Combining scar-modulating agents for the treatment of hypertrophic scars and keloids: A systematic review.

Injury to the skin can cause abnormal wound healing and continuous inflammation that leads to the formation of hypertrophic scars and keloids. These lesions often cause significant negative impact on a patient's life due to aesthetic, physical, social, and psychological consequences. Numerous treatment modalities exist for these hypertrophic scars and keloids, which include silicone sheeting, pressure garments, intralesional injection/topical application of scar-modulating agents, laser therapy, and surgical excision. Due to increased efficacy, an evolving treatment paradigm encourages the use of multiple treatment modalities instead of one treatment modality. However, no gold standard treatment exists for these lesions, leaving many people with unsatisfactory results. Adding scar-modulating agents such as 5-Fluorouracil, bleomycin, or Botulinum Toxin A to triamcinolone monotherapy has emerged as a potential drug combination for treating hypertrophic scars and keloids. We sought to critically analyze the evidence that exists for the use of more than one scar-modulating agent. This was done by conducting a systematic review to determine the efficacy of these combined drug regimens. We found that many of these combinations show evidence of increased efficacy and fewer/similar adverse events to triamcinolone monotherapy. Triamcinolone and 5-Fluorouracil showed the strongest and most consistent evidence out of all combinations. With this review, we intend to encourage more research into unique drug combinations that may improve outcomes for patients with symptomatic hypertrophic scars or keloids.

Assessing Scar Outcomes Using Objective Scar Measurement Tools: An Adjunct to Validated Scar Evaluation Scales.

INTRO: The assessment of scar outcomes is important to both patient care and research focused on understanding the results of medical and surgical interventions. The Vancouver Scar Scale and Patient and Observer Scar Assessment Scale are validated and simple instruments to assess scars. However, these subjective scales have shortcomings. The VSS fails to capture patient perception and has indeterminate validity and reliability. The POSAS captures patient perception, but the observer scale has been shown to have moderate amounts of inter-rater variability. Studies highlighting the ability of objective scar assessment tools to produce reliable and reproducible results are needed. In this study, we aimed to validate the use of the Fibrometer ®, Elastimeter ®, and SkinColorCatch ® as an objective adjunct in the assessment of hypertrophic scar and keloid outcomes. METHODS: This was a prospective single-center study which assessed patient scars using the Vancouver Scar Scale, the Patient and Observer Scar Assessment scale, and the aforementioned objective study tools. Correlations between the different methods of scar assessment were measured. RESULTS: The Fibrometer ® and SkinColorCatch ® showed significant correlations with the VSS total and the Observer POSAS total. The Elastimeter ® showed significant correlations with both the Patient and Observer POSAS totals. Unexpected correlations between Elastimeter ® measurements and the vascularity/pigmentation of scars indicate that scoring of these categories may be influenced by how severe the scar looks to the observer subjectively, further necessitating the need for reliable objective scar assessment tools. CONCLUSION: These results highlight the ability of these devices to assess scars and demonstrate their potential in serving as an important adjunct to previously validated scar assessment scales.

Laser-Assisted Drug Delivery in the Treatment of Hypertrophic Scars and Keloids: A Systematic Review.

Hypertrophic scars and keloids are the results of an exaggerated healing process and are often associated with significant patient morbidity. Fractional ablative lasers create microchannels in the skin and penetrate into the substance of the scar, inducing a normal healing response in zones of created damage. Focal delivery of scar-modulating agents into the scar through these microchannels-a process termed laser-assisted drug delivery (LADD)-is a promising and developing treatment modality. In this systematic review, we aim to critically examine the evidence of LADD in the treatment of hypertrophic scars and keloids. The evidence suggests that LADD improves outcomes in hypertrophic scars and keloids. LADD is a more effective treatment modality than the topical application of agents in hypertrophic scars and equally effective as the intralesional injection of agents in keloids. There were few reports of adverse events. Evidence supports the use of LADD as an adjunct to non-surgical measures or a treatment modality to be used before more invasive measures such as surgical excision. However, the quality of evidence supporting this conclusion is inconsistent and lacks power. Additional studies are required to optimize dosages, laser settings, and agent choices for the treatment of these lesions.

