Search

Introduction: Diabetes mellitus is increasing rapidly worldwide, and treatment comes with many challenges. It is estimated that in 2030, approximately 500 million people will live with diabetes across the world—most of which will be type 2 diabetes mellitus (T2DM). Obesity often coincides with T2DM and has been linked to increased insulin resistance, high blood pressure, and high blood lipids. Thus, pharmacological management should be aimed at promoting weight loss or at very least be weight neutral. In many cases the risks of hypoglycaemia and weight gain may delay titration of diabetic agents to HbA1C targets. Both insulin and sulfonylureas are proven medications which are beneficial for tight glycemic control but with an increased risk of weight gain and hypoglycaemia. Newer agents under the drug class glucagon-like peptide receptor antagonists (GLP-1RA) are increasingly being used. Various randomized clinical trials support that obese T2DM patients treated with GLP-1RA lead to better glycaemic control, weight reduction and reduced risk of hypoglycaemia. Case Summary: A 56-year-old female was diagnosed with T2DM in 2003 and had been regularly followed up in diabetes clinic since 2014. During the initial clinic review she had a body weight of 114.9 kg (BMI 40.7), fasting blood glucose was 8 - 9, 2-hour CBG 11-13 and HbA1c of 87. At that time, she was taking insulin glargine (Lantus) 36 units once daily, gliclazide 40 mg in the morning / 120 mg in the evening, metformin slow release 2 g in the evening, and simvastatin 20 mg at bedtime. After discussion with her she was started on the GLP-1RA liraglutide subcutaneously. She had no diabetic related complication. She continued liraglutide since then. Her HbA1c started to improve and also noticed in change in body weight which had gradually decreased from 114.9 to 109 kg. Her liraglutide was held at the latter end of 2018 as her glucose control and weight had been maintained. It was noticed that after stopping liraglutide her blood glucose and weight started to go up again even though her other medications remained same. Her case was discussed at Diabetes MDT and liraglutide1.8mg restarted in September 2019 and since then she able to lose around 5% of her body weight and HBA1C also started to drop. It is noticed that since the starting of her liraglutide her HBA1C level and weight fall by around 1% and 4% respectively. In late 2018 once she stopped liraglutide her HbA1C and weight started to rise again. In 2019 liraglutide was restarted and she managed to reduce body weight by 5kg and HbA1C by 2%. During the whole time period she maintained lifestyle intervention. Discussion: Excessive fat accumulation with potential impairing effects on health know as overweight and obesity, is a major risk factor for type 2 diabetes mellitus. Most T2DM people around 80-90% fall in mild to moderate obesity or overweight need either behaviour or medication-based weight loss programme. In these patients losing as little as 5% of body weight positively affect their cardiovascular mortality and glycemic control. There is no need to mention that losing body weight and maintaining it is a challenge for the majority of diabetic patients and it is especially true for those are on oral hypoglycaemic agents such as insulin, sulfonylurea and thiazolidinediones and insulin. In that case GLP-! Receptor agonists (GLP-1 Ras) is exceptional and it is proven benefit in reducing weight in T2DM obese patients. Liraglutide is first approved in 2010 as an adjunct therapy to diet and exercise for management of type 2 diabetes. Liraglutide is a derivative of GLP-1, a polypeptide incretin hormone secreted by the L-cell of the gastrointestinal tract. It stimulates glucose dependent insulin secretion causing a decrease in plasma glucagon concentrations, delayed gastric emptying, suppress appetite and increased heart rate. It is believed that the weight lowering effect of GLP-1RA is due to appetite suppression and delayed gastric emptying. After liraglutide administration peak absorption occur at 11 hours and its absolute bioavailability is 55%. Its half-life in 13 hours, allowing it once daily administration. It eliminates through liver and kidneys and does not interfere with cytochrome p450 system. Most common side effects are nausea, hypoglycaemia, diarrhoea, constipation, abdominal pain and increased serum lipase. Gastrointestinal intolerance is the most common reason for drug discontinuation in patients. There is also an increased correlation with acute pancreatitis, serious hypoglycaemic episodes, tachycardia, and suicidal behaviour. Liraglutide is contraindicated in pregnancy and should be avoided in nursing mothers, children, and coincident use with other GLP-1 agonists. Five large scale randomized multicenter phase III trials have been conducted to evaluate the efficacy of liraglutide as a weight loss agent. Four of these are part of the Satiety and Clinical Adiposity – Liraglutide evidence in non‐diabetic and diabetic individuals (SCALE) program. During these trails, all participants were encouraged to continue their lifestyle modification. The result of the trail was satisfactory. It was found that mean weight loss was between 6% to 4.7% in comparison to placebo group (2%). A dose dependent weight loss was first observed in LEAD Trials and subsequently in SCALE programme it is confirmed. In a study in Chinese population liraglutide treatment help T2DM patient in weight reduction after 24 weeks of treatment. In long term weight reduction, the 5-year treatment with liraglutide reduce HBA1c level by almost 1%. In various study it confirmed that liraglutide has greater impact on T2DM female gender. In SCALE study it showed that 50% difference in body weight loss between man and women could be due to higher exposure to liraglutide to women. Although exposure was equal in healthy male and female subject. Reference: 1. Randomized control trials for GLP-1Ra 2. Liraglutide for weight management: A critical review of the evidence 3. A review of efficacy and safety data regarding the use of liraglutide, a once-daily human glucagon-like peptide 1 analogue, in the treatment of type 2 diabetes mellitus. 4. Long-Term Effectiveness of Liraglutide for Weight Management and Glycemic Control in Type 2 Diabetes

