Efficacy of saxagliptin as an add-on to oral monotherapy in the phase 3 clinical development program: predictive factors of the treatment response in type 2 diabetes.

Saxagliptin, a dipeptidyl peptidase-4 inhibitor, has been the focus of a large clinical development programme, including Phase 3 randomized vs placebo-controlled clinical trials as add-on therapy in patients with type 2 diabetes (T2D) with inadequate glycemic control using initial monotherapy (metformin, glibenclamide, thiazolidinedione). This clinical programme has shown saxagliptin to be effective in the control of fasting and postprandial glycemic parameters, in addition to a good overall safety profile. The present paper aims at reviewing the overall short-term and long-term efficacy of saxagliptin in its Phase 3 development program and tries to pinpoint some factors that may be more predictive of treatment response in clinical practice. In individual and pooled analyses of the three pivotal add-on to monotherapy trials, saxagliptin (5mg once daily) led to significant reductions in HbA(1c) from baseline to 24 weeks. Additional analyses showed that reductions in HbA(1c) were maintained in the long-term, notably for 102 weeks, in combination with metformin. Data have also shown that the absolute reduction in HbA(1c) seen with saxagliptine from baseline to Week 24 was numerically greater with an elevated baseline HbA(1c). In these recently published pooled analyses, clinically pertinent reductions in HbA(1c) were also obtained with saxagliptin across a wide range of subgroups of T2D patients when examined either by specific baseline demographic characteristics or by ß-cell function indices such as the HOMA-ß.

The Third Injection Technique Workshop in Athens (TITAN).

The first Injection Technique workshop brought together endocrinologists and injection experts from around the world in Strasbourg in 1997. From its work came groundbreaking recommendations which advanced best practices in areas such as the use of a skin fold when injecting. The second Injection Technique workshop, with an expanded format including nurses and diabetes educators, took place in Barcelona in 2000. The initial stimulus to use shorter injecting needles can be said to date from this meeting. The third Injection Technique workshop was held in Athens in September 2009 and involved 127 experts from across the globe. After a comprehensive review of all publications since 2000 as well as several unpublished studies, the attendees divided into smaller groups to debate and draft new injecting recommendations based on the new data and their collective experience. This paper summarizes all the formal presentations given at this practical consensus workshop.

New injection recommendations for patients with diabetes.

AIM: Injections administered by patients are one of the mainstays of diabetes management. Proper injection technique is vital to avoiding intramuscular injections, ensuring appropriate delivery to the subcutaneous tissues and avoiding common complications such as lipohypertrophy. Yet few formal guidelines have been published summarizing all that is known about best practice. We propose new injection guidelines which are thoroughly evidence-based, written and vetted by a large group of international injection experts. METHODS: A systematic literature study was conducted for all peer-reviewed studies and publications which bear on injections in diabetes. An international group of experts met regularly over a two-year period to review this literature and draft the recommendations. These were then presented for review and revision to 127 experts from 27 countries at the TITAN workshop in September, 2009. RESULTS: Of 292 articles reviewed, 157 were found to meet the criteria of relevance to the recommendations. Each recommendation was graded by the weight it should have in daily practice and by its degree of support in the medical literature. The topics covered include The Role of the Professional, Psychological Challenges, Education, Site Care, Storage, Suspension and Priming, Injecting Process, Proper Use of Pens and Syringes, Insulin analogues, Human and Pre-mixed Insulins, GLP-1 analogs, Needle Length, Skin Folds, Lipohypertrophy, Rotation, Bleeding and Bruising, Pregnancy, Safety and Disposal. CONCLUSION: These injecting recommendations provide practical guidance and fill an important gap in diabetes management. If followed, they should help ensure comfortable, effective and largely complication-free injections.

Subcutaneous insulin: pharmacokinetic variability and glycemic variability.

