High burden of kidney disease in youth-onset type 2 diabetes

OBJECTIVE

To evaluate renal outcomes and survival in youth with type 2 diabetes (T2DM) versus type 1 diabetes (T1DM) versus nondiabetic control subjects.

RESEARCH DESIGN AND METHODS

In total, 342 prevalent youth (aged 1–18 years) with T2DM, 1,011 youth with T1DM, and 1,710 control subjects identified from 1986 to 2007 were anonymously linked to health care records housed at the Manitoba Centre for Health Policy to assess long-term outcomes using ICD codes.

RESULTS

Youth with T2DM were found to have a fourfold increased risk of renal failure versus youth with T1DM. Risk factors associated with renal failure were renin angiotensin aldosterone system inhibitor use and albuminuria in adolescence. Compared with control subjects (age, sex, and postal code matched), youth with T2DM had a 23-fold increased risk of renal failure and a 39-fold increased risk of dialysis. Kaplan-Meier survival at 10 years was 91.4% in the type 2 diabetic group versus 99.5% in the type 1 diabetic group (P < 0.0001). Renal survival was 100% at 10 years in both groups. It decreased to 92.0% at 15 years and 55.0% at 20 years in the type 2 diabetic group but remained stable in the type 1 diabetic group (P < 0.0001).

CONCLUSIONS

Youth with T2DM are at high risk of adverse renal outcomes and death. Albuminuria and angiotensin aldosterone system inhibitor use, which may be a marker of severity of disease, are associated with poor outcomes in early adulthood.The prevalence of type 2 diabetes (T2DM) in youth continues to increase and now accounts for 8–45% of incident cases of diabetes in children (1). In adults, diabetes accounts for 30–40% of end-stage kidney disease (ESKD) in North America and is associated with a 5-year survival rate as low as 34% (2). The time to progress from microalbuminuria to ESKD has been estimated at 15–20 years (3).T2DM diagnosed in childhood is a relatively new disease, and the natural history is still largely unknown. Evidence suggests that complications may occur at an earlier age with a shorter duration of diabetes (4). Cross-sectional studies show a higher prevalence of albuminuria in youth with T2DM compared with youth with type 1 diabetes (T1DM) at various disease time points (5–7), and data from the Pima Indian population have shown a fivefold increased risk of ESKD in middle age in individuals diagnosed with T2DM before 20 years of age (8). The only study comparing long-term outcomes in T1DM with early onset T2DM is based on a cohort of Japanese young adults <30 years of age at diagnosis and reveals a significantly higher cumulative incidence of nephropathy in T2DM compared with T1DM (44.4 vs. 20.2%; P < 0.0001) (9). These authors also reported diabetic nephropathy in 60% (mean age 31 years) and renal failure requiring dialysis in 23% (mean age 35 years) of a subgroup of their cohort with proliferative retinopathy (n = 135) (10). Graduates from our pediatric clinic also have previously been reported to develop ESKD before 30 years of age (11).In adults with T2DM, rigorous glycemic control and treatment of hypertension, as well as the use of renin angiotensin aldosterone system (RAAS) inhibitors (including ACE and angiotensin II receptor antagonists), have been shown to abrogate progression of renal disease (3). Observational studies suggest that poor glycemic control may be an important modifiable risk factor in youth with T2DM (6,12); however, studies evaluating the role of other risk factors for progression, including hypertension, are conflicting (6,13,14), and RAAS inhibitors have never been formally evaluated in a published randomized controlled trial in youth.Manitoba has an incidence of youth-onset T2DM that is 12.5-fold higher than any other province in Canada (15). A genetic single nucleotide polymorphism (hepatocyte nuclear factor [HNF]-1α G319S), which is present in one of the aboriginal Oji-Cree language groups in Manitoba, has been shown to increase the risk of T2DM and may contribute to the high disease prevalence (16). As a result of the high burden of youth-onset T2DM in Manitoba, this study was designed to describe the long-term renal complications and survival and to identify potentially modifiable, pediatric specific, disease progression factors in this population.     

