Michael J. Theodorakis

GIP does not potentiate the antidiabetic effects of GLP-1 in hyperglycemic patients with type 2 diabetes.

OBJECTIVE The incretin glucagon-like peptide 1 (GLP-1) exerts insulinotropic activity in type 2 diabetic patients, whereas glucose-dependent insulinotropic polypeptide (GIP) no longer does. We studied whether GIP can alter the insulinotropic or glucagonostatic activity of GLP-1 in type 2 diabetic patients. RESEARCH DESIGN AND METHODS Twelve patients with type 2 diabetes (nine men and three women; 61 ± 10 years; BMI 30.0 ± 3.7 kg/m2; HbA1c 7.3 ± 1.5%) were studied. In randomized order, intravenous infusions of GLP-1(7-36)-amide (1.2 pmol · kg−1 · min−1), GIP (4 pmol · kg−1 · min−1), GLP-1 plus GIP, and placebo were administered over 360 min after an overnight fast (≥1 day wash-out period between experiments). Capillary blood glucose, plasma insulin, C-peptide, glucagon, GIP, GLP-1, and free fatty acids (FFA) were determined. RESULTS Exogenous GLP-1 alone reduced glycemia from 10.3 to 5.1 ± 0.2 mmol/L. Insulin secretion was stimulated (insulin, C-peptide, P < 0.0001), and glucagon was suppressed (P = 0.009). With GIP alone, glucose was lowered slightly (P = 0.0021); insulin and C-peptide were stimulated to a lesser degree than with GLP-1 (P < 0.001). Adding GIP to GLP-1 did not further enhance the insulinotropic activity of GLP-1 (insulin, P = 0.90; C-peptide, P = 0.85). Rather, the suppression of glucagon elicited by GLP-1 was antagonized by the addition of GIP (P = 0.008). FFA were suppressed by GLP-1 (P < 0.0001) and hardly affected by GIP (P = 0.07). CONCLUSIONS GIP is unable to further amplify the insulinotropic and glucose-lowering effects of GLP-1 in type 2 diabetes. Rather, the suppression of glucagon by GLP-1 is antagonized by GIP.

Rationale for and design of the Acarbose Cardiovascular Evaluation (ACE) trial

Patients with cardiovascular disease and impaired glucose tolerance are at increased risk of cardiovascular events and type 2 diabetes mellitus (T2DM). Lifestyle modification or pharmacological intervention can delay progression to T2DM, but there is no clear evidence that they reduce cardiovascular risk in this population. Acarbose, an α-glucosidase inhibitor that lowers postprandial blood glucose, has been shown to reduce T2DM risk by 25%, and possibly cardiovascular risk in impaired glucose tolerance subjects without cardiovascular disease.

On the potential of acarbose to reduce cardiovascular disease.

In the emerging landscape of cardiovascular (CV) outcome trials evaluating the effects of blood glucose lowering drugs in individuals with type 2 diabetes, it is becoming increasingly apparent that since the promising signals coming from the United Kingdom Prospective Diabetes Study (UKPDS) no unequivocal benefits have been established for any single therapy thus far. There is an unmet need for introducing an effective pharmacological agent which could target both correlates of glycaemic regulation and CV risk factors, to ameliorate the enormous burden of fatal and non-fatal CV events in diabetic patients. Acarbose, like other alpha-glucosidase inhibitors (AGIs), has been proven to be an effective antidiabetic treatment for decades, but the overall significant impact of this class of drugs on modulating CV risk has only recently been appreciated. Accumulating evidence has shown that apart from its multiple effects on primarily postprandial glucose dysmetabolism, a key component of mechanisms linked to increased incidence of CV events, acarbose therapy also associates with a favorable impact on an array of surrogate markers of CV disease. Data stemming from in vitro testing of human cell lines as well as from preliminary trials in diabetic populations, like the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) trial, have highlighted – though not undisputed – the potential beneficial effects of the drug on CV morbidity. Large scale trials, like the ongoing Acarbose Cardiovascular Evaluation (ACE) trial, aim at conclusively establishing such a positive effect in patients with coronary heart disease and impaired glucose tolerance. In view of its usually acceptable level of side effects that are, if they occur, mostly limited to transient gastrointestinal symptoms, acarbose could well be a strong future player in CV disease secondary prevention. Current discouraging results from many trials of antidiabetic medications to significantly lower CV event rates in diabetic patients, should only draw further attention on alternative glucose lowering agents, among which acarbose is indeed promising.