The therapeutic goal in insulin-treated diabetic patients is to maintain on the long-term a tight glucose control (HbA1, < 6.5-7% or less) through an insulin regimen which "mimic" the physiological insulin profile: a basal insulin secretion to maintain glucose homeostasis and an acute post-prandial secretion in response to meal intake. Such goal represents a challenge for the clinician as conventional human insulins have major drawbacks: slow absorption and too late peak with regular insulins, delayed peak and often occuring at an unwanted time with intermediate and long-acting insulins. Furthermore, these insulins are characterised by a large within- and between-subjects variability, which complicate patients' task to self-adapt their daily doses, even for those well educated and compliants. These limitations and unpredictable variations in insulin action are responsible for an increased risk of hypoglycemic events, between meals as well as during the night period. As a consequence, glucose control is frequently insufficient in type 1 diabetic patients, and these limitations may contribute also to the delayed initiation of insulin therapy in type 2 diabetics when oral antidiabetic agents fail. This variability and the non-reproducibility of the conventional insulin pharmacodynamics are explained by several exogenous and endogenous factors describe in this review. Availability of new short-acting (lispro, aspart and glulisine) and long-acting analogs (glargine, detemir) of human insulin, with improved pharmacokinetic characteristics, and a lesser variability and better reproducibility, should facilitate a tight glucose control in insulin-treated patients. The main pharmacokinetic and pharmacodynamic characteristics of these new insulin analogs are presented and discussed in the light of there intra- and inter-individual variability. Their reduced variability should permit to reinforce near "physiological" insulin regimen such as "basal-bolus" technique and to consider new approaches and therapeutic strategies in type 1 and type 2 diabetic patients.

[Pioglitazone insulin sensitivity and type 2 diabetes mellitus: recent data]. / Pioglitazone, insulinosensibilité et diabète de type 2: données récentes.

Thiazolidinediones ("glitazones") were recently added to the oral treatment of type 2 diabetes. Two glitazones are available in France, pioglitazone and rosiglitazone, which progressively were granted broader therapeutic indications since their launch in 2002. This review presents the most recent pioglitazone pharmacological and clinical data, with a particular emphasis on the QUARTET clinical study program results. Available information generates perspectives and hopes: prevention of the progressive decline in beta-pancreatic cell function (and possibly, prevention of type 2 diabetes in at-risk subjects), cardiovascular prevention in type 2 diabetic patients depending on the results of the ongoing prospective morbi-mortality studies in high risk type 2 diabetic patients.

[What allows a type 1 diabetic to be well controlled]. / Ce qui permet a un diabetique de type 1 d'aviur sa glycemie sous controle.

Long-term studies carried out in type 1 insulin-dependent diabetic population have clearly demonstrated a tight glycaemic control to be a key factor in type 1 diabetes mellitus survival. A better HbA1c is associated with lesser retina and kidney complications. The DCCT study has clearly shown intensive insulin treatment (3 or more insulin injections per day) to be superior to conventional regimen (one or 2 insulin injections per day) to reduce the risk for development (primary prevention) of late diabetic complications. However, such intensive insulin regimen should be started early, maintained on the long-term, and should be based on a regular and adequate blood glucose self-monitoring. The beneficial effects of a tight glycaemic control to reduce the risk for progression (secondary prevention) of late diabetic complications has not been proved yet. Consequently, at this stage, non-glycaemic interventions (antihypertensive treatment with angiotensin-converting-enzyme inhibitors, laser photocoagulation surgery) are the most useful treatment modalities. The global prognosis of type 1 insulin-dependent diabetics is strongly linked to the patient attitude, to his understanding of the disease and to his motivation to participate in the disease management. This requests permanent, long-term, intensive patient's information and education. Information tools (from oral information to website) and strategies (from usual educational courses by the diabetes care team to general public information) remain to be fully evaluated.

[Dietary assessment in current clinical practice: how to conciliate rapidity, simplicity and reliability?]. / Evaluation alimentaire en pratique courante: comment concilier rapidité, simplicité et fiabilité?