Influence of preprandial vs. postprandial insulin glulisine on weight and glycaemic control in patients initiating basal-bolus regimen for type 2 diabetes: a multicenter, randomized, parallel, open-label study (NCT00135096).

AIM: Insulin therapy is commonly associated with weight gain. The timing of prandial insulin administration may enhance its efficacy/safety and maintain effective weight control. This study examined the effect of postprandial vs. preprandial insulin glulisine on weight gain and glycaemic control in type 2 diabetes patients taking basal insulin. METHODS: This was a multicenter, randomized, open-label trial conducted in 45 centres in the USA. A total of 716 patients with type 2 diabetes and glycated haemoglobin A(1c) (HbA(1c) ) ≥ 7.5% and ≤10.0% were screened; 345 were randomized and 322 comprised the intent-to-treat group (premeal, 163; postmeal, 159). Insulin glargine once daily, ±metformin and subcutaneous injections of premeal or postmeal insulin glulisine were given for 52 weeks. Main outcome measures included changes in HbA(1c) , fasting plasma glucose and weight from study baseline to endpoint (week 52). RESULTS: At study end, insulin glulisine achieved similar glycaemic control whether it was administered before or after meals (HbA(1c) : 7.04% premeal vs. 7.16% postmeal, p = NS). Overall hypoglycaemia incidence and severe hypoglycaemia rates were not significantly different between premeal and postmeal groups; however, symptomatic and nocturnal hypoglycaemia rates were higher in the postprandial group. Mean body weight was lower in the postmeal group, with the difference between postmeal and premeal weight change from baseline to week 52 of -0.87 kg (p = 0.243). CONCLUSION: Postprandial glulisine administration provided similar glycaemic control and was non-inferior to preprandial administration on weight gain, without additional risk of severe hypoglycaemia, showing dosing flexibility and the feasibility of such approach when clinically indicated.

Alogliptin added to insulin therapy in patients with type 2 diabetes reduces HbA(1C) without causing weight gain or increased hypoglycaemia.

AIMS: To assess the efficacy and safety of alogliptin added to insulin in patients with type 2 diabetes inadequately controlled with insulin alone or combined with metformin. METHODS: In this 26-week, double-blind, placebo-controlled study, 390 patients were randomized to receive alogliptin 12.5 mg (n = 131), alogliptin 25 mg (n = 129) or placebo (n = 130) once daily, as add-on to stable insulin therapy with or without metformin. The primary endpoint was change in haemoglobin A(1C) (HbA(1C)) at week 26. RESULTS: At week 26, mean HbA(1C) changes from the mean baseline value of 9.3% were significantly greater for alogliptin 12.5 mg (-0.63 +/- 0.08%) and alogliptin 25 mg (-0.71 +/- 0.08%) than placebo (-0.13 +/- 0.08%; p < 0.001). Significantly greater proportions of patients receiving alogliptin 12.5 or 25 mg than placebo had HbA(1C) decreases of > or =0.5, > or =1.0 and > or =1.5%. Insulin doses remained unchanged, and there were no differences in the proportions of patients experiencing hypoglycaemia among placebo (24%), alogliptin 12.5 mg (27%) and alogliptin 25 mg (27%). Mean weight increases from baseline at week 26 were similar for placebo (0.6 +/- 0.2 kg), alogliptin 12.5 mg (0.7 +/- 0.2 kg) and alogliptin 25 mg (0.6 +/- 0.2 kg). Incidences of overall adverse events, and of gastrointestinal, dermatological and infection-related events, were similar among groups. CONCLUSIONS: Adding alogliptin to previous insulin therapy (with or without metformin) significantly improved glycaemic control in patients with type 2 diabetes inadequately controlled on insulin, without causing weight gain or increasing the incidence of hypoglycaemia. Further studies are warranted to explore the role of alogliptin added to optimized basal insulin regimens.

Ligand binding to multiple equivalent sites with steric hindrance.

