Safety Assessment of Glucose-Lowering Drugs and Importance of Structured Education during Ramadan: A Systematic Review and Meta-Analysis.

BACKGROUND: Ramadan is the sacred month of the Islamic Hijri (lunar) calendar, and during this entire month, healthy adult Muslims abstain from eating and drinking from dawn to sunset. Muslims with Type 2 Diabetes Mellitus (T2DM) who choose to fast during Ramadan encounter major risks such as hypoglycemia, hyperglycemia, diabetic ketoacidosis, dehydration, and thrombosis. Although patients with poor glycemic control and on multiple insulin injections are at high risk and exempt from fasting, many still insist on it. Thus, healthcare professionals play a pivotal role in managing diabetes-related complications in patients who fast during Ramadan. However, there is a lack of standard guidelines to be followed in association with structured education and administration of drugs and dosage. Therefore, we performed a systematic review and meta-analysis of the literature to determine the safety and efficacy of different classes of drugs and the importance of structured education during Ramadan. METHODS: In this review, an extensive PubMed search was performed to obtain literature on T2DM patients who fast during the month of Ramadan until the year 2020. Preference was given to fully downloadable articles. The articles were extracted based on the eligibility criteria. The extracted data were analyzed using Review Manager software version 5.3. RESULTS: A total of 32 articles were included for the review and 7 studies for meta-analysis. Majority of the studies demonstrated the importance of structured education either as a group session or as a one-on-one session with the healthcare professionals in preventing diabetes-related risks during Ramadan. As far as glucose-lowering drugs are concerned, DPP-4 inhibitor combined with metformin remains the drug of choice for T2DM patients who fast during Ramadan. The newer class of glucose-lowering agents appear to lower the risk of hypoglycemia in comparison with sulphonylureas, while among sulphonylureas gliclazide is relatively safe. The meta-analysis indicates that DPP-4 inhibitors would significantly reduce the risk of hypoglycemia as compared to sulphonylurea (odds ratio = 0.38, 95% CI: 0.26 to 0.55, p < 0.00001). CONCLUSION: The results of our systematic review show that structured education and counselling by healthcare professionals can be an effective tool in preventing complications associated with fasting during Ramadan in people with T2DM. Additionally, the safest class of oral glucose-lowering drugs preferred during Ramadan fasting in T2DM patients is DPP-4 inhibitors.

Patterns of Diabetes Care Among People with Type 1 Diabetes During Ramadan: An International Prospective Study (DAR-MENA T1DM).

INTRODUCTION: To describe the characteristics and care of participants with type 1 diabetes during Ramadan in the Middle East and North Africa. METHODS: The DAR-MENA (Diabetes and Ramadan-Middle East and North Africa) study was a prospective, observational study of adults with type 1 and type 2 diabetes who were Muslim and did/did not intend to fast during Ramadan 2016. Baseline data were collected 6 weeks prior to Ramadan, with a follow-up visit 1-2 months after Ramadan. This is the analysis of the population with type 1 diabetes. Measurements included proportion who fasted, reasons for fasting and not fasting, changes in diabetes treatment, hypoglycemic events, and proportion with access to diabetes education. RESULTS: Of 136 participants with type 1 diabetes, 76.9% (100/130) fasted for at least 1 day, 72.3% (94/130) fasted for at least 15 days, and 48.5% (63/130) fasted for 30 days. The majority (63.0%, 63/100) reported personal decision as a reason to fast. Fear of diabetic complications (58.6%, 17/29) and previous complications related to fasting (48.3%, 14/29) were the most common reasons for not fasting. Adjustment of diabetic medication regimen occurred for 84.6% (115/136) of participants, and 72.8% (99/136) changed their treatment dose. The incidence and number of adverse events for confirmed and severe hypoglycemia were similar before and during Ramadan. Almost half of participants had access to diabetes education (45.6%, 62/136). CONCLUSION: The DAR-MENA study showed that despite the risks associated with fasting for people with type 1 diabetes, almost half fasted for the full 30 days of Ramadan with no significant change in hypoglycemia events. Since the current International Diabetes Federation and Diabetes and Ramadan guidelines do not endorse fasting for people with type 1 diabetes, it is important that those who insist on fasting work closely with their healthcare practitioner to avoid any complications.

Effect of Sudarshan Kriya Yoga on anxiety, depression, and quality of life in people with type 2 diabetes: A pilot study in Kuwait.

