https://www.thelancet.com/pdfs/journals/lancet/PIIS0140673605677008.pdf

Wound healing and its impairment in the diabetic foot

Diabetic foot ulcers (DFUs), a leading cause of amputations, affect 15% of people with diabetes. A series of multiple mechanisms, including decreased cell and growth factor response, lead to diminished peripheral blood flow and decreased local angiogenesis, all of which can contribute to lack of healing in persons with DFUs. In this issue of the JCI, Gallagher and colleagues demonstrate that in diabetic mice, hyperoxia enhances the mobilization of circulating endothelial progenitor cells (EPCs) from the bone marrow to the peripheral circulation (see the related article beginning on page 1249). Local injection of the chemokine stromal cell–derived factor–1α then recruits these EPCs to the cutaneous wound site, resulting in accelerated wound healing. Thus, Gallagher et al. have identified novel potential targets for therapeutic intervention in diabetic wound healing.

/pdf/cellular-and-molecular-basis-of-wound-healing-in-diabetes-4zuyldpnza.pdf

Cellular and molecular basis of wound healing in diabetes

Significance: Chronic wounds include, but are not limited, to diabetic foot ulcers, venous leg ulcers, and pressure ulcers. They are a challenge to wound care professionals and consume a great deal of healthcare resources around the globe. This review discusses the pathophysiology of complex chronic wounds and the means and modalities currently available to achieve healing in such patients. Recent Advances: Although often difficult to treat, an understanding of the underlying pathophysiology and specific attention toward managing these perturbations can often lead to successful healing. Critical Issues: Overcoming the factors that contribute to delayed healing are key components of a comprehensive approach to wound care and present the primary challenges to the treatment of chronic wounds. When wounds fail to achieve sufficient healing after 4 weeks of standard care, reassessment of underlying pathology and consideration of the need for advanced therapeutic agents should be undertaken. However, selection ...

/pdf/challenges-in-the-treatment-of-chronic-wounds-2jwybcph6f.pdf

Challenges in the Treatment of Chronic Wounds.

Foot infections are a common and serious problem in persons with diabetes Diabetic foot infections (DFIs) typically begin in a wound, most often a neuropathic ulceration While all wounds are colonized with microorganisms, the presence of infection is defined by ≥2 classic findings of inflammation or purulence Infections are then classified into mild (superficial and limited in size and depth), moderate (deeper or more extensive), or severe (accompanied by systemic signs or metabolic perturbations) This classification system, along with a vascular assessment, helps determine which patients should be hospitalized, which may require special imaging procedures or surgical interventions, and which will require amputation Most DFIs are polymicrobial, with aerobic gram-positive cocci (GPC), and especially staphylococci, the most common causative organisms Aerobic gram-negative bacilli are frequently copathogens in infections that are chronic or follow antibiotic treatment, and obligate anaerobes may be copathogens in ischemic or necrotic wounds Wounds without evidence of soft tissue or bone infection do not require antibiotic therapy For infected wounds, obtain a post-debridement specimen (preferably of tissue) for aerobic and anaerobic culture Empiric antibiotic therapy can be narrowly targeted at GPC in many acutely infected patients, but those at risk for infection with antibiotic-resistant organisms or with chronic, previously treated, or severe infections usually require broader spectrum regimens Imaging is helpful in most DFIs; plain radiographs may be sufficient, but magnetic resonance imaging is far more sensitive and specific Osteomyelitis occurs in many diabetic patients with a foot wound and can be difficult to diagnose (optimally defined by bone culture and histology) and treat (often requiring surgical debridement or resection, and/or prolonged antibiotic therapy) Most DFIs require some surgical intervention, ranging from minor (debridement) to major (resection, amputation) Wounds must also be properly dressed and off-loaded of pressure, and patients need regular follow-up An ischemic foot may require revascularization, and some nonresponding patients may benefit from selected adjunctive measures Employing multidisciplinary foot teams improves outcomes Clinicians and healthcare organizations should attempt to monitor, and thereby improve, their outcomes and processes in caring for DFIs

2012 Infectious Diseases Society of America Clinical Practice Guideline for the Diagnosis and Treatment of Diabetic Foot Infections

Wound healing is a complex, highly regulated process that is critical in maintaining the barrier function of skin. With numerous disease processes, the cascade of events involved in wound healing can be affected, resulting in chronic, non-healing wounds that subject the patient to significant discomfort and distress while draining the medical system of an enormous amount of resources. The healing of a superficial wound requires many factors to work in concert, and wound dressings and treatments have evolved considerably to address possible barriers to wound healing, ranging from infection to hypoxia. Even optimally, wound tissue never reaches its pre-injured strength and multiple aberrant healing states can result in chronic non-healing wounds. This article will review wound healing physiology and discuss current approaches for treating a wound.