A general model is developed for the binding of ligands to multiple receptor sites in which steric blockage of sites is taken into account. Analytical expressions for extent of ligand binding as a function of ligand concentration are derived employing a stochastic matrix approach. Using simple numerical techniques to evaluate these expressions it is possible to obtain the inherent affinity of each site for a ligand, the number of sites available and the number of sites excluded when a ligand binds to any site. The expressions derived here are contrasted with other expressions based on simple equilibrium considerations in which there are no interactions between sites and no interactions between ligands in different sites. It is shown that the expressions derived here predict significant departures from linearity in Scatchard plots and a strong negative cooperatively, especially toward the saturation limit.

Red cell filterability determined using the cell transit time analyzer (CTTA): effects of ATP depletion and changes in calcium concentration.

Cell transit time analysis (CTTA) is a new filtrometric technique for assessing red blood cell deformability by measuring the conductivity change caused by passage of erythrocytes through a polycarbonate filter. Most reported studies to date using CTTA have focused on the transit time (TT), the duration of passage of an individual red cell through a micropore. Bulk flow rate has not been previously measured via CTTA. The use of new enzyme based cleaning solutions make it possible to reduce clogging in micropore filters. Therefore, valid measures of the number of red cell transits per unit time (counts/s: C/S) can now be obtained. We evaluated both parameters, TT and C/S, as indicators of red cell filterability. Our goal was to evaluate the effect of metabolic changes shown by alternative techniques to affect red cell deformability. The two best established factors are changes in intracellular [ATP] and [Ca2+]. ATP depletion produces a very small increase in TT but a very marked decrease in C/S. In contrast, the addition of low concentrations of calcium produces an increase in TT with minimal decrease in C/S. The effects of calcium appear to be complex. The substantial changes in intracellular calcium induced by the ionophore A23187 result in a curvilinear pattern of increase in transit times and reduction in counts per s. Lanthanum, which inhibits egress of intracellular calcium, causes an increase in TT with a drop in C/S. We conclude that CTTA demonstrates the same changes in red cell deformability measurable by alternative filtrometric techniques; however, CTTA furnishes two separate and independent parameters which may be used to evaluate red cell deformability.

Estimation of the secretion rate of insulin from the urinary excretion rate of C-peptide. Study in obese and diabetic subjects.

Direct methods for measuring the secretion rate of insulin are too cumbersome for clinical application. Since C-peptide is secreted in an equimolar ratio with insulin and is excreted into the urine, measuring the urinary excretion rate of C-peptide (U-C) could serve as an indicator of its secretion rate (SR-C) if its urinary clearance (UCI-C) is constant and unaffected by plasma C-peptide concentration, body mass, or diabetes. We measured clearance ratios of C-peptide/creatinine (CR) in the fasting state and integrated 0-1, 1-3, and 3-5 h after 100 g of glucose p.o. as well as over a full 24-h in eight obese, eight lean, and six maturity-onset diabetic subjects. CR did not differ significantly when values in the fasting state were compared with those in the postprandial periods and was therefore unaffected by plasma C-peptide concentration. Furthermore, CR was similar in the lean, obese, and diabetic subjects. SR-C, determined as the product of the metabolic clearance rate of C-peptide and its fasting or integrated plasma concentrations, correlated significantly with U-C in all the subjects (r = 0.87, P less than 0.0001). The correlation of U-C with SR-C in the diabetic subjects alone was also significant (r = 0.88, P less than 0.0001). In conclusion, our data support the use of U-C as an indirect measure of SR-C and therefore of SR-I.

Microvascular blood flow, volume, and velocity measured by laser Doppler techniques in IDDM.

A laser Doppler device with the capability to simultaneously measure skin blood flow, microvascular volume, and erythrocyte velocity was used to assess blood flow changes in 35 insulin-dependent diabetes mellitus (IDDM) subjects, mean age 33 +/- 1 yr, with average duration of diabetes 14 +/- 1 yr, and in a nondiabetic control group. Blood flow was determined at 35 and 44 degree C at several sites on the upper and lower extremities with a temperature-regulated probe. Blood flow was highest at both temperatures on the pulps of the index finger and the first toe, regions of high density of arteriovenous anastomoses. There was significantly greater blood flow at most locations for the nondiabetic than the diabetic group at 35 degree C, and the differences between the two groups were substantially larger at 44 degree C. At 44 degree C, blood flow in the control group was approximately 40% greater in the upper extremity and 50% greater in the lower extremity than it was in the diabetic subjects. The differences were attributed to decreases of both microvascular volume and velocity in the diabetic group. In the upper extremity, volumes in the diabetic patients were 10-15% lower and velocities 10-40% lower than in the nondiabetic subjects. In the lower extremity, volumes were 20-25% lower and velocities 40-50% lower. We conclude that laser Doppler techniques can be used to assess microvascular changes in the skin of diabetic patients. This approach may be useful to evaluate and model diabetic microangiopathy.

