Failure Of Oral Hypoglycemic Agents Research Articles

Giving Insulin Is Not a Guessing Game: Insulin Replacement Therapy in Type 2 Diabetes Mellitus

In 2021, 537 million adults were living with diabetes. Being a progressive disease, there would eventually be failure of oral hypoglycemic agents (OHA) to maintain good glycemic control and a majority will require insulin. However, optimal glycemic control has not been satisfactory in a significant proportion of patients who were on insulin therapy. Patient factors (eg, awareness, compliance, socioeconomic) have been identified but physician-related factors are as important. These include incorrect choice and inappropriate combination of insulin therapy which could be corrected by making the treatment physiologic. The purpose of this article is to improve management decisions in type 2 diabetes by reviewing its pathophysiology and identifying the optimum insulin regimen that could mimic such. Since eventual beta cell failure is central to its pathophysiology, it is but reasonable to replace insulin by mimicking its physiologic secretion. Hence, the term Insulin Replacement Therapy (IRT) should be utilized. This could be provided by the combination of premix insulin (ie, NPH + regular insulin) and rapid-acting insulin which has been reported to provide an initial 17.5% HbA1c reduction and even 18% reduction on 5-year follow-up providing sustainable control. A stepwise approach is an effective tool for insulin intensification. Hypoglycemia in insulin therapy could be prevented with an appropriate dietary regimen through automatic snacking. Keywords: Insulin replacement therapy, type 2 diabetes mellitus, pathophysiology

Comparative evaluation of biphasic insulin with metformin and triple oral hypoglycemic agents (OHA) in type 2 diabetes patients

IntroductionThe prevalence of secondary failure to oral hypoglycemic agents among type 2 diabetes mellitus (T2DM) patients ranges from 30 to 60%. The alternative approaches to overcome this issue are either switching to triple oral hypoglycemic agents (OHA) or intensifying the regimen by adding insulin. ObjectiveTo compare the glycemic control achieved with biphasic insulin plus metformin and triple OHA in T2DM patients who were not adequately controlled with two OHA regimen. MethodsA qualitative prospective study was conducted at Asir diabetes center, Abha, KSA. Poorly controlled T2DM patients with two OHA for at least 1 year with glycated hemoglobin (HbA1c) >7.0% were included. Subjects were divided into group I (a third OHA was added to the existing two OHA regimen) and group II (switched over to Biphasic insulin and metformin). At baseline and 3-month intervals, level of HbA1C, Fasting Plasma Glucose (FPG), Postprandial Plasma Glucose (PPG), Blood Pressure (BP), lipid profile and hypoglycemic episodes were obtained and evaluated for one year. Results41.1% of patients were in group I and 58.9% were in group II. At the end of the study, there was a significant reduction in HbA1c in group II subjects comparing to group I (8.18 ± 1.32 vs 8.79 ± 1.81, p = 0.0238). FPG and PPG were improved also in group II. The mean body weight increased from baseline in group II is +4.48 kg and decreased from baseline in group I (−0.46 kg). 11.3% from group I and 23.7% from group II reported hypoglycaemic incidences. ConclusionBiphasic insulin and metformin regimen could be an appropriate therapeutic option for achieving good glycemic control compared with triple OHA in patients with two OHA failure.

The choice of initial insulin treatment plan for type 2 diabetes mellitus patients with failure of oral hypoglycemic agents

