analysis on CJO 2015 doi:10.1017/ice.2015.249

New study suggests that in hospital patients with T2DM, premixed insulin provides similar glycemic control as a basal-bolus insulin regimen.

In the outpatient setting for the management of T2DM, premixed insulin is a commonly prescribed formulation. However, the safety and efficacy of the same formulation for inpatient type 2 diabetics is unknown. Therefore, researchers conducted a study to identify these factors.

Researcher Virginia Bellido conducted a randomized prospective open-label study. Researchers analyzed 72 patients who were 18 years old or greater with a diagnosis of T2DM. These patients presented to general medicine and surgery services and they were randomly assigned to either a basal-bolus regimen (insulin glargine) once-daily and Apidra (insulin glulisine) before meals (n=33) or a premixed human insulin regimen with 30% regular insulin and 70% Mixtard 30 (NPH insulin) twice daily (n=39). Endpoints were mean capillary daily blood glucose during each day.

It was found that mean capillary blood glucose levels were comparable between basal-bolus and premixed insulin groups at admission (203.1 mg/dL vs. 221.3 mg/dL). Furthermore, similar immediate and long-term improvements in mean daily blood glucose were observed in both groups (175 mg/dL vs 179 mg/dL). There were no differences between mean, fasting, pre-meal or postprandial measurements. In addition, no differences were seen between groups with glucose measures between 80-180 mg/dL (55.9% vs. 54.3%).

Authors believe that an increased incidence of hypoglycemia is associated with premixed insulin regimen as a planned interim analysis displayed this effect. This finding exceeded the pre-specified stopping rule of 50% in the mixed insulin group and the trial was stopped early. Hypoglycemia in the basal-bolus vs. mixed insulin was 8 patients (24.2%) vs. 25 patients (64.1%) respectively. Nonetheless, authors caution the use of premixed human insulin in the management of T2DM in general medicine and surgery patients.

Practice Pearls:

• Premixed insulin regimen provides similar glycemic control as a basal-bolus insulin regimen; however, it results in significantly higher incidence of hypoglycemia.
• Caution should be used when using premixed human insulin to manage T2DM in the general medicine and surgery settings.
• No differences are observed in either premixed insulin or basal-bolus regimen with respect to average, fasting, pre-meal, and postprandial levels.

Bellido, Virginia, et al. “Comparison of Basal-Bolus and Premixed Insulin Regimens in Hospitalized Patients With Type 2 Diabetes.” Diabetescare, (Oct122015):dc150160.

Therapeutic options are limited for type 2 diabetics with severe renal insufficiency due to contraindications and/or risk of hypoglycemia. Dipeptidyl peptidase-4 (DPP4) inhibitors are approved for use in this patient population; however, there is limited data directly comparing the safety and efficacy between these agents.

All DPP-4 inhibitors prolong meal-induced increases in GLP1 and GIP for several hours in order to decrease the rate of GLP1 and GIP inactivation. The mechanism of action and low risk of hypoglycemia associated with DPP-4 inhibitors make them an appealing option for difficult-to-treat patients. Since differences in binding kinetics exist within the class of DPP-4 inhibitors, a study was conducted to compare the safety and efficacy of vildagliptin and sitagliptin in type 2 diabetics who suffer from severe renal impairment.

The study was a parallel-arm, randomized, multicenter, double blind, 24-week study conducted in 87 centers across Brazil and the USA. Researchers randomized a total of 148 patients, and divided 83 to vildagliptin treatment group and 65 to sitagliptin treatment group. Patients included were diagnosed with type 2 diabetes and were either drug naïve or currently being treated with anti-diabetic agents. Baseline HbA1C were between 6.5% to 10% and an estimated GFR of less than 30 mL/min. Patients received recommended doses of either 50 mg vildagliptin once daily or sitagliptin 25 mg once daily. Parameters to measure efficacy were changes in HbA1C and fasting plasma. Parameters to measure safety were assessment of treatment-emergent adverse events.

In the study analysis after 24 weeks, the adjusted mean difference in HbA1C for vildagliptin was -0.54% (5.9 mmol/mol) from a baseline of 7.52% (59 mmol/mol). The results for sitagliptin was -0.56% (6.1 mmol/mol) from a baseline of 7.80% (62 mmol/mol). There was no statistical significance recognized with this difference (p=0.185). HbA1C and FPG were measured at all visits, and safety parameters were recorded and evaluated by the investigator. Both drugs studied displayed similar safety profiles. The drugs were well-tolerated; however, it is important to note that these patients had multiple concomitant medical conditions, where nearly all patients also received antihypertensive, lipid-lowering, and platelet inhibitor agents. Therefore, although unlikely, the safety profile specific to anti-diabetics may not have been as accurate.

The authors conclude that this is the first study performed to directly compare the safety and efficacy of vildagliptin and sitagliptin. In addition, it is recognized that both of these agents have a similar propensity of lowering HbA1C with relatively well-tolerated adverse event profiles.