Endogenous insulin secretion measured by C-peptide in maturity-onset diabetes controllable by diet alone.

Endogenous insulin secretion was quantified in patients with maturity-onset diabetes (MOD) whose diabetes was controllable solely by caloric regulation as primary therapy. Insulin was used adjunctively only and persistent attempts were made to withdraw it as weight loss occurred in response to diet. Insulin secretory capacity was measured by C-peptide response during a standard 100-g oral glucose tolerance test in 24 patients who achieved normalization of plasma glucose level as a result of dietary therapy alone. Summed C-peptide levels for the diet-controlled diabetic patients was 7.8 +/- 0.7 pmol/mL as compared with 6.1 +/- 0.45 pmol/mL for a group of ten normal-weight, nondiabetic volunteers.

The health care status of the diabetic population as reflected by physician claims to a major insurer.

BACKGROUND: Conventional epidemiologic data suggest that diabetic patients use more health care resources than nondiabetic patients, yet overall health care use by diabetic individuals has never been fully quantitated. We took a new approach to this issue based on the actual economics of the provision of health care to diabetic insured individuals. METHODS: The claims records in the Mutual of Omaha Current Trends database, which contains information on more than 400,000 individuals, were surveyed to identify patients with diabetes and create the contrast population of nondiabetic patients by exclusion. International Classification of Diseases, Ninth Revision, Clinical Modification, codes and Physicians' Current Procedural Terminology, Fourth Edition, codes were used to determine all diagnoses recorded and all physician services rendered to the contrast populations. Age- and sex-adjusted comparisons were performed using Mantel-Haenszel procedures to determine an adjusted odds ratio (AOR). RESULTS: A total of 13,304 diabetic individuals and 388,053 nondiabetic individuals who received health care services from January 1, 1988, to January 1, 1989, were identified. Diabetic insured individuals constituted 3.1% of the overall insured population yet accounted for 8.3% of the charges (P < .01). Inpatient charges accounted for 81% of total diabetic charges but only 61.5% of total nondiabetic charges (P < .001). Diabetic insured individuals had twice as many physician office visits (AOR = 1.87; 95% confidence interval [CI], 1.79 to 1.96), with 2.5 times more physician hospital visits [AOR = 2.50; 95% CI, 2.27 to 2.75). However, the increases in physician care were not uniformly distributed across the diagnostic spectrum. The frequencies of well-established complications of diabetes, such as ischemic heart disease (AOR = 3.32; 95% CI, 3.12 to 3.53), peripheral vascular disease (AOR = 3.14; 95% CI, 2.79 to 3.53), and eye disease (AOR = 3.10; 95% CI, 2.94 to 3.27), were threefold higher in the diabetic group, with parallel increases in related medical services, such as cardiac catheterization (AOR = 3.02; 95% CI, 2.27 to 4.0), vascular surgery (AOR = 2.94; 95% CI, 2.64 to 3.27), and ophthalmologic procedures (AOR = 2.94; 95% CI, 2.72 to 3.18). In contrast, most diagnostic categories showed little or no increase. For example, the frequency of neoplasms (AOR = 1.11; 95% CI, 1.03 to 1.19) was minimally increased, and the associated procedural concomitants of therapeutic radiology (AOR = 0.81; 95% CI, 0.47 to 1.39) and chemotherapy (AOR = 0.98; 95% CI, 0.60 to 1.60) were not increased in the diabetic group. CONCLUSIONS: Our most important new finding is that diabetic patients have neither an elevated risk for a wide spectrum of diseases nor an increase in the receipt of physician services for diagnostic categories without increased risk, despite more frequent physician encounters. We provide real-world risk estimates that help in calculating the effect of offering specific insurance to diabetic individuals or including them in group health plans. The techniques we have developed to analyze computerized claims databases in this way may serve to better quantify the true impact of chronic diseases on the health care system.