Objective To investigate the insulin treatment plan after the failure of oral hypoglycemic agents for type 2 diabetes in China. Methods 180 patients with type 2 diabetes who failed to oral hypoglycemic drugs were randomly divided into three groups on average: A group(insulin glargine+ metformin+ gliclazide sustained-release tablets), B group(insulin aspart 30+ metformin) and C group(insulin glargine+ metformin+ insulin aspart). 24 weeks later, the hypoglycemic effect and security were observed.Three years later, the compliance that patients used original treatment plan were observed. Results 24 weeks later, HbA1c of the three group significantly decreased compared with that before the study[A group: (7.3±0.8)% vs.(10.2±1.7)%; B group: (7.0±0.8)% vs.(9.9±1.5)%; C group: (6.9±0.7)% vs.(10.4±1.8)%, all P<0.05]. The incidence of hypoglycemia in C group(1.66 times·year-1·people-1) was significantly higher than that in A group(1.04 times·year-1·people-1) and B group(1.31 times·year-1·people-1)(χ2=11.777, 4.362, all P<0.05). However, the daily average cost of the drug in the B group[(12.9±3.0)yuan]was significantly lower than that in A group[(25.6±3.8)yuan]and C group[(22.7±4.7)yuan](t=18.943, 13.226, all P<0.05). Three years later, the percentage of patients who used original treatment plan in the C group(40.0%) was significantly less than that in A group(68.0%) and B group(73.0%)(χ2=8.656, 12.398, all P<0.05). Conclusion Type 2 diabetic patients who failed to oral hypoglycemic agents, according to their own economic conditions, might choose aspart 30 or glargine.The hypoglycemic treatment of aspart 30 has better long term effect, lower costs and incidence of hypoglycemia, better compliance. Key words: Diabetes mellitus, type 2; Insulin aspart 30; Medication adherence

Characteristics Predictive for a Successful Switch from Insulin Analogue Therapy to Oral Hypoglycemic Agents in Patients with Type 2 Diabetes.

PurposeThe objective of this study was to investigate clinical and laboratory parameters that could predict which patients could maintain adequate glycemic control after switching from initial insulin therapy to oral hypoglycemic agents (OHAs) among patients with type 2 diabetes (T2D).Materials and MethodsWe recruited 275 patients with T2D who had been registered in 3 cohorts of initiated insulin therapy and followed up for 33 months. The participants were divided into 2 groups according to whether they switched from insulin to OHAs (Group I) or not (Group II), and Group I was further classified into 2 sub-groups: maintenance on OHAs (Group IA) or resumption of insulin (Group IB).ResultsOf 275 patients with insulin initiation, 63% switched to OHAs (Group I) and 37% continued insulin (Group II). Of these, 44% were in Group IA and 19% in Group IB. The lowest tertile of baseline postprandial C-peptide-to-glucose ratio (PCGR), higher insulin dose at switching to OHAs, and higher HbA1c level at 6 months after switching to OHAs were all associated with OHA failure (Group IB; p=0.001, 0.046, and 0.014, respectively). The lowest tertile of PCGR was associated with ultimate use of insulin (Group IB and Group II; p=0.029).ConclusionHigher baseline level of PCGR and lower HbA1c levels at 6 months after switching to OHAs may be strong predictors for the successful maintenance of OHAs after switching from insulin therapy in Korean patients with T2D.

Prevalence of lipohypertrophy and associated risk factors in insulin-treated patients with type 2 diabetes mellitus.

Background:Secondary failure of oral hypoglycemic agents is common in patients with type 2 diabetes mellitus (T2DM); thus, patients often need insulin therapy. The most common complication of insulin treatment is lipohypertrophy (LH).Objectives:This study was conducted to estimate the prevalence of LH among insulin-treated patients with Patients with T2DM, to identify the risk factors for the development of LH, and to examine the association between LH and glycemic control.Patients and Methods:A total of 1090 patients with T2DM aged 20 to 89 years, who attended the diabetes clinics at the National Center for Diabetes, Endocrinology, and Genetics (NCDEG, Amman, Jordan) between October 2011 and January 2012, were enrolled. The presence of LH was examined by inspection and palpation of insulin injection sites at the time of the visit as relevant clinical and laboratory data were obtained. The LH was defined as a local tumor-like swelling of subcutaneous fatty tissue at the site of repeated insulin injections.Results:The overall prevalence of LH was 37.3% (27.4% grade 1, 9.7% grade 2, and 0.2% grade 3). The LH was significantly associated with the duration of diabetes, needle length, duration of insulin therapy, lack of systematic rotation of insulin injection sites, and poor glycemic control.Conclusions:The LH is a common problem in insulin-treated Jordanian patients with T2DM. More efforts are needed to educate patients and health workers on simple interventions such as using shorter needles and frequent rotation of the insulin injection sites to avoid LH and improve glycemic control.