The reality of type 2 diabetes treatment today

The 5-year targets set by the St Vincent Declaration for cardiovascular events and other diabetes outcomes have still not been met, despite concerted efforts to treat cardiovascular risk factors in this population. Since St. Vincent we have seen a new focus on the care of Type 2 diabetes towards multiple risk factor reduction, including blood pressure, lipids, smoking and glycaemic control. The other new concept is that insulin resistance is a key abnormality in the pathogenesis of Type 2 diabetes. The thiazolidinediones are a new class of drug that ameliorate insulin resistance, and we await to see if their use is associated with improved diabetes outcomes. The third key issue is that modern day diabetes care requires polypharmacy. However, adding several drugs to the list of medications taken by many patients with Type 2 diabetes may bring problems of compliance. A typical patient might be taking several tablets for diabetes, plus medications to address cardiovascular risk factors/disease and typical co-morbidities of an ageing population. There is evidence that adherence to therapy is a major issue in diabetes care. More research is needed to define ways of improving adherence [corrected].     

Islet beta cell failure in type 2 diabetes

The major focus of this Review is on the mechanisms of islet beta cell failure in the pathogenesis of obesity-associated type 2 diabetes (T2D). As this demise occurs within the context of beta cell compensation for insulin resistance, consideration is also given to the mechanisms involved in the compensation process, including mechanisms for expansion of beta cell mass and for enhanced beta cell performance. The importance of genetic, intrauterine, and environmental factors in the determination of "susceptible" islets and overall risk for T2D is reviewed. The likely mechanisms of beta cell failure are discussed within the two broad categories: those with initiation and those with progression roles.     

The treatment of obesity in type 2 diabetes mellitus.

Obesity has a critical role in the pathophysiology of type 2 diabetes mellitus, and prevention of weight gain and treatment after onset of obesity is crucial to the management of the disease. A recent National Institutes of Health (NIH) report on the evaluation and treatment of overweight and obesity serves as a model for managing obese individuals with type 2 diabetes. Lifestyle intervention is the fundamental approach and should be implemented by a multidisciplinary team of health professionals. Adjunctive therapies, such as anti-obesity pharmacotherapy and surgery, should only be considered if at least 6 months of lifestyle intervention has produced suboptimal results. If adjunctive therapy is indicated, it will only be successful long term if lifestyle therapy remains central to treatment. The objective of this review is to integrate the recommendations of the NIH into the primary care management of the obese individual with type 2 diabetes.     

The case for insulin treatment early in type 2 diabetes

Most patients with type 2 diabetes ultimately need insulin therapy. This paper presents the case for starting insulin therapy sooner rather than later, preferably without oral drugs and in a "basal/bolus" regimen consisting of a daily dose of a long-acting insulin for basal coverage plus preprandial doses of a short-acting insulin.     

The incidence of congestive heart failure in type 2 diabetes: an update

OBJECTIVE: The aims of this study were to update previous estimates of the congestive heart failure (CHF) incidence rate in patients with type 2 diabetes, compare it with an age- and sex-matched nondiabetic group, and describe risk factors for developing CHF in diabetic patients over 6 years of follow-up. RESEARCH DESIGN AND METHODS: We performed a retrospective cohort study of 8,231 patients with type 2 diabetes and 8,845 nondiabetic patients of similar age and sex who did not have CHF as of 1 January 1997, following them for up to 72 months to estimate the CHF incidence rate. In the diabetic cohort, we constructed a Cox regression model to identify risk factors for CHF development. RESULTS: Patients with diabetes were much more likely to develop CHF than patients without diabetes (incidence rate 30.9 vs. 12.4 cases per 1,000 person-years, rate ratio 2.5, 95% CI 2.3-2.7). The difference in CHF development rates between persons with and without diabetes was much greater in younger age-groups. In addition to age and ischemic heart disease, poorer glycemic control (hazard ratio 1.32 per percentage point of HbA(1c)) and greater BMI (1.12 per 2.5 units of BMI) were important predictors of CHF development. CONCLUSIONS: The CHF incidence rate in type 2 diabetes may be much greater than previously believed. Our multivariate results emphasize the importance of controlling modifiable risk factors for CHF, namely hyperglycemia, elevated blood pressure, and obesity. Younger patients may benefit most from risk factor modification.     

The use of insulin to improve treatment in type 2 diabetes

Diabetes is a global problem of increasing proportions and requires adherence to tight treatment targets to prevent complications. This article focuses on the use of insulin to gain good glycaemia control in type 2 diabetes.     