AIM: This pilot study in Kuwait was aimed to assess the effect of Sudarshan kriya yoga (SKY) on anxiety, depression and total quality of life in people with type 2 diabetes mellitus (T2DM). METHODS: 26 T2DM patients aged greater than 30, male and female visiting the outpatient clinic of Dasman Diabetes Institute were enrolled for the study. Pre and post 5 day SKY intervention responses of participants on psychosocial problems were evaluated using four questionnaires (Hamilton anxiety, patient health questionnaire (PHQ-9), Hospital anxiety depression and WHO total quality of life (QOL). Biochemical parameters; such as lipid profile, glycated hemoglobin (HbA1c) were measured at baseline and after 15 weeks of SKY practice. RESULTS: The mean age of the participants was 56.7 (±11.4 SD) years, and mean duration of diabetes 15.0 (±9.3 SD) years. Comparison of responses before and after intervention indicated a significant improvement in the QOL, depression, anxiety and insomnia. But no significant improvement in glycemic control. CONCLUSION: Results indicate that SKY can be potentially beneficial for treating anxiety, insomnia, and depression associated in people with T2DM and in improving the quality of life in people with T2DM.

The characteristics and pattern of care for the type 2 diabetes mellitus population in the MENA region during Ramadan: An international prospective study (DAR-MENA T2DM).

AIMS: We aimed to describe the characteristics and care of participants with diabetes during Ramadan in the Middle East and North Africa (MENA). METHODS: In this prospective, observational study, we analysed the number of fasted days, number of participants fasting, glycemic control, rate of hypoglycemic events, and lifestyle patterns for participants with T2DM during Ramadan 2016. RESULTS: The population included 1749 participants with T2DM. The mean (SD) duration of fasting was 27.7 (5.0) days, and 57.3% of participants fasted for the full duration of Ramadan. Following Ramadan, a significant improvement in HbA1c, FPG, and PPG was observed (p < 0.0001). Confirmed hypoglycemia increased significantly from before to during Ramadan (incidence: 4.9% vs. 10.4%, p < 0.001; adverse events: 0.11 vs. 0.22 events/month/participant, p < 0.001) and was dependent on the treatment regimen. Severe hypoglycemia incidence was 0.2% before versus 0.9% during Ramadan (p = 0.031), whereas adverse events remained comparable (0.01 events/month/participant; p = 0.154). Most participants (97.4%) reported lifestyle changes during Ramadan. CONCLUSIONS: This prospective study is the first to describe the characteristics and care of participants with T2DM during Ramadan in MENA, and can be utilized in the development of evidence-based care to ensure the safety of participants who fast.

Investigation of genetic variation and lifestyle determinants in vitamin D levels in Arab individuals.

BACKGROUND: Differences in the concentrations of circulating 25-hydroxyvitamin D [25(OH)D] are associated with a wide range of health outcomes; however, most studies on genetic variants that impact 25(OH)D levels have been conducted in European populations. Here we aimed to identify common genetic variants that affect vitamin D concentrations in individuals of self-reported Arab ethnicity. METHODS: The study included 1151 Arab subjects living in Kuwait. Common variants of single-nucleotide polymorphisms and genes previously associated with vitamin D levels, such as GC, PDE3B, CYP2R1, and NADSYN1, were genotyped. Raw vitamin D level data were corrected for age, body mass index, and sex and then normalized. Regression tree analyses were performed to identify the impact of genetic variants on vitamin D levels. RESULTS: Compared with other gene variants, the GC gene variants exhibited the greatest impact on vitamin D levels in our study population, of which rs2298850 had the lowest p value (0.003). Individuals homozygous for the derived allele C had lower vitamin D levels. Analyses of the interaction between the number of years for which the subjects had lived in Kuwait and genetic variation in the GC gene showed that those with the CC genotype of rs2298850 who had lived in Kuwait for < 51 years had a mean 25(OH)D level of 10 ng/ml, whereas those who were homozygous for the ancestral allele had a mean 25(OH)D level of 17 ng/ml. Furthermore, subjects who had lived in Kuwait for > 51 years had higher vitamin D levels (mean 28 ng/ml) regardless of the genotype of their GC gene. CONCLUSIONS: The GC gene may play a major role in determining vitamin D levels in Arab populations.

Diabetes and Ramadan: Practical guidelines.

Ramadan fasting is one of the five pillars of Islam and is compulsory for all healthy Muslims from puberty onwards. Exemptions exist for people with serious medical conditions, including many with diabetes, but a large number will participate, often against medical advice. Ensuring the optimal care of these patients during Ramadan is crucial. The International Diabetes Federation (IDF) and Diabetes and Ramadan (DAR) International Alliance have come together to deliver comprehensive guidelines on this subject. The key areas covered include epidemiology, the physiology of fasting, risk stratification, nutrition advice and medication adjustment. The IDF-DAR Practical Guidelines should enhance knowledge surrounding the issue of diabetes and Ramadan fasting, thereby empowering healthcare professionals to give the most up-to-date advice and the best possible support to their patients during Ramadan.

