Pathophysiologic approach to therapy in patients with newly diagnosed type 2 diabetes
TL;DR: It is believed that the most important consideration is to select antidiabetes agents that correct specific pathophysiologic disturbances present in T2DM and that have complementary mechanisms of action.
Abstract: Two general approaches to the treatment of type 2 diabetes mellitus (T2DM) have been advocated. 1 ) A “guideline” approach that advocates sequential addition of antidiabetes agents with “more established use” (1); this approach more appropriately should be called the “treat to failure” approach, and deficiencies with this approach have been discussed (2). And 2 ) a “pathophysiologic” approach using initial combination therapy with agents known to correct established pathophysiologic defects in T2DM (3). Within the pathophysiologic approach, choice of antidiabetes agents should take into account the patient’s general health status and associated medical disorders. This individualized approach, which we refer to as the ABCD(E) of diabetes treatment (4), has been incorporated into the updated American Diabetes Association (ADA) guidelines (5).
Even though physicians must be cognizant of these associated conditions (ABCDE) when initiating therapy in newly diagnosed T2DM patients, we believe that the most important consideration is to select antidiabetes agents that correct specific pathophysiologic disturbances present in T2DM and that have complementary mechanisms of action. Although it has been argued that the pathogenesis of T2DM differs in different ethnic groups (6), evidence to support this is weak. Although the relative contributions of β-cell failure and insulin resistance to development of glucose intolerance may differ in different ethnic groups (6), the core defects of insulin resistance in muscle/liver/adipocytes and progressive β-cell failure (3) are present in virtually all T2DM patients and must be treated aggressively to prevent the relentless rise in HbA1c that is characteristic of T2DM.
In subsequent sections, we provide a review of the natural history of T2DM, specific pathophysiologic abnormalities responsible for T2DM, currently …
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23 Jul 2015
TL;DR: The greatest need is for agents that enhance insulin sensitivity, halt the progressive pancreatic β-cell failure that is characteristic of T2DM and prevent or reverse the microvascular complications.
Abstract: Type 2 diabetes mellitus (T2DM) is an expanding global health problem, closely linked to the epidemic of obesity. Individuals with T2DM are at high risk for both microvascular complications (including retinopathy, nephropathy and neuropathy) and macrovascular complications (such as cardiovascular comorbidities), owing to hyperglycaemia and individual components of the insulin resistance (metabolic) syndrome. Environmental factors (for example, obesity, an unhealthy diet and physical inactivity) and genetic factors contribute to the multiple pathophysiological disturbances that are responsible for impaired glucose homeostasis in T2DM. Insulin resistance and impaired insulin secretion remain the core defects in T2DM, but at least six other pathophysiological abnormalities contribute to the dysregulation of glucose metabolism. The multiple pathogenetic disturbances present in T2DM dictate that multiple antidiabetic agents, used in combination, will be required to maintain normoglycaemia. The treatment must not only be effective and safe but also improve the quality of life. Several novel medications are in development, but the greatest need is for agents that enhance insulin sensitivity, halt the progressive pancreatic β-cell failure that is characteristic of T2DM and prevent or reverse the microvascular complications. For an illustrated summary of this Primer, visit: http://go.nature.com/V2eGfN.
1,757 citations
TL;DR: Exenatide plus dapagliflozin was significantly superior to either drug alone for all secondary efficacy endpoints, with greater reductions in fasting plasma and postprandial glucose, more patients with an HbA1c less than 7·0%.
304 citations
TL;DR: This review summarises the biochemical, histological and macromolecular changes that contribute to oxidative liver damage among diabetic individuals.
Abstract: Diabetes mellitus is a non-communicable disease that occurs in both developed and developing countries. This metabolic disease affects all systems in the body, including the liver. Hyperglycaemia, mainly caused by insulin resistance, affects the metabolism of lipids, carbohydrates and proteins and can lead to non-alcoholic fatty liver disease, which can further progress to non-alcoholic steatohepatitis, cirrhosis and, finally, hepatocellular carcinomas. The underlying mechanism of diabetes that contributes to liver damage is the combination of increased oxidative stress and an aberrant inflammatory response; this activates the transcription of pro-apoptotic genes and damages hepatocytes. Significant involvement of pro-inflammatory cytokines-including interleukin (IL)-1β, IL-6 and tumour necrosis factor-α-exacerbates the accumulation of oxidative damage products in the liver, such as malondialdehyde, fluorescent pigments and conjugated dienes. This review summarises the biochemical, histological and macromolecular changes that contribute to oxidative liver damage among diabetic individuals.
266 citations
TL;DR: An urgent call is issued for the review of the current DM classification system toward the consensus on a new, more useful system that obviates the inherent and unintended confusions.
Abstract: The current classification system presents challenges to the diagnosis and treatment of patients with diabetes mellitus (DM), in part due to its conflicting and confounding definitions of type 1 DM, type 2 DM, and latent autoimmune diabetes of adults (LADA). The current schema also lacks a foundation that readily incorporates advances in our understanding of the disease and its treatment. For appropriate and coherent therapy, we propose an alternate classification system. The β-cell-centric classification of DM is a new approach that obviates the inherent and unintended confusions of the current system. The β-cell-centric model presupposes that all DM originates from a final common denominator-the abnormal pancreatic β-cell. It recognizes that interactions between genetically predisposed β-cells with a number of factors, including insulin resistance (IR), susceptibility to environmental influences, and immune dysregulation/inflammation, lead to the range of hyperglycemic phenotypes within the spectrum of DM. Individually or in concert, and often self-perpetuating, these factors contribute to β-cell stress, dysfunction, or loss through at least 11 distinct pathways. Available, yet underutilized, treatments provide rational choices for personalized therapies that target the individual mediating pathways of hyperglycemia at work in any given patient, without the risk of drug-related hypoglycemia or weight gain or imposing further burden on the β-cells. This article issues an urgent call for the review of the current DM classification system toward the consensus on a new, more useful system.