Chemical hyperthyroidism: serum triiodothyronine levels in clinically euthyroid individuals treated with levothyroxine.

We have observed many patients treated with levothyroxine sodium who have elevated serum thyroxine (T4) levels but appear clinically euthyroid. Such patients generally have normal serum triiodothyronine (T3) values. A retrospective review at The Johns Hopkins Hospital, Baltimore, comparing the correlation of T3 and T4 values in levothyroxine-treated patients with that in patients not so treated was carried out from 1977 to 1979. Mean free thyroxine index (FTI) value in 104 levothyroxine-treated patients was 4.70 +/- 0.2 and mean T3 value was 177 +/- 9 ng/dL. In a group of 50 hyperthyroid patients, mean FTI value was 7.26. +/- 0.5, with a mean T3 value of 389 +/- 26 ng/dL. In 71 euthyroid patients, mean FTI value was 2.36 +/- 0.1, with a T3 value of 137 +/- 3 ng/dL. Computed ratios of T3 to FTI and T3 to T4 were significantly lower in the group treated with levothyroxine than in either the hyperthyroid or euthyroid nontreated groups. Levothyroxine-treated patients with high T4 levels but normal T3 levels were clinically euthyroid. Patients not treated with levothyroxine with similarly elevated T4 levels had elevated T3 levels and were clinically hyperthyroid. It is concluded that lower relative T3 levels in levothyroxine-treated patients may explain why these patients appear clinically euthyroid despite elevated T4 values. Serum T3 determination is the procedure of choice for evaluation of levothyroxine-treated individuals. Furthermore, an elevated FTI value in such an individual does not, in itself, dictate need to reduce dosage.

Fingerstick glycosylated hemoglobin, plasma protein, and albumin.

We have developed techniques that permit the affinity-chromatographic determination of glycosylated hemoglobin, plasma protein, and albumin on fingerstick samples of whole blood. The fingerstick glycohemoglobin technique takes advantage of the high sensitivity of measurement of hemoglobin by absorbance at 414 nm. The glycosylated plasma protein is assayed by a highly sensitive method based on binding of Coomassie blue. An enzyme-linked immunosorbent assay is used to measure albumin in the bound and nonbound fractions of an aminophenylboronic acid chromatographic separation. The fingerstick method for assay of glycosylated plasma albumin gives results that are approximately 40% higher than comparable values obtained on the same patient with a 1-ml plasma sample determined with the bromcresol green technique. There is good correlation of fingerstick glycoalbumins with fingerstick glycohemoglobins and glycosylated plasma protein values. These procedures should be useful for children and for large-scale ambulatory screening for diabetes mellitus.

The dawn phenomenon, an early morning glucose rise: implications for diabetic intraday blood glucose variation.

Eleven insulin-dependent (type I) diabetic subjects were studied during a 24-h period to assess intraday blood glucose (BG) variation and related free insulin (FI) levels. Ten patients exhibited the dawn phenomenon, a rise in early morning fasting blood glucose (123 +/- 81.1 m/dl; mean +/- SD). This increase was positively and significantly correlated with the morning postprandial BG peak (r = 0.723; P = 0.012). FI/BG ratios were highest during the night (0.717 and 0.666 at 2200 and 0400 h, respectively) and lowest during the early morning (0.294 at 0800 h) (P less than 0.01). Three of the four observed hypoglycemic episodes occurred during the period when free insulin levels were high relative to BG. We conclude that the dawn phenomenon contributed directly and significantly to the BG maximum and indirectly, in some cases, to nocturnal hypoglycemia. It thus played an important role in the intraday blood glucose variation of such patients.

Recovery from decompensated non-insulin-dependent diabetes mellitus: studies of C-peptide secretion.