Objective We evaluated pain in leucine-rich glioma inactivated1(LGI1) and contactin-associated protein2(CASPR2)-antibody positive(Ab+) patients, to evaluate clinical associations and pathophysiology of treatable pain syndromes. Methods 108 LGI-Ab+, 33 CASPR2-Ab+, and 6 LGI1/CASPR-Ab+patients were phenotyped. Pain questionnaires were undertaken to identify neuropathic pain using the Douleur Neuropathique(DN4), patient reported outcome measurement information system(PROMIS), and quality of life(EQ5D). Skin biopsies, and serum binding to cell-based assays, sensory neuronal cocultures, and dorsal root ganglion(DRG) cultures were undertaken. Results 39/147 patients described pain, including 17/33 CASPR2-Ab+(52%), 20/108 LGI1-Ab+(19%), and 2 LGI/CASPR2-Ab+patients. Questionnaires completed in 23/39(59%) revealed comparable DN4 scores(p=0.319) with 58% of LGI1-Ab+ and 67% of CASPR2-Ab+patients having neuropathic pain. Patients rated >50% response in 8/30(27%) analgesia trials, versus 20/40(55%) immunotherapy trials(p=0.045). PROMIS ratings were similar between LGI1-Ab+ and CASPR2-Ab+patients at nadir(p=0.662), but showed more improvement following immunotherapy in LGI1-Ab+(p=0.008) than CASPR2-Ab+patients(p=0.125). At follow-up(median 57 months) CASPR2-Ab+patients showed more impairment in mobility(p=0.014), daily activities(p=0.019), and anxiety/depression(p=0.043); and lower overall health(p=0.019) on the EQ5D compared to LGI1-Ab+patients. Intraepidermal nerve fibre density was reduced in 2 LGI1-Ab+ and 1 CASPR2-Ab+patients. Serum immunoglobulin G(IgG) from 6/16 CASPR2-Ab+patients bound to sensory neuronal cocultures compared to 0/14 LGI1-Ab+patients(p=0.019) and 0/12 healthy controls. Serum IgG from 10/16 CASPR2-Ab+patients bound to DRG cultures compared to 1/14 LGI1-Ab+patients(p=0.0024) and 1/12 healthy controls. Conclusion Neuropathic pain may be present in both LGI-Ab+ and CASPR2-Ab+patients, and is immunotherapy responsive. Serum IgG from CASPR2-Ab+patients more frequently bound sensory neurons and dorsal root ganglia, suggesting pathophysiological differences which may underlie the more severe pain in these patients.

Introduction Coronary bifurcation lesions (CBL) constitute a fifth of all coronary lesions and have no optimal method for treatment.(1) Multiple trials were conducted to investigate different modalities of treatment such as drug eluting stents, bioresorbable scaffolds, and dedicated bifurcation stents.(2) There are limited data discussing the clinical outcomes of these trials as most tend to report procedural outcomes.(3) This systematic review aimed to compare clinical outcomes of DBS compared to DES, while excluding bare metal stents and bioresorbable scaffolds.(4) Methods Following the PRISMA guidelines,(5) a systematic data search was conducted including EMBASE, PUBMED, MEDLINE, CINAHL, Cochrane database, TRIP database, and clinicaltrials.gov. Inclusion criteria were for prospective two-arm randomised trials published between the years from 2015 to 2018 comparing DBS and DES exclusively and reported clinical outcomes including cardiac death, myocardial infarction, target lesion revascularisation, and stent thrombosis. Risk of bias was assessed using Cochrane risk of bias assessment tool RoB1.(6) Two reviewers extracted data independently using Microsoft Excel 365 ProPlus. Meta-analysis is performed by restricted maximum-likelihood method comparing relative risks (RR) of clinical outcomes,(7) using MAJOR R pack through Jamovi platform and reported in logarithmic relative risk (Log RR).(8, 9) Results Six trials comparing DBS and DES involving 1914 patients met the inclusion criteria. Most of the studies were conducted in Europe, participants’ ages were DBS: 65.56, DES: 65.18 (p-value = 0.52). Participants of male gender were DBS: 74.9% DES: 77.5% (p-value = 0.44) and patients with smoking history were DBS: 28%, DES: 27.36% (p-value=0.70). Patients who presented with acute coronary syndrome were a fifth of all participants (p-value = 0.74). Around 70% of each arm participants had hypertension, and around 25% suffer from diabetes, as well as smoking. A third of participants had previous myocardial infarction (Table-1). Clinical outcomes were reported for 12 months in all study but one (Genereux et al. – 9 months).(10) There was only one cardiac death in the DBS arm compared to six cardiac deaths in the DES arm. A meta-analysis was performed for MACE (Figure-1), myocardial infarction (MI), stent thrombosis (ST), and target lesion revascularisation (TLR). Major adverse cardiac events (MACE) were 13.3% for DBS and 12.4% for DES with a RR of 1.078 (Log RR = 0.07, p-value = 0.612) (Figure-1 & Table-2). Other measured outcomes showed no superiority for either arms. Conclusion When comparing the one-year clinical outcomes for coronary bifurcation lesions stenting; there was no statistically significant difference between dedicated bifurcation stents and drug eluting stents regarding MACE, CD, MI, TLR, and ST. Conflict of Interest None