A critical analysis of the concept of secondary Oral Hypoglycemic Agent (OHA) failure in type 2 diabetes at a tertiary care hospital

Data from UKPDS study suggests that the onset of s cell dysfunction in diabetes occurs well before the development of hyperglycemia. To study the concept of secondary OHA failure in type 2 diabetes patients of more than 10 years duration in a tertiary care hospital. A retrospective analysis of all the cases of type 2 diabetes mellitus of more than 10 years duration from 2002 to 2003 was done and the data was divided into three groups: oral hypoglycemic agents (OHA) only, Insulin only, OHA + insulin. ANOVA/Students t test was the primary statistical test used. Odds ratio and 95% CI were calculated to compare risks of other diseases and drug use. 62.35% were on only OHAs, 8.82% on only insulin and 28.82% on both insulin and OHAs. This confirms good efficacy of OHAs. Diabetic population in our study tends to have a preserved beta cell function and secondary OHA failure is a late feature.

スルフォニルウレア剤2次無効の糖尿病患者における抗グルタミン酸脱炭酸酵素 (GAD) 抗体の臨床的意義

スルフォニルウレア剤2次無効の糖尿病患者における抗グルタミン酸脱炭酸酵素 (GAD) 抗体の臨床的意義

Transaminase levels in the upper normal range are associated with oral hypoglycemic drug therapy failure in patients with type 2 diabetes

Incident diabetes and the worsening of diabetes have recently been linked to hepatic steatosis. Aim of our study was to determine whether oral hypoglycemic agent failure is associated with higher transaminase levels (valid measure of liver steatosis). We selected 200 patients, attenders (3 consecutive annual evaluations) in our clinic, with type 2 diabetes among which 100 with oral hypoglycemic agents failure and 100 who were still responsive to oral therapy. Failure to therapy was defined as glycated hemoglobin >7.5% despite maximal-dose oral therapy. We analyzed patient histories and laboratory data. Compared with oral-therapy-responsive patients, those with failure had a significantly higher level mostly of alanine aminotransferase at the time of therapy failure and 2 years before. They were more likely to have had symptoms of hyperglycemia at the time of diabetes diagnosis. Regression analysis indicated that each 5-unit increase in transaminase levels independently increased the risk for oral hypoglycemic agents failure by 1.70. Higher liver transaminase levels, especially in patients who had symptomatic hyperglycemia at diabetes diagnosis, associate with oral hypoglycemic agent failure. The possible pathogenetic link between transaminase and declining islet function might consist of insulin resistance and increased circulating fatty acid levels, in turn causing liver steatosis and beta-cell dysfunction.

Parameters Measuring Beta-Cell Function Are Only Valuable in Diabetic Subjects with Low Body Mass Index, High Blood Glucose Level, or Long-Standing Diabetes

PurposeThe aim of this study was to identify the most precise and clinically practicable parameters that predict future oral hypoglycemic agent (OHA) failure in patients with type 2 diabetes, and to determine whether these parameters are valuable in various subgroups.Materials and MethodsWe took fasting blood samples from 231 patients for laboratory data and standard breakfast tests for evaluation of pancreatic beta-cell function. Hemoglobin A1c (HbA1c) levels were tested, and we collected data related to hypoglycemic medications one year from the start date of the study.ResultsFasting C-peptide, postprandial insulin and C-peptide, the difference between fasting and postprandial insulin, fasting beta-cell responsiveness (M0), postprandial beta-cell responsiveness (M1), and homeostasis model assessment-beta (HOMA-B) levels were significantly higher in those with OHA response than in those with OHA failure. The area under the curve (AUC) of the receiver operating characteristic (ROC) measured with postprandial C-peptide to predict future OHA failure was 0.720, and the predictive power for future OHA failure was the highest of the variable parameters. Fasting and postprandial C-peptide, M0, and M1 levels were the only differences between those with OHA response and those with OHA failure among diabetic subjects with low body mass index, high blood glucose level, or long-standing diabetes.ConclusionIn conclusion, postprandial C-peptide was most useful in predicting future OHA failure in type 2 diabetic subjects. However, these parameters measuring beta-cell function are only valuable in diabetic subjects with low body mass index, high blood glucose level, or long-standing diabetes.