Eleven non-insulin-dependent diabetic patients presented with decompensated hyperglycemia. Nine had pronounced ketonuria, five with acidosis. In seven cases, precipitating factors were identified. In the other four cases, including three cases of diabetic ketoacidosis, no identifiable triggering events were present. In each case, recovery from the initially decompensated diabetic state occurred. Eventually, all patients were managed by diet alone. Seven patients demonstrated nondiabetic glucose tolerance tests (GTT). Several patients underwent stressful situations after "recovery" without recurrence of hyperglycemia. Glucose-stimulated C-peptide levels were determined postrecovery. C-peptide secretion was in the normal range and, in fact, was identical, in relation to glucose levels, to that in a group of nondiabetic volunteers. In 6 of the 11 cases, C-peptide secretion was measured at the time of initial presentation. These levels were markedly lower than comparable values during the GTT postrecovery. Non-insulin-dependent diabetes, even when presenting in a decompensated state, is subject to a considerable degree of reversibility and even recovery to a nondiabetic state in some cases. Recovery is associated with a return to normal C-peptide secretion.

A randomized trial of rosiglitazone therapy in patients with inadequately controlled insulin-treated type 2 diabetes.

OBJECTIVE: To determine the efficacy and safety of rosiglitazone (RSG) when added to insulin in the treatment of type 2 diabetic patients who are inadequately controlled on insulin monotherapy. RESEARCH DESIGN AND METHODS: After 8 weeks of insulin standardization and placebo (PBO) run-in, 319 type 2 diabetic patients with mean baseline HbA(1c) > or = 7.5% (8.9 +/- 1.1 to 9.1 +/- 1.3) on twice-daily insulin therapy (total daily dose > or = 30 U) were randomized to 26 weeks of additional treatment with RSG (4 or 8 mg daily) or PBO. Insulin dose could be down- titrated only for safety reasons. The primary end point was reduction of HbA(1c) from baseline. RESULTS: RSG 4 and 8 mg daily significantly improved glycemic control, which was unchanged on PBO. By intent-to-treat analysis, treatment with RSG 8 mg plus insulin resulted in a mean reduction from baseline in HbA(1c) of 1.2% (P < 0.0001), despite a 12% mean reduction of insulin dosage. Over 50% of subjects treated daily with RSG 8 mg plus insulin had a reduction of HbA(1c) > or = 1.0%. Neither total:HDL cholesterol nor LDL:HDL cholesterol ratios significantly changed with RSG treatment. Serious adverse events did not differ among groups. CONCLUSIONS: The addition of RSG to insulin treatment results in significant improvement in glycemic control and is generally well tolerated.

Efficacy and safety of acarbose in insulin-treated patients with type 2 diabetes.

OBJECTIVE: To demonstrate the efficacy, tolerability, and safety of acarbose compared with placebo in patients with type 2 diabetes inadequately controlled with diet and insulin. RESEARCH DESIGN AND METHODS: A multicenter randomized double-blind placebo-controlled parallel-group comparison study was conducted. The trial was 26 weeks with a 2-week screening period and a 24-week period of treatment with acarbose or placebo, with forced titration from 25 mg t.i.d. to 50 mg t.i.d. after 4 weeks, and titration of 50 mg t.i.d. to 100 mg t.i.d. after 12 weeks based on glucose control. The dosage of insulin was to remain stable. The primary efficacy variable was mean change from baseline in HbA1c, and secondary efficacy variables included mean changes in fasting and postprandial plasma glucose and triglyceride levels. RESULTS: The addition of acarbose to the treatment of patients receiving background insulin and diet therapy resulted in a statistically significant reduction in mean HbA1c of 0.69% compared with placebo. There were statistically significant reductions in postprandial plasma glucose and glucose area under the curve, and in postprandial serum triglyceride levels in the acarbose-treated patients. Gastrointestinal side effects were more frequently reported in the acarbose-treated patients. There were no significant differences in hypoglycemic events or liver transaminase elevations between groups. CONCLUSIONS: This study demonstrated that the addition of acarbose to patients with type 2 diabetes who are inadequately controlled with insulin and diet is safe and generally well tolerated and that it significantly lowers HbA1c and postprandial glucose levels.

A randomized placebo-controlled trial of repaglinide in the treatment of type 2 diabetes.