Pharmacological treatment of hyperglycemia in type 2 diabetes

Diabetes mellitus is a major public health problem, affecting about 10% of the population. Pharmacotherapy aims to protect against microvascular complications, including blindness, end-stage kidney disease, and amputations. Landmark clinical trials have demonstrated that intensive glycemic control slows progression of microvascular complications (retinopathy, nephropathy, and neuropathy). Long-term follow-up has demonstrated that intensive glycemic control also decreases risk of macrovascular disease, albeit rigorous evidence of macrovascular benefit did not emerge for over a decade. The US FDA’s recent requirement for dedicated cardiovascular outcome trials ushered in a golden age for understanding the clinical profiles of new type 2 diabetes drugs. Some clinical trials with sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP1) receptor agonists reported data demonstrating cardiovascular benefit (decreased risk of major adverse cardiovascular events and hospitalization for heart failure) and slower progression of diabetic kidney disease. This Review discusses current guidelines for use of the 12 classes of drugs approved to promote glycemic control in patients with type 2 diabetes. The Review also anticipates future developments with potential to improve the standard of care: availability of generic dipeptidylpeptidase-4 (DPP4) inhibitors and SGLT2 inhibitors; precision medicine to identify the best drugs for individual patients; and new therapies to protect against chronic complications of diabetes.

Diabetes mellitus is a major public health problem, affecting about 10% of the population (1). Chronic complications of diabetes cause enormous human suffering, including blindness, kidney failure, amputations, myocardial infarction, and stroke. Inspired by the desire to develop better therapies, many researchers have investigated the pathophysiology of type 2 diabetes (T2D). While type 1 diabetes (T1D) is caused by autoimmune destruction of insulin-secreting β cells of the pancreas, T2D is often associated with obesity and is characterized by both impaired insulin secretion and insulin resistance (2). T2D is a progressive disease. Insulin resistance manifests early in the natural history prior to occurrence of overt hyperglycemia. So long as pancreatic β cells secrete sufficient insulin to compensate for insulin resistance, glucose levels are maintained at relatively normal levels (3). Overt diabetes occurs when β cells no longer secrete sufficient insulin to maintain normoglycemia. Fasting hyperglycemia is driven by increased hepatic glucose production due to relatively low insulin levels combined with hepatic insulin resistance. Severity of metabolic defects increases over time, primarily because of increasingly severe impairment in insulin secretion.This Review will discuss the state of the art in pharmacotherapy of T2D. Treatment aims to prevent or delay occurrence of microvascular and macrovascular complications — the main causes of morbidity and mortality in T2D. We focus specifically on hemoglobin A_1c–lowering (HbA1c-lowering) drugs, although antihypertensives, lipid-lowering drugs, optimal nutrition, and physical exercise also contribute to a holistic approach to treatment.     

胰岛素加吡格列酮联合治疗磺脲类继发性失效2型糖尿病的疗效观察

目的比较胰岛素加吡格列酮联合治疗和单用胰岛素治疗磺脲类继发性失效2型糖尿病患者的疗效.方法将磺脲类继发性失效2型糖尿病患者62例随机分为两组,治疗组32例,每日早餐及晚餐前皮下注射人胰岛素诺和灵50R及服吡格列酮15～30 mg;对照组30例,每日单用人胰岛素诺和灵50R于早餐及晚餐前皮下注射,12周后评价两组患者空服及餐后2小时血糖、糖化血红蛋白(HbA1c)、胰岛素用量、体质量指数、血压、胰岛素分泌及血脂[总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)]变化情况.结果两组患者治疗后血糖均得到良好控制,但治疗组胰岛素日需求量明显低于对照组(P<0.01);治疗组血TG较对照组下降,而HDL-C较对照组升高(P<0.05);治疗组空腹及餐后2小时胰岛素分泌较对照组减少(P<0.05).结论磺脲类继发性失效2型糖尿病患者选用胰岛素加吡格列酮联合治疗优于单用胰岛素治疗.     

Drug treatment of type 2 diabetes in adults

This article outlines the pharmacological management of type 2 diabetes and its complications in adults. Practical aspects of the drug options and the evidence supporting their use are discussed. The need for a holistic, patient-centred approach to achieve the treatment goals of glycaemic control and prevention of complications is emphasised.     