Treatment of Langerhans Cell Histiocytosis with 2 Chlorodeoxyadenosine

Langerhans-cell histiocytosis (LCH) is a rare condition with a wide clinical spectrum and variable prognosis. Patients with multisystem LCH have been treated with a variety of agents but may develop resistant and progressive disease. Based on a preliminary encouraging report on the activity of 2 chlorodoxyadenosine in this disease, we administered this agent to a patient with LCH which was resistant to corticosteroids and etoposide. After 4 courses of treatment the patient achieved a complete remission which is currently ongoing for 12 months. 2 CdA appears to be effective in patients with resistant LCH and warrants investigation in previously untreated patients with poor risk disease.

Type 2 diabetes mellitus and heart failure: a position statement from the Heart Failure Association of the European Society of Cardiology

The coexistence of type 2 diabetes mellitus (T2DM) and heart failure (HF), either with reduced (HFrEF) or preserved ejection fraction (HFpEF), is frequent (30–40% of patients) and associated with a higher risk of HF hospitalization, all‐cause and cardiovascular (CV) mortality. The most important causes of HF in T2DM are coronary artery disease, arterial hypertension and a direct detrimental effect of T2DM on the myocardium. T2DM is often unrecognized in HF patients, and vice versa, which emphasizes the importance of an active search for both disorders in the clinical practice. There are no specific limitations to HF treatment in T2DM. Subanalyses of trials addressing HF treatment in the general population have shown that all HF therapies are similarly effective regardless of T2DM. Concerning T2DM treatment in HF patients, most guidelines currently recommend metformin as the first‐line choice. Sulphonylureas and insulin have been the traditional second‐ and third‐line therapies although their safety in HF is equivocal. Neither glucagon‐like preptide‐1 (GLP‐1) receptor agonists, nor dipeptidyl peptidase‐4 (DPP4) inhibitors reduce the risk for HF hospitalization. Indeed, a DPP4 inhibitor, saxagliptin, has been associated with a higher risk of HF hospitalization. Thiazolidinediones (pioglitazone and rosiglitazone) are contraindicated in patients with (or at risk of) HF. In recent trials, sodium–glucose co‐transporter‐2 (SGLT2) inhibitors, empagliflozin and canagliflozin, have both shown a significant reduction in HF hospitalization in patients with established CV disease or at risk of CV disease. Several ongoing trials should provide an insight into the effectiveness of SGLT2 inhibitors in patients with HFrEF and HFpEF in the absence of T2DM.

Pharmacological interventions for preventing or delaying onset of type 2 diabetes mellitus.

Prevention or delay of onset of type 2 diabetes in individuals at varying risk across the dysglycaemia continuum before overt diabetes becomes clinically manifest constitutes a leading objective of global disease prevention schemes. Pharmacological intervention has been suggested as a means to help prevent diabetes and reduce the global burden of this chronic condition. However, there is no credible evidence that early pharmacological intervention leads to long‐term benefit in reducing diabetes‐related complications or preventing early mortality, compared to treating people with diagnosed diabetes who have crossed the glycaemic threshold. In this review, we examine published evidence from trials using pharmacological agents to delay or prevent progression to diabetes. We also explore the benefit/risk impact of such therapies, safety issues and relevant off‐target effects. Current evidence suggests none of the drugs currently available sustainably lower cumulative diabetes incidence, none provides a durable delay in diabetes diagnosis and none provides a convincing concomitant excess benefit for microvascular or macrovascular risk.

Treatment outcomes after initiation of exenatide twice daily or insulin in clinical practice: 12-month results from CHOICE in six European countries

Objective: The CHanges to treatment and Outcomes in patients with type 2 diabetes initiating InjeCtablE therapy (CHOICE) study assessed time to, and reasons for, significant treatment change after patients with type 2 diabetes (T2DM) initiated their first injectable glucose-lowering therapy (exenatide twice daily [BID] or insulin) in routine clinical practice, and these patients’ clinical outcomes, in six European countries. This paper reports interim data from the first 12 months of the study. Research design and methods: CHOICE (NCT00635492) is a prospective, noninterventional, observational study. Clinical data were collected at initiation of first injectable therapy and after approximately 3, 6, and 12 months. Results: Of 2497 patients enrolled in CHOICE, 1096 in the exenatide BID and 1239 in the insulin cohorts had ≥1 post-baseline assessment and were included in this analysis. Overall, 32.2% of the exenatide BID cohort and 29.1% of the insulin cohort (Kaplan–Meier estimates) had significant treatment change during the first 12 months, most commonly discontinuing injectable therapy or adding new T2DM therapy, respectively. Glycemic control improved in both cohorts, but weight loss occurred only in the exenatide BID cohort (mean change −3.3 kg). Hypoglycemia occurred in 13.2% of the exenatide BID cohort and 28.6% of the insulin cohort (82.8% and 55.6% of these patients, respectively, received sulfonylureas). The post hoc endpoint of glycated hemoglobin < 7%, no weight gain, and no hypoglycemia was attained at 12 months by 24.3% and 10.3% of patients who had data at 12 months and who were receiving exenatide BID and insulin, respectively. Conclusion: About 30% of patients in CHOICE changed treatment in the first 12 months after initiation of first injectable therapy (exenatide BID or insulin). Overall, both cohorts achieved improved glycemic control, which was accompanied by a mean weight loss in the exenatide BID cohort.