OBJECTIVE: The objective of the study was to assess the efficacy and safety of repaglinide compared with placebo in the treatment of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a phase II multicenter, double-blind, placebo-controlled, randomized, dose-adjustment and maintenance trial. After screening and a 2-week washout period, 99 patients were randomized to receive either repaglinide (n = 66) or placebo (n = 33). Patients underwent 6 weeks of dose adjustment followed by 12 weeks of dose maintenance. Fasting and stimulated glycosylated hemoglobin (HbA1c), plasma glucose, insulin, and C-peptide were measured at predetermined intervals. Adverse events and hypoglycemic episodes were recorded. RESULTS: From baseline to last visit, mean HbA1c decreased from 8.5 to 7.8% in patients treated with repaglinide and increased from 8.1 to 9.3% in patients receiving placebo, with a statistically significant difference of - 1.7% (P < 0.0001) between treatment groups at the last visit. Mean fasting plasma glucose and postprandial glucose increased in patients receiving placebo and decreased in patients treated with repaglinide, with statistically significant (P < 0.01) differences between groups at the last visit. Concentrations of fasting and postprandial insulin and C-peptide were lower at the last visit compared with baseline for patients treated with placebo and higher for patients treated with repaglinide, and the differences between groups were statistically significant (P < 0.05). Overall, repaglinide was well tolerated. CONCLUSIONS: This study demonstrated that repaglinide was safe and efficacious in lowering blood glucose concentrations. In addition to overall improvement in glycemic control noted with repaglinide in both sulfonylurea-treated patients and oral hypoglycemic agent-naive patients, repaglinide had a potent glucose-lowering effect in the postprandial period.

Mapping diabetic sensory neuropathy by current perception threshold testing.

Detailed clinical neurological examinations were conducted on 44 nondiabetic volunteers and 59 diabetic subjects. The examinations focused particularly on sensory symptomatic and physical evaluation. Standardized assessment of symptoms and physical testing of light touch, pain, vibratory, and thermal sensation was performed at the hand, wrist, elbow, foot, ankle, and knee. A total symptom score and physical score were defined by summing test scores at each site. Current perception threshold (CPT) testing that used constant sine-wave-alternating current was conducted at the same anatomic sites. CPT correlations with the physical score gave r values of .55 for 5 Hz, .60 for 250 Hz, and .62 for 2000 Hz (n = 618). Correlations with the symptom score were not as strong: r = .45 for 5 Hz, .46 for 250 Hz, and .51 for 2000 Hz. The correlation with symptom score was due primarily to a strong relationship for the symptom of numbness (r = .53 for all 3 frequencies). Correlations with pain and paresthesia were much lower. CPTs for diabetic subjects at the three frequencies were higher at most locations than for the nondiabetic volunteers. However, CPTs were no different from normal values in diabetic subjects without evidence of neuropathy. CPT testing appears to be a useful technique for assessment of diabetic sensory neuropathy.

First fixed-ratio combination of insulin degludec and liraglutide for the treatment of type 2 diabetes.

When oral hypoglycemic agents do not successfully suppress hyperglycemia, the traditional approach has been to add insulin injections. With the coming of glucagon-like peptide 1 (GLP-1) receptor agonists carrying the benefits of weight loss and reduced risk of hypoglycemia, it has been suggested that GLP-1 agents should be used instead. There is equivalent lowering of HbA1c with either treatment. Insulin therapy is associated with hypoglycemia and weight gain while GLP-1 receptor agonists promote weight loss. Gastrointestinal (GI) intolerance is the chief obstacle to GLP-1 treatment. The combined use of basal insulin and GLP-1 receptor agonists results in improved glycemic control and mitigates weight gain. The recent approval of insulin degludec/liraglutide administered in a fixed ratio combination is unique not simply for the additive benefits of the two agents, but because it now permits adjustable dosing of liraglutide together with insulin, providing better glucose control than with either agent alone at lower dose levels. Lower dosage of insulin degludec reduces the risk of hypoglycemia. Liraglutide combats the weight gain that accompanies the introduction of insulin therapy, and a reduced dose of liraglutide induces less GI intolerance. This first combined basal insulin-GLP-1 receptor agonist combination represents a conceptual advance in the treatment of insulin-requiring type 2 diabetes.