/pdf/chronic-wound-healing-a-review-of-current-management-and-542ufe3spb.pdf

Chronic Wound Healing: A Review of Current Management and Treatments

OBJECTIVE —To determine if a human fibroblast–derived dermal substitute could promote the healing of diabetic foot ulcers. RESEARCH DESIGN AND METHODS —A randomized, controlled, multicenter study was undertaken at 35 centers throughout the U.S. and enrolled 314 patients to evaluate complete wound closure by 12 weeks. Patients were randomized to either the Dermagraft treatment group or control (conventional therapy). Except for the application of Dermagraft, treatment of study ulcers was identical for patients in both groups. All patients received pressure-reducing footwear and were allowed to be ambulatory during the study. RESULTS —The results demonstrated that patients with chronic diabetic foot ulcers of >6 weeks duration experienced a significant clinical benefit when treated with Dermagraft versus patients treated with conventional therapy alone. With regard to complete wound closure by week 12, 30.0% (39 of 130) of Dermagraft patients healed compared with 18.3% (21 of 115) of control patients ( P = 0.023). The overall incidence of adverse events was similar for both the Dermagraft and control groups, but the Dermagraft group experienced significantly fewer ulcer-related adverse events. CONCLUSIONS —The data from this study show that Dermagraft is a safe and effective treatment for chronic diabetic foot ulcers.

https://care.diabetesjournals.org/content/diacare/26/6/1701.full.pdf

The Efficacy and Safety of Dermagraft in Improving the Healing of Chronic Diabetic Foot Ulcers: Results of a prospective randomized trial

OBJECTIVE To determine whether dapagliflozin, which selectively inhibits renal glucose reabsorption, lowers hyperglycemia in patients with type 2 diabetes that is poorly controlled with high insulin doses plus oral antidiabetic agents (OADs). RESEARCH DESIGN AND METHODS This was a randomized, double-blind, three-arm parallel-group, placebo-controlled, 26-center trial (U.S. and Canada). Based on data from an insulin dose-adjustment setting cohort ( n = 4), patients in the treatment cohort ( n = 71) were randomly assigned 1:1:1 to placebo, 10 mg dapagliflozin, or 20 mg dapagliflozin, plus OAD(s) and 50% of their daily insulin dose. The primary outcome was change from baseline in A1C at week 12 (dapagliflozin vs. placebo, last observation carried forward [LOCF]). RESULTS At week 12 (LOCF), the 10- and 20-mg dapagliflozin groups demonstrated −0.70 and −0.78% mean differences in A1C change from baseline versus placebo. In both dapagliflozin groups, 65.2% of patients achieved a decrease from baseline in A1C ≥0.5% versus 15.8% in the placebo group. Mean changes from baseline in fasting plasma glucose (FPG) were +17.8, +2.4, and −9.6 mg/dl (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin, respectively). Postprandial glucose (PPG) reductions with dapagliflozin also showed dose dependence. Mean changes in total body weight were −1.9, −4.5, and −4.3 kg (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin). Overall, adverse events were balanced across all groups, although more genital infections occurred in the 20-mg dapagliflozin group than in the placebo group. CONCLUSIONS In patients receiving high insulin doses plus insulin sensitizers who had their baseline insulin reduced by 50%, dapagliflozin decreased A1C, produced better FPG and PPG levels, and lowered weight more than placebo.

https://care.diabetesjournals.org/content/diacare/32/9/1656.full.pdf

A Study of Dapagliflozin in Patients With Type 2 Diabetes Receiving High Doses of Insulin Plus Insulin Sensitizers Applicability of a novel insulin-independent treatment

Importance
The effects of tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, as an addition to insulin glargine for treatment of type 2 diabetes have not been described.


Objective
To assess the efficacy and safety of tirzepatide added to insulin glargine in patients with type 2 diabetes with inadequate glycemic control.


Design, Setting, and Participants
Randomized phase 3 clinical trial conducted at 45 medical research centers and hospitals in 8 countries (enrollment from August 30, 2019, to March 20, 2020; follow-up completed January 13, 2021) in 475 adults with type 2 diabetes and inadequate glycemic control while treated with once-daily insulin glargine with or without metformin.


Interventions
Patients were randomized in a 1:1:1:1 ratio to receive once-weekly subcutaneous injections of 5-mg (n = 116), 10-mg (n = 119), or 15-mg (n = 120) tirzepatide or volume-matched placebo (n = 120) over 40 weeks. Tirzepatide was initiated at 2.5 mg/week and escalated by 2.5 mg every 4 weeks until the assigned dose was achieved.