The effect of vildagliptin relative to sulfonylurea as dual therapy with metformin (or as monotherapy) in Muslim patients with type 2 diabetes fasting during Ramadan in the Middle East: the VIRTUE study.

OBJECTIVE: To assess the effect of vildagliptin relative to sulfonylurea (SU) on hypoglycemic events, in Muslim patients from the Middle East with type 2 diabetes who fast during Ramadan. The primary endpoint was the proportion of patients with at least one hypoglycemic event (HE) during the fasting period. Secondary endpoints included change in weight, HbA1c levels, treatment adherence and overall safety. DESIGN AND METHODS: This multicenter, prospective, observational cohort study enrolled Muslim adult T2DM patients from Middle Eastern countries who received treatment with vildagliptin or SU as add on to metformin or monotherapy. During a ∼16 week observation period, data was collected up to 6 weeks before and 6 weeks after Ramadan fasting. RESULTS: A total of 584 patients from the Middle East enrolled in the study; 308 patients received vildagliptin and 265 received SU. Significantly fewer vildagliptin patients reported at least one HE (3.7% vildagliptin vs. 25.5% SU; p < .001). No grade 2 HEs were reported in vildagliptin patients versus two in SU patients (p = .128). Mean change in HbA1c at the end of study showed -0.18% between treatment difference in favor of vildagliptin, p = .001. Mean body weight change at the end of study showed -0.68 kg between treatment difference in favor of vildagliptin, p < .001. Treatment exposure and adherence were high and similar in both cohorts. There were 4.3% adverse events reported in vildagliptin compared to 25.3% in the SU cohort, with hypoglycemia being the most experienced event in both cohorts. LIMITATIONS: Being observational and not mandating HE confirmation with blood glucose measurement (though it was done in a large number of patients) were key limitations. CONCLUSION: Anti-hyperglycemic treatment with vildagliptin led to significantly fewer hypoglycemia events compared to sulfonylurea treatment among Muslim diabetic patients who fast during Ramadan. Good glycemic control, weight control and safety results supported this outcome.

Management of Type 2 diabetes in Ramadan: Low-ratio premix insulin working group practical advice.

The challenge of insulin use during Ramadan could be minimized, if people with diabetes are metabolically stable and are provided with structured education for at least 2-3 months pre-Ramadan. Although, American diabetes association (ADA) recommendations 2010 and South Asian Consensus Guideline 2012 deal with management of diabetes in Ramadan and changes in insulin dosage, no specific guidance on widely prescribed low-ratio premix insulin is currently available. Hence, the working group for insulin therapy in Ramadan, after collective analysis, evaluation, and opinion from clinical practice, have formulated a practical advice to empower physicians with pre-Ramadan preparation, dose adjustment, and treatment algorithm for self-titration of low-ratio premix insulin.

Vitamin D insufficiency in Arabs and South Asians positively associates with polymorphisms in GC and CYP2R1 genes.

BACKGROUND: A number of genetic studies have reported an association between vitamin D related genes such as group-specific component gene (GC), Cytochrome P450, family 2, subfamily R, polypeptide 1 (CYP2R1) and 7-dehydrocholesterol reductase/nicotinamide-adenine dinucleotide synthetase 1 (DHCR7/NADSYN1) and serum levels of the active form of Vitamin D, 25 (OH) D among African Americans, Caucasians, and Chinese. Little is known about how genetic variations associate with, or contribute to, 25(OH)D levels in Arabs populations. METHODS: Allele frequencies of 18 SNPs derived from CYP2R1, GC, and DHCR7/NADSYN1 genes in 1549 individuals (Arabs, South Asians, and Southeast Asians living in Kuwait) were determined using real time genotyping assays. Serum levels of 25(OH)D were measured using chemiluminescence immunoassay. RESULTS: GC gene polymorphisms (rs17467825, rs3755967, rs2282679, rs7041 and rs2298850) were found to be associated with 25(OH)D serum levels in Arabs and South Asians. Two of the CYP2R1 SNPs (rs10500804 and rs12794714) and one of GC SNPs (rs1155563) were found to be significantly associated with 25(OH)D serum levels only in people of Arab origin. Across all three ethnicities none of the SNPs of DHCR7/NADSYN1 were associated with serum 25(OH)D levels and none of the 18 SNPs were significantly associated with serum 25(OH)D levels in people from South East Asia. CONCLUSION: Our data show for the first time significant association between the GC (rs2282679 and rs7041), CYP2R1 (rs10741657) SNPs and 25(OH)D levels. This supports their roles in vitamin D Insufficiency in Arab and South Asian populations respectively. Interestingly, two of the CYP2R1 SNPs (rs10500804 and rs12794714) and one GC SNP (rs1155563) were found to correlate with vitamin D in Arab population exclusively signifying their importance in this population.