Practice Pearls:

• At recommended doses for maximal effectiveness, both vildagliptin and sitagliptin show similar efficacy and safety in treating type 2 diabetics with severe renal impairment
• The percentage of patients achieving an HbA1C target of ≤ 6.5% was higher in vildagliptin treated group compared to sitagliptin.
• It is important to note that majority of patients studied were treated with insulin; therefore, insulin likely diminishes any differences observed with prolonging effects of GLP1 with vildagliptin during the overnight period.

doi: 10.2337/dc06-0706 Diabetes Care December 2006 vol. 29 no. 12 2638-2643

There are some mornings she realizes she must have been low during the night because her sheets are wet from perspiration, and she remembers having had vivid dreams. She wants to know what she can do. Although we have tweaked her plan, she continues to have these unexpected events about once a week. Besides the readjustments, we once again recommended CGM. She once again refused, therefore we recommended she get another dog, which she did.

She called us a month later to let us know how well she, her husband, and her new dog are getting along. Her new dog is now waking her up by licking her face when her glucose levels are falling. She is able to wake up and treat her low. She’s so pleased and thanked us.

Lessons Learned:

• Sometimes you and your patients do all you know and is recommended to prevent hypo- and hyperglycemic events, but they may continue to occur.
• Not all patients agree with their health care professionals’ recommendations.
• Work with patients to design an individualized plan for each patient.

The CANagliflozin CardioVascular Assessment Study is a double-blind, placebo-controlled study that randomized participants to placebo, canagliflozin 100 mg, or canagliflozin 300 mg once daily, added to a range of therapies. The primary end point of this substudy was the change in HbA1c from baseline at 18 weeks among patients using insulin; 52-week effects were also examined.

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Individuals receiving insulin at baseline were randomized to receive placebo (n = 690), canagliflozin 100 mg (n = 692), or canagliflozin 300 mg (n = 690). These individuals were 66% male and had a median age of 63 years, mean HbA1c of 8.3% (67 mmol/mol), BMI of 33.1 kg/m2, estimated glomerular filtration rate of 75 mL/min/1.73 m2, fasting plasma glucose of 9.2 mmol/L, and a median daily insulin dose of 60 IU. Most individuals were using basal/bolus insulin. Reductions in HbA1c with canagliflozin 100 and 300 mg versus placebo were −0.62% (95% CI −0.69, −0.54; −6.8 mmol/mol [95% CI −7.5, −5.9]; P < 0.001) and −0.73% (95% CI −0.81, −0.65; −8.0 mmol/mol [95% CI −8.9, −7.1]; P < 0.001) at 18 weeks and −0.58% (95% CI −0.68, −0.48; −6.3 mmol/mol [95% CI −7.4, −5.2]) and −0.73% (95% CI −0.83, −0.63; −8.0 mmol/mol [95% CI −9.1, −6.9]) at 52 weeks. There were significant falls in fasting plasma glucose, body weight, and blood pressure at both time points and there was a greater incidence of hypoglycemia, genital mycotic infections, and hypovolemia with both canagliflozin doses.

The researchers concluded that canagliflozin added to insulin therapy improved glycemic control and decreased body weight. There was a greater frequency of several anticipated side effects, although few led to discontinuation of treatment. There were clear beneficial effects on HbA1c of adding canagliflozin to background insulin therapy. These benefits were apparent at 18 weeks and were sustained through 52 weeks for both doses of canagliflozin compared with placebo. The reductions in HbA1c were accompanied by favorable effects on body weight and blood pressure, which were also observed for both doses and over 52 weeks. These benefits were accompanied by the adverse effects anticipated for the drug class. Effects on lipid metabolism were inconsistent, but the broad pattern was similar to that reported previously. The net impact of the changes in lipid parameters produced by canagliflozin is uncertain, with the elevation in LDL cholesterol accompanied by a rise in HDL cholesterol that leaves the ratio of LDL cholesterol to HDL cholesterol unchanged. The hazard ratio for cardiovascular events reported during the regulatory review process prior to marketing was not suggestive of harm and ruled out large adverse effects of the compound.

The observed additive effects of canagliflozin on top of insulin are anticipated on the basis of the different mechanism of action of the compound. Because canagliflozin acts independently of insulin, it should be an effective treatment choice at most stages of the disease and also when used in conjunction with most other glucose-lowering therapies. Furthermore, the combination of canagliflozin with insulin may offer advantages compared with the combination of insulin with other oral agents because the use of canagliflozin may mitigate against the risks of hypoglycemia and weight gain that can be exacerbated by some other drug classes. The subset of patients among whom glucose-lowering efficacy might be reduced is those with renal impairment, and this might explain the lesser effect of canagliflozin among older individuals in this study.

Practice Pearls:

• A key strength of this study is its large size and its robust randomized and controlled design.
• The completeness of follow-up for the main efficacy and safety outcomes was good and the findings were robust to a series of sensitivity analyses.
• In conclusion, canagliflozin appears to offer significant benefits when used in conjunction with insulin therapy.

Bruce Neal. Efficacy and Safety of Canagliflozin, an Inhibitor of Sodium–Glucose Cotransporter 2, When Used in Conjunction With Insulin Therapy in Patients With Type 2 Diabetes. Published online before print December 2, 2014, doi: 10.2337/dc14-1237
Diabetes Care March 2015 vol. 38 no. 3 403-411