Factors Associated with Long-Term Oral Hypoglycemic Agent Responsiveness in Korean Patients with Type 2 Diabetes Mellitus

BackgroundThis study was performed to determine the factors associated with long-term oral hypoglycemic agent (OHA) responsiveness in Korean type 2 diabetic patients.MethodsTwo groups of patients were selected among the type 2 diabetic patients who were followed for more than two years at a university hospital diabetes clinic. The OHA responsive group consisted of 197 patients whose HbA1c levels were maintained at ≤7% with OHA for more than two years. The OHA failure group consisted of 180 patients whose HbA1c levels were >8% in spite of optimal combined OHA therapy or patients who required insulin therapy within the two years of the study.ResultsThe OHA failure group had higher baseline values of fasting and postprandial glucose, HbA1c, and lower fasting, postprandial, and delta C-peptide compared to those of the OHA responsive group. The OHA failure group also had a higher proportion of female patients, longer diabetic duration, and more family history of diabetes. There were no significant differences in body mass index (BMI) or insulin resistance index between the two groups. Multiple logistic regression analysis showed that the highest quartile of baseline fasting, postprandial glucose, and HbA1c and the lowest quartile of postprandial and delta C-peptide were associated with an increased odds ratio of OHA failure after adjustment for age, sex, body mass index, and family history of diabetes.ConclusionLower baseline values of postprandial and delta C-peptide and elevated fasting glucose and HbA1c are associated with long-term OHA responsiveness in Korean patients with type 2 diabetes mellitus.

Antibodies to GAD and ICA in Type 2 DM with Secondary Failure of Oral Hypoglycemic Therapy

Background: Secondary failure of oral hypoglycemic agents is defined as tha t blood glucose is no longer controlled with sulfonylurea after a proven period of good glycemic control. There are many causes of secondary failure, including that drug problem, acute illnesses, inappropriate drug dosages, oxidative stress & glucose toxicity of β-cell, etc. And many studies have suggested role of immunologic process such as islet cell antibody (ICA) and/or glutamic acid decarboxylase antibody (GADA) for the causes of secondary failure. So we evaluated the prevalence of ICA & GADA in type 2 diabetes with secondary failure of oral hypoglycemic agents and the pathogenesis of the secondary failure. Methods: We studied 267 patients with type 2 diabetes. We regarded 84 pa tients who could not control HbA1c less than 8% after good glycemic control for at least 1 y ear as secondary failure group (group 1) and regarded the other 183 patients as group 2. We measured GADA in both group, and measured the prevalence of GADA and ICA in secondary failure group who were especially divided into obese group and nonobese group according to BMI and were divided into insulin deficiency group and noninsulin deficiency group according to fasting C-peptide level. Results: The prevalence of GADA in all subjects was 4.1%, which was 9.5 % in group 1 and 1.6% in group 2 (P < 0.05). Among 35 patients of the group 1 who could be checked ICA, the prevalence of GADA & ICA were 33% & 25% in insulin deficiency group and 4.3% & 0% in non-insulin deficiency group, respectively (P < 0.05). The prevalence of GADA & ICA were none in obese group and 33.3% & 20% in nonobese group, respectively (P < 0.05). The prevalence of GADA & ICA were 36.4% & 27.3% in nonobese and insulin deficiency, 4.2% & 0% in obese and non-insulin deficiency. Conclusion: We suggest that autoimmune mechanism is associated with increased risk for secondary failure of oral hypoglycemic agents in type 2 diabetes, so the measurement of GADA and ICA could help to predict the potential risk and insulin treatment. (J Kor Diabetes Assoc 31:402~409, 2007)