Recurrent subacute cutaneous lupus erythematosus following exposure to different drugs.

A 70-year-old woman presented with multiple infiltrating, erythematous scaly plaques on her chest and back (Fig. 1a). She also had a personal history of xerostomia and xerophthalmia, but no other symptoms were reported. The differential diagnosis included CLE, pityriasis rosea, autoimmune bullous dermatosis, and contact dermatitis following external application of a homeopathic tincture to the affected areas. Her medical history revealed four new drugs; amiodarone (an anti-arrhythmic), torasemide (a loop diuretic), losartan (an angiotensin II antagonist – anti-hypertonic), and phenprocoumone (a vitamin K antagonist – anticoagulant), initiated 10 days before the appearance of the lesions, prescribed due to an aortic valve replacement operation with biological prosthesis. The patient was also on long-term medication with bisoprolol (a β-blocker) and acetylsalicylic acid. The specific laboratory investigation detected an antinuclear antibody titre of 1:1280 (normal < 1:160) anti-Ro/SS-A autoantibodies > 240 units/ml (normal < 10 units/ml) and circulating immune complexes 70.9 g/ml (normal < 45.0 g/ml). ds-DNA, anti-histone and anti-nucleosome antibodies, myoglobin, creatine kinase, transglutaminase and gliadin antibodies, as well as complement and antibodies characteristic for autoimmune bullous diseases, were either normal or negative. Skin biopsies demonstrated superficial interface dermatitis, thus subacute CLE (SCLE), lichenoid drug reaction and erythema exsudativum multiforme came into consideration histologically. However, the associated increase in dermal mucinous material following application of Alcian blue stain favoured LE, namely SCLE of papulosquamous (psoriasiform) form, according to the classification of Gilliam & Sontheimer (4). The medical history also revealed similar clinical signs in 2005, after administration of terbinafine because of a tinea. Laboratory investigation had also detected an increased antinuclear antibody (ANA) titre at that time (1:1280), along with an increased anti-SS-A antibody titre. After discontinuation of terbinafine the patient rapidly became symptom-free. At the current admission, the suspected drugs could not be discontinued or replaced, due to the recent aortic valve replacement operation. The patient was treated with oral chloroquine, 250 mg/day, and mild and potent topical corticosteroids and antiseptics. Three months later there was marked improvement of the skin lesions, but complete healing did not occur (Fig. 1b).

Comment on Færch et al. GLP-1 Response to Oral Glucose Is Reduced in Prediabetes, Screen-Detected Type 2 Diabetes, and Obesity and Influenced by Sex: The ADDITION-PRO Study. Diabetes 2015;64:2513–2525

On the basis of their Danish study population, Faerch et al. (1) concluded that glucagon-like peptide 1 (GLP-1) response to oral glucose tolerance testing (OGTT) was up to 25% impaired in prediabetes and screen-detected diabetes compared with normal glucose tolerance (NGT) and more pronounced in women than men. This finding supports the concept introduced more than two decades ago that a diminishing incretin effect is associated with the development of type 2 diabetes (T2DM), with early impaired GLP-1 release occurring before rather than after diabetes becomes clinically manifest. The authors cite the Baltimore Longitudinal Study of Aging (BLSA) …

Baseline Characteristics and Temporal Differences in Acarbose Cardiovascular Evaluation (ACE) Trial Participants

; The ACE trial is examining whether acarbose, an insulin-sparing postprandial glucose-lowering agent, can reduce cardiovascular (CV) events in patients who have coronary heart disease (CHD) and impaired glucose tolerance (IGT), with prevention of type 2 diabetes (T2D) as a secondary outcome. This update report evaluates the impact of the protocol-driven 4-week CV risk management optimization strategy during the run-in period, lists participant baseline characteristics, and examines whether temporal differences occurred during the 7-year recruitment period.