IL-33 is negatively associated with the BMI and confers a protective lipid/metabolic profile in non-diabetic but not diabetic subjects.

OBJECTIVE: Recent studies have demonstrated a protective role for IL-33 against obesity-associated inflammation, atherosclerosis and metabolic abnormalities. IL-33 promotes the production of T helper type 2 (Th2) cytokines, polarizes macrophages towards a protective alternatively activated phenotype, reduces lipid storage and decreases the expression of genes associated with lipid metabolism and adipogenesis. Our objective was to determine the level of serum IL-33 in non-diabetic and diabetic subjects, and to correlate these levels with clinical (BMI and body weight) and metabolic (serum lipids and HbA1c) parameters. METHODS: The level of IL-33 was measured in the serum of lean, overweight and obese non-diabetic and diabetic subjects, and then correlated with clinical and metabolic parameters. RESULTS: Non-lean subjects had significantly (P = 0.01) lower levels of IL-33 compared to lean controls. IL-33 was negatively correlated with the BMI and body weight in lean and overweight, but not obese (non-diabetic and diabetic), subjects. IL-33 is associated with protective lipid profiles, and is negatively correlated with HbA1c, in non-diabetic (lean, overweight and obese) but not diabetic subjects. CONCLUSIONS: Our data support previous findings showing a protective role for IL-33 against adiposity and atherosclerosis, and further suggest that reduced levels of IL-33 may put certain individuals at increased risk of developing atherosclerosis and insulin resistance. Therefore, IL-33 may serve as a novel marker to predict those who may be at increased risk of developing atherosclerosis.

Elevated expression of the toll like receptors 2 and 4 in obese individuals: its significance for obesity-induced inflammation.

BACKGROUND: Expression profile of the toll like receptors (TLRs) on PBMCs is central to the regulation of proinflammatory markers. An imbalance in the TLRs expression may lead to several types of inflammatory disorders. Furthermore, the dynamic regulation of inflammatory activity and associated impaired production of cytokines by peripheral blood mononuclear cells (PBMCs) in obese individulas remain poorly understood. Therefore, we determined the perturbation in TLRs (TLR2 and TLR4), their adaptor proteins (MyD88, IRAK1 and TRAF6) expression in PBMCs/subcutaneous adipose tissue (AT) as well as inflammatory cytokines changes in obese individuals. METHODS: mRNA expression levels of TLR2, TLR4, IL-6, TNF-α and adaptor proteins were determined by RT-PCR. TLR2, TLR4 and adaptor proteins expression in AT was determined by immunohistochemistry. RESULTS: Obese and overweight individuals showed significantly increased expression of TLR2, TLR4 and MyD88 in both PBMCs and AT as compared with lean individuals (P < 0.05). Interestingly, we found a remarkably higher expression of TLRs in obese and overweight individuals with type 2 diabetes (P < 0.05). Increased expression of TLR2, TLR4, MyD88 and IRAK1 correlated with body mass index (BMI) (TLR2: r = 0.91; TLR4: r = 0.88, P <0.0001; MyD88: r = 0.95, P < 0.0001; IRAK1 r = 0.78, P < 0.002). TLRs' expression was also correlated with fasting blood glucose (FBG) (TLR2: r = 0.61, P < 0.002; TLR4: r = 0.52, P < 0.01) and glycated haemoglobin (HbA1c) ( TLR2: r = 0.44, P <0.03; TLR4: r = 0.48, P < 0.03). Transcript levels of IL-6 and TNF-α were highly elevated in obese subjects compared to lean subjects. There was a strong association of TLRs' expression in PBMCs with TNF-α (TLR2: r = 0.92; TLR4: r = 0.92; P < 0.0001) and IL-6 (TLR2: r = 0.91, P < 0.0001; TLR4: r = 0.81; P < 0.001). Similarly adaptor proteins were significantly correlated with TNF-α (MyD88: r = 0.9, P < 0.0001; IRAK1: r = 0.86; P < 0.0002) and IL-6 (MyD88: r = 0.91, P < 0.0001; IRAK1: 0.77; P < 0.002). CONCLUSIONS: TLRs and adapter proteins were overexpressed in PBMCs from obese subjects, which correlated with increased expression of TNF-α and IL-6. This association may explain a potential pathophysiological link between obesity and inflammation leading to insulin resistance.