Trial of low Glycemic diet and Acarbose therapy for control of post-prandial hyperglycemia in type 2 diabetes mellitus: Preliminary report

Several trials have shown low glycemic index (G.I.) foods have beneficial effects in control of hyperglycemia especially in type 2 diabetes mellitus (T2DM) where first phase insulin secretion by beta cells of pancreas is defective. Substantially reducing high G.I. starchy rice and wheat preparations in daily diet and replacing them by low G.I. and popular Bengal gram and pulses as staples, helped ensure satiety and adequate calories. Combined with acarbose, the modified diet resulted in significant decline in postprandial blood glucose during six months follow-up of T2DM cases, large majority of which were cases of secondary failure with oral hypoglycemic agents (OHA). It is suggested that before adding Insulin in cases of OHA failure, adequate trial of low G.I. diet and acarbose should be routinely tried.

Non-obese adult onset diabetes with oral hypoglycemic agent failure: islet cell autoantibodies or reversible beta cell refractoriness?

Pancreatic beta cell function and insulin sensitivity, analyzed by the homeostasis model assessment, before and after 24 weeks of insulin therapy were studied and correlated with the presence of autoantibodies against beta cells (islet cell and anti-glutamic acid decarboxylase antibodies), in a group of 18 Brazilian lean adult non-insulin-dependent diabetes mellitus (NIDDM) patients with oral hypoglycemic agent failure (OHAF). Median fasting plasma glucose before and after insulin treatment was 19.1 and 8.5 mmol/l, respectively (P < 0.001); median HbA1c was 11.7% before vs 7.2% after insulin treatment (P < 0.001). Forty-four percent of the patients were positive (Ab+) to at least one autoantibody. Fasting C-peptide levels were lower in Ab+ than Ab- patients, both before (Ab+: 0.16+/-0.09 vs Ab-: 0.41+/-0.35 nmol/l, P < 0.003) and after insulin treatment (Ab+: 0.22+/-0.13 vs Ab-: 0.44+/-0.24 nmol/l, P < 0.03). Improvement of H was seen in Ab- (median before: 7.3 vs after insulin therapy: 33.4%, P = 0.003) but not in Ab+ patients (median before: 6.6 vs after insulin therapy: 20.9%). These results show that the OHAF observed in the 18 NIDDM patients studied was due mainly to two major causes: autoantibodies and beta cell desensitization. Autoantibodies against beta cells could account for 44% of OHAF, but Ab- patients may still present beta cell function recovery, mainly after a period of beta cell rest with insulin therapy. However, the effects of beta cell function recovery on the restoration of the response to oral hypoglycemic agents need to be determined.

Diagnostic Significance of Antibodies to Glutamic Acid Decarboxylase in Japanese Diabetic Patients with Secondary Oral Hypoglycemic Agents Failure

Some non-insulin-dependent diabetes mellitus (NIDDM) patients are positive for antibodies to glutamic acid decarboxylase (anti-GAD), and they tend to develop insulin deficiency. The aim of this study was to evaluate the prevalence of anti-GAD in NIDDM with secondary failure of sulfonylurea agents (NIDDM-SF) and to investigate the diagnostic significance of seropositivity for anti-GAD in NIDDM-SF patients by evaluating human leukocyte antigen (HLA)-DRB1 alleles concurrently. The prevalence of anti-GAD in NIDDM-SF, NIDDM, and new-onset (within 1 year after onset) insulin-dependent diabetes mellitus (IDDM) was 9.3% (39/420), 3.1% (12/392), and 65.0% (13/20), respectively. Pancreatic beta cell function deteriorated in NIDDM-SF patients positive for anti-GAD. HLA-DRB1 allele typing revealed that NIDDM-SF patients positive for anti-GAD were significantly associated with DRB1*0901 (RR = 2.81,P< 0.01), which is one of the susceptible alleles to IDDM. Shorter interval before development of secondary failure and insulin deficiency were significantly associated with the presence of DRB1*0901 (P< 0.05) in NIDDM-SF patients positive for anti-GAD. In conclusion, nearly 10% of NIDDM-SF patients are positive for anti-GAD, suggesting that an autoimmune mechanism might play an important role in the pathogenesis of NIDDM-SF patients. In addition, a combination of serological marker (anti-GAD) and genetic marker (HLA-DRB1) is useful for predicting clinical course of NIDDM patients with secondary failure of sulfonylurea agents.