Main Outcomes and Measures
The primary end point was mean change from baseline in glycated hemoglobin A1c (HbA1c) at week 40. The 5 key secondary end points included mean change in body weight and percentage of patients achieving prespecified HbA1c levels.


Results
Among 475 randomized participants (211 [44%] women; mean [SD] age, 60.6 [9.9] years; mean [SD] HbA1c, 8.31% [0.85%]), 451 (94.9%) completed the trial. Treatment was prematurely discontinued by 10% of participants in the 5-mg tirzepatide group, 12% in the 10-mg tirzepatide group, 18% in the 15-mg tirzepatide group, and 3% in the placebo group. At week 40, mean HbA1c change from baseline was -2.40% with 10-mg tirzepatide and -2.34% with 15-mg tirzepatide vs -0.86% with placebo (10 mg: difference vs placebo, -1.53% [97.5% CI, -1.80% to -1.27%]; 15 mg: difference vs placebo, -1.47% [97.5% CI, -1.75% to -1.20%]; P < .001 for both). Mean HbA1c change from baseline was -2.11% with 5-mg tirzepatide (difference vs placebo, -1.24% [95% CI, -1.48% to -1.01%]; P < .001]). Mean body weight change from baseline was -5.4 kg with 5-mg tirzepatide, -7.5 kg with 10-mg tirzepatide, -8.8 kg with 15-mg tirzepatide and 1.6 kg with placebo (5 mg: difference, -7.1 kg [95% CI, -8.7 to -5.4]; 10 mg: difference, -9.1 kg [95% CI, -10.7 to -7.5]; 15 mg: difference, -10.5 kg [95% CI, -12.1 to -8.8]; P < .001 for all). Higher percentages of patients treated with tirzepatide vs those treated with placebo had HbA1c less than 7% (85%-90% vs 34%; P < .001 for all). The most common treatment-emergent adverse events in the tirzepatide groups vs placebo group were diarrhea (12%-21% vs 10%) and nausea (13%-18% vs 3%).


Conclusions and Relevance
Among patients with type 2 diabetes and inadequate glycemic control despite treatment with insulin glargine, the addition of subcutaneous tirzepatide, compared with placebo, to titrated insulin glargine resulted in statistically significant improvements in glycemic control after 40 weeks.


Trial Registration
ClinicalTrials.gov Identifier: NCT04039503.

Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes: The SURPASS-5 Randomized Clinical Trial.

OBJECTIVE —We sought to evaluate the effects of muraglitazar, a dual (α/γ) peroxisome proliferator–activated receptor (PPAR) activator within the new glitazar class, on hyperglycemia and lipid abnormalities. RESEARCH DESIGN AND METHODS —A double-blind, randomized, controlled trial was performed in 1,159 patients with type 2 diabetes inadequately controlled with metformin. Patients received once-daily doses of either 5 mg muraglitazar or 30 mg pioglitazone for a total of 24 weeks in addition to open-label metformin. Patients were continued in a double-blind fashion for an additional 26 weeks. RESULTS —Analyses were conducted at week 24 for HbA 1c (A1C) and at week 12 for lipid parameters. Mean A1C at baseline was 8.12 and 8.13% in muraglitazar and pioglitazone groups, respectively. At week 24, muraglitazar reduced mean A1C to 6.98% (−1.14% from baseline), and pioglitazone reduced mean A1C to 7.28% (−0.85% from baseline; P P CONCLUSIONS —We found that 5 mg muraglitazar resulted in greater improvements in A1C and lipid parameters than a submaximal dose of 30 mg pioglitazone when added to metformin. Weight gain and edema were more common when muraglitazar was compared with a submaximal dose of pioglitazone.

https://care.diabetesjournals.org/content/diacare/29/5/1016.full.pdf

Improvement of Glycemic Control, Triglycerides, and HDL Cholesterol Levels With Muraglitazar, a Dual (α/γ) Peroxisome Proliferator–Activated Receptor Activator, in Patients With Type 2 Diabetes Inadequately Controlled With Metformin Monotherapy: A double-blind, randomized, pioglitazone-comparative study

Paul Norwood

Papers

The Efficacy and Safety of Dermagraft in Improving the Healing of Chronic Diabetic Foot Ulcers: Results of a prospective randomized trial

A Study of Dapagliflozin in Patients With Type 2 Diabetes Receiving High Doses of Insulin Plus Insulin Sensitizers Applicability of a novel insulin-independent treatment

Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes: The SURPASS-5 Randomized Clinical Trial.