Hepatitis C virus infection in a population with high incidence of type 2 diabetes: impact on diabetes complications.

A growing number of reports suggest a connection between hepatitis C virus (HCV) infection and type 2 diabetes (T2D). However, the association of HCV infection with diabetes-related complications has not yet been clarified. The aim of this study was to determine the prevalence of HCV infection in T2D-patients in Kuwait which has a high incidence of type 2 diabetes, and to investigate the association between HCV viremia and diabetes-related complications. A total of 438 patients with T2D (325 Kuwaitis and 113 Egyptians), and 440 control subjects, were enrolled for this study. HCV infection was assessed by testing for serum HCV-specific antibodies, and by detection of HCV RNA. HCV viral load and hemoglobin A1c (HbA1c) levels were assessed in patients with and without diabetes complications. Thirty one (7%) out of 438 T2D-patients had evidence of HCV infection compared to 4 (1%) out of 440 control adults (p<0.0001). The prevalence of HCV infection in Kuwaiti and Egyptian T2D-patients was 3% and 18%, respectively. Most of the HCV sequences detected in T2D patients and control subjects were of genotype 4. The HbA1c levels in T2D-patients with HCV viremia were significantly higher than those in HCV-negative patients. HCV viremia, female sex, age, family history of diabetes were found to be independent risk factors for diabetes complications. The results suggest that T2D-patients in Kuwait have higher prevalence of HCV infection than controls, and that HCV viremia is associated with diabetes-related complications.

Risk factors for the development of diabetes mellitus in chronic hepatitis C virus genotype 4 infection.

BACKGROUND AND AIM: A high occurrence of type 2 diabetes (T2D) in patients with chronic hepatitis C virus (HCV) infection has been reported in Kuwait and other countries. However, HCV genotype 4 has been underrepresented in all previous studies. Our aim was to investigate the viral and host risk factors associated with the development of T2D in patients with chronic hepatitis C genotype 4 infection in the absence of liver fibrosis and steatosis. METHODS: The study population consisted of 181 HCV-positive patients and 170 control HCV-negative patients with T2D. RESULTS: The prevalence of HCV-patients with T2D was 39.8%. There was no significant association of T2D with gender, nationality, obesity, HCV viral load, or antiviral therapy. Older age (>or= 50 years) and family history of diabetes were the only independent risk factor for T2D in HCV patients. However, the median age and the prevalence of obesity in HCV-positive patients with T2D were significantly lower than those in diabetic HCV-negative patients. By following-up HCV-patients receiving antiviral drugs, a significant decrease of fasting plasma glucose and glycosylated hemoglobin levels was observed in diabetic patients who achieved a sustained viral response (SVR). CONCLUSIONS: The risk factors associated with the development of T2D in the general population cannot alone account for the high prevalence of T2D obtained in chronic HCV genotype 4 infection. In the absence of liver fibrosis and steatosis, the improvement in glycemic control obtained in SVR patients may imply direct involvement of HCV in the development of T2D.

Association of periodontal disease severity with diabetes duration and diabetic complications in patients with type 1 diabetes mellitus.

OBJECTIVES: The association between periodontal disease severity and diabetes complications and duration in patients with type 1 diabetes mellitus (DM) was investigated in this comparative cross-sectional study. MATERIALS AND METHODS: Twenty-nine patients with type 1 DM of < or = 5 years duration were compared with 43 patients with > 5 years duration of DM. Complete medical history and examination and assessments of retinopathy, neuropathy, and nephropathy were performed, followed by assessments of the plaque index (PI), pocket depth (PD), clinical attachment level (CAL), and the number of missing teeth by one examiner masked to the diabetic status of the patients. RESULTS: The number of missing teeth (4 versus 0) and CAL (2.88 vs 2.56 mm) were significantly higher in patients with longer DM duration (p < 0.05). For patients with > or = 5 years DM duration, periodontal disease severity was also greater in patients with one or more DM complications, as assessed by the number of missing teeth (17 vs 0; p < 0.001) and CAL (4.74 vs 2.81 mm; p < 0.01). Stepwise multiple regression analysis associated the presence of > or = 1 DM complications and smoking history with severe attachment loss (CAL > or = 7 mm; p < 0.001). CONCLUSION: Periodontal disease severity is associated with both DM duration and the presence of DM complications in this sample of type 1 DM patients.