Insulin versus a combination of insulin and sulfonylurea in the treatment of NIDDM patients with secondary oral failure

Aim: Comparison of the effectiveness of combined therapy vs. an insulin regimen in NIDDM patients with secondary failure of oral hypoglycemic agents. Research design, patients and methods: 27 NIDDM patients were randomly allocated to Group A ( n = 14, insulin) and Group B ( n = 13, insulin and sulfonylurea) with crossover after 3 months. After the next 3 months a decision was made about the further treatment according to the metabolic control. The patients were then treated for another year with the more successful regimen. Metabolic control, residual β-cell secretory capacity, degree of peripheral insulin resistance (clamp) and insulin dose were followed during the whole study. Results: (median, interquartile range, in brackets; ∗, statistically significant difference at P < 0,05): the combined therapy was better then insulin alone in 2 3 of patients. Glycemic control was better (HbA 1c at 3 months: Group A = 7.9(1.1)% vs. Group B = 7.0(0.5)% ∗; HbA 1c at 6 months: Group A = 7.4(1.5)% vs. Group B = 8.1(1.5)%. Insulin dose was lower during the combined therapy in the first 3 months: Group A = 0.62(0.18) U/kg body weight vs. Group B = 0.39(0.16) U/kg body weight ∗. Combined treatment was associated with increased C-peptide excretion both fasting and postprandially. No significant differences in peripheral insulin resistance were noted between the two groups. The combined treatment remained successful even after one year. The two groups of patients with different effective treatment did not differ significantly in any of the observed parameters. Conclusions: the combined therapy was more effective than insulin alone. Its favourable effect persisted after treatment for a year. It seems better to start the treatment of the oral failure with combined therapy compared with insulin first and later followed by combined therapy. On the basis of the observed parameters it is impossible to determine in advance which kind of treatment is more suitable for the individual patient.

Marked Islet Amyloid Polypeptide-Positive Amyloid Deposition

An insulin-deficient 51-year-old man was put on dietary therapy and sulfonylurea (SU). Although there was good glycemic control for 2 years, the fasting blood glucose (FBG) level increased gradually over the subsequent 4-year period, and there was a marked increase in body weight. Secondary failure of SU therapy 20 years after the initial diagnosis led to insulin therapy. The FBG became unstable, and the C-peptide response disappeared. The patient died of nonketotic hyperosmolar coma and pneumonia at the age of 87. At autopsy, the pancreas showed marked atrophy (32 g) with extensive fatty degeneration. Islets replaced by islet amyloid polypeptide (IAPP)-positive amyloid (IAPP-AM) amounted to 77% in the tail, 74% in the body, and 73% in the head of the pancreas. All islets were positive for IAPP-AM throughout the pancreas, except for a pancreatic polypeptide-rich lobe, where none were positive. IAPP-AM-positive islets had also undergone fatty change of the surrounding pancreatic acinar cells. beta-Cells decreased remarkably in number and were displaced to the periphery of the islets by the IAPP-AM deposits. These findings suggest that IAPP-related diabetes could have a progressive course, with secondary oral hypoglycemic agent failure and the subsequent development of severe insulin deficiency similar to that seen in insulin-dependent diabetes mellitus.