Insulin lispro in the treatment of patients with type 2 diabetes mellitus after oral agent failure

This study assessed the safety profile and efficacy of a new combination therapy (insulin lispro plus sulfonylurea) in patients with type 2 diabetes mellitus experiencing secondary oral agent failure. A total of 423 patients were randomly assigned to 3 treatment groups: preprandial insulin lispro plus sulfonylurea (L + S), bedtime neutral protamine Hagedorn (NPH) insulin plus sulfonylurea (N + S), and preprandial insulin lispro plus bedtime NPH insulin (L + N). Mean decreases in glycosylated hemoglobin from baseline were 1.60%+/-1.27% for patients receiving L + S, 1.21%+/-1.21% for those receiving N + S, and 1.40%+/-1.46% for those receiving L + N (within treatment, P<0.001; for L + S vs. N + S, P = 0.003). Fasting blood glucose level was higher in patients receiving L + S (171+/-46.5 mg/dL) or L + N (166+/-52.5 mg/dL) than in those receiving N + S (144+/-48.2 mg/dL) (P<0.001, for both comparisons). Conversely, postprandial blood glucose level was lower in patients receiving L + S (165+/-41.6 mg/dL) or L + N (165+/-46.3 mg/dL) than in those receiving N + S (213+/-58.3 mg/dL) (P<0.001, for both comparisons). The overall rate of hypoglycemia (episodes per 30 days) was not statistically significant when the L + S, N + S, and L + N therapies were compared (0.99+/-1.74 vs. 0.87+/-2.31 vs. 1.16+/-2.38, respectively). The rate of nocturnal hypoglycemia was lowest in the L + S group (0.00+/-0.00 vs. 0.10+/-0.37 for the N + S group vs. 0.15+/-0.54 for the L + N group; P = 0.004). L + S, which has a safety profile equal to those of N + S and L + N, is an effective treatment for patients with type 2 diabetes who experience oral sulfonylurea agent failure. L + S offers an alternative to these established combination therapies in patients whose type 2 diabetes cannot be controlled with a sulfonylurea alone.     

Matching treatment to pathophysiology in type 2 diabetes

BACKGROUND: Because type 2 diabetes is a progressive condition, >50% of all patients whose disease is initially controlled with diet and exercise will eventually need single or multiple pharmacologic agents to maintain adequate glycemic control. Although current treatment standards require that combination therapy be instituted only after the failure of monotherapy, the results of the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study suggest that aggressive initial treatment is crucial to slowing the evolution of long-term complications associated with this disease. OBJECTIVES: This article reviews the diagnosis and classification of type 2 diabetes, describes the multiple defects in glucose metabolism associated with the disease, and discusses the various pharmacologic options for achieving glycemic control in these patients. METHODS: The information in this review was compiled through a search of MEDLINE. Search terms included but were not limited to type 2 diabetes and antihyperglycemic agents. In addition, abstracts were identified using the Web sites of diabetes-related professional organizations. RESULTS: Two pathophysiologic mechanisms, insulin resistance and impaired insulin secretion, are usually present at diagnosis in type 2 diabetes. Several studies have shown that combination therapy with antihyperglycemic agents having different mechanisms of action provides greater efficacy than treatment with single agents. CONCLUSIONS: Current research suggests that early aggressive treatment with combination therapy achieves glycemic control at lower doses and with fewer side effects than monotherapy with either component.     

小檗碱治疗2型糖尿病40例疗效观察

目的探讨小檗碱在治疗2型糖尿病中的临床疗效。方法2型糖尿病患者共40例,男24例,女16例。年龄36~62岁。病程2~14年。所有患者均执行糖尿病饮食及运动治疗,在口服小檗碱的同时,原用药种类及剂量不变。观察治疗前后血脂、血糖(空腹及餐后2 h)、胰岛素(空腹及餐后2 h)的变化。结果治疗后空腹血糖及餐后2 h血糖明显下降,差异有显著性(P<0.05),空腹及餐后2 h胰岛素明显升高(P<0.05),差异显著,胆固醇及甘油三酯的降低亦有显著性差异(P<0.05)。结论小檗碱能明显降低2型糖尿病患者的血糖、血脂,并能改善胰岛素分泌。     

手术治疗2型糖尿病——回顾性临床研究及近期临床试用报告

目的探讨胃旁路手术（GBP）治疗2型糖尿病（NIDDM）。方法回顾性观察11例并存NIDDM的病人因其它疾病接受过类似GBP手术（胃大部切除，Roux—en—Y型毕2式胃肠吻合）者11例；4例NIDDM病人用GBP治疗。结果葡萄糖耐量试验提示NIDDM病人手术治疗前后各时相血糖改变非常显著（P〈0．001），糖尿病及其并发症也得到缓解和治愈。结论无论是否并存肥胖症，GBP是治疗NIDDM的有前景的方法。