219 citations
Cites background from "Pathophysiologic approach to therap..."
...This stratification establishes undue competition between classes, which should more rightly be viewed as complementary options rather than salvage therapy after inevitable treatment failure (19,73)....
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TL;DR: In adults at risk for diabetes, LSM and medications (weight loss and insulin-sensitizing agents) successfully reduced diabetes incidence, suggesting that interventions to preserve effects are needed.
Abstract: Importance Diabetes prevention is imperative to slow worldwide growth of diabetes-related morbidity and mortality. Yet the long-term efficacy of prevention strategies remains unknown. Objective To estimate aggregate long-term effects of different diabetes prevention strategies on diabetes incidence. Data Sources Systematic searches of MEDLINE, EMBASE, Cochrane Library, and Web of Science databases. The initial search was conducted on January 14, 2014, and was updated on February 20, 2015. Search terms included prediabetes , primary prevention , and risk reduction . Study Selection Eligible randomized clinical trials evaluated lifestyle modification (LSM) and medication interventions (>6 months) for diabetes prevention in adults (age ≥18 years) at risk for diabetes, reporting between-group differences in diabetes incidence, published between January 1, 1990, and January 1, 2015. Studies testing alternative therapies and bariatric surgery, as well as those involving participants with gestational diabetes, type 1 or 2 diabetes, and metabolic syndrome, were excluded. Data Extraction and Synthesis Reviewers extracted the number of diabetes cases at the end of active intervention in treatment and control groups. Random-effects meta-analyses were used to obtain pooled relative risks (RRs), and reported incidence rates were used to compute pooled risk differences (RDs). Main Outcomes and Measures The main outcome was aggregate RRs of diabetes in treatment vs control participants. Treatment subtypes (ie, LSM components, medication classes) were stratified. To estimate sustainability, post-washout and follow-up RRs for medications and LSM interventions, respectively, were examined. Results Forty-three studies were included and pooled in meta-analysis (49 029 participants; mean [SD] age, 57.3 [8.7] years; 48.0% [n = 23 549] men): 19 tested medications; 19 evaluated LSM, and 5 tested combined medications and LSM. At the end of the active intervention (range, 0.5-6.3 years), LSM was associated with an RR reduction of 39% (RR, 0.61; 95% CI, 0.54-0.68), and medications were associated with an RR reduction of 36% (RR, 0.64; 95% CI, 0.54-0.76). The observed RD for LSM and medication studies was 4.0 (95% CI, 1.8-6.3) cases per 100 person-years or a number-needed-to-treat of 25. At the end of the washout or follow-up periods, LSM studies (mean follow-up, 7.2 years; range, 5.7-9.4 years) achieved an RR reduction of 28% (RR, 0.72; 95% CI, 0.60-0.86); medication studies (mean follow-up, 17 weeks; range, 2-52 weeks) showed no sustained RR reduction (RR, 0.95; 95% CI, 0.79-1.14). Conclusions and Relevance In adults at risk for diabetes, LSM and medications (weight loss and insulin-sensitizing agents) successfully reduced diabetes incidence. Medication effects were short lived. The LSM interventions were sustained for several years; however, their effects declined with time, suggesting that interventions to preserve effects are needed.
215 citations
Cites background from "Pathophysiologic approach to therap..."
...Physiologically, it has been shown that losing weight depletes free fatty acids frombothmuscle and liver, resulting in improved insulin sensitivity and glucose homeostasis.(75) Additional research has demonstrated that obesity-inducedβ-cell dysfunction canbe restoredwithcaloric restrictionandreversion tonormalweight in overweight and obese individuals....
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References
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Journal Article•
TL;DR: In this article, the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial were compared.
17,108 citations
Journal Article•
TL;DR: The effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial were compared.
8,546 citations
Journal Article•
TL;DR: Since intensive glucose control with metformin appears to decrease the risk of diabetes-related endpoints in overweight diabetic patients, and is associated with less weight gain and fewer hypoglycaemic attacks than are insulin and sulphonylureas, it may be the first-line pharmacological therapy of choice in these patients.
7,395 citations
TL;DR: Patients and providers should consider the potential for serious adverse cardiovascular effects of treatment with rosiglitazone for type 2 diabetes mellitus as well as the availability of outcome data for myocardial infarction and death from cardiovascular causes.
Abstract: �Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that had borderline significance. Our study was limited by a lack of access to original source data, which would have enabled time-to-event analysis. Despite these limitations, patients and providers should consider the potential for serious adverse cardiovascular effects of treatment with rosiglitazone for type 2 diabetes.
4,570 citations
"Pathophysiologic approach to therap..." refers background in this paper
...Rosiglitazone has been removed from the market or its use severely restricted because of cardiovascular safety concerns (147)....
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TL;DR: Properties of currently available glucose-lowering agents that may guide treatment choice in individual patients with type 2 diabetes mellitus are explored.
Abstract: Erratum to: DiabetologiaDOI 10.1007/s00125-012-2534-0In the text box ‘Properties of currently available glucose-lowering agents that may guide treatment choice in individualpatients with type 2 diabetes mellitus ’ vildagliptin was incor-rectly assigned footnote ‘a’ (Limited use in the USA/Europe)instead of footnote ‘b’ (Not licensed in the USA).
4