Dietary interviews and food diaries are traditionally used for nutritional assessments. In clinical practice, these methods are time consuming, require high training, and thus remain poorly used. Furthermore, the results are frequently impaired by the underreporting phenomenon which can be due either to underrecording (failure to record what is eaten) or to undereating (volontary food restriction during the assessment period). These difficulties can be overcome by using rapid questionnaires based on 2 principles: 1) underreporting is less for proteins than for other macronutrients; 2) in developed countries, calories from proteins are relatively stable and contribute approximately to one sixth of the total daily energy intake. Estimations given by the rapid questionnaire lead to less misleading results than those provided by 7 day-food records. On the other hand, the rapid questionnaire gives an estimate of specific dietary behaviors such as nibbling, festive meals and consumption of salted entrées, sweet desserts and caloric beverages. In conclusion, helpful and simple recommendations for correcting main nutritional errors can be drawn from estimation of the above mentioned specific behaviors that correspond to a daily average of 500 kcalories.

[Present and future of insulin therapy in type 2 diabetic patients]. / Présent et futur de l'insulinothérapie dans le diabète de type 2.

Type 2 diabetes natural history and progressive deterioration requires a therapeutic approach starting with diet and physical activity changes, then associated with pharmacological interventions (monotherapy, then multiple therapy). When oral anti-diabetics at optimal dosage have failed to maintain good diabetic control (HbA1c 6.5% Pounds), insulin treatment has to be considered and should be used when diabetic controls remain poor (HbA1c > 8%). The most adequate insulin regimen are bedtime NPH associated or not with oral anti-diabetics, or alternatively 2 daily injections (morning and evening) of intermediate insulin. Intensive insulin (3 daily injections or more), and particularly the use of short-acting analogues is an effective regimen when bedtime or conventional regimen have failed. Insulin glargin could be an interesting alternative to bedtime NPH but needs further data in type 2 diabetes. Insulin treatment has to be initiated with an adequate patient (and family) education. Glycaemic objectives (fasting blood glucose and HbA1c) should be regularly assessed and adapted taking into consideration diabetic control, clinical effects and safety assessments (weight gain, hypoglycaemic events...).

Effect of a conjugated oestrogen (Premarin) cream on ageing facial skin. A comparative study with a placebo cream.

The effects of Premarin cream on ageing facial skin were studied in a randomised, double-blind, parallel group study. Fifty-four women aged 52-70 years who had moderate to severe facial cutaneous ageing, applied 1 g of either Premarin cream (0.625 mg conjugated oestrogens per gram of cream), or placebo cream (same composition with the exclusion of conjugated oestrogens) to the face nightly for 24 weeks. Each morning these women protected their face with a sunblock SPF 15. Skin thickness was measured by B-scan ultrasonic echography, and skin microrelief by profilometry. Each subject's facial appearance was also evaluated by the subject herself and by the clinician. A statistically significant difference (P = 0.013) in favour of Premarin cream was detected in skin thickness at week 24. Skin thickness (dermal plus epidermal) for the women who used Premarin cream increased from 1.56 +/- 0.20 mm at baseline to 1.68 +/- 0.19 mm, compared with 1.52 +/- 0.20 mm at baseline to 1.59 +/- 0.19 mm in the placebo group. Premarin cream was also significantly more effective than placebo cream in improving fine wrinkles according to the results at weeks 12 and 24 (P = 0.010 and P = 0.012, respectively). Significant improvement from baseline was detected in both groups for roughness, laxity and mottled pigmentation and/or lentigines; however, there was no significant difference in these parameters between the two treatment groups. No subjects discontinued treatment for a safety reason. In conclusion, Premarin cream produced better results than the placebo cream; the difference was statistically significant for skin thickness and fine wrinkles. Premarin cream was well tolerated locally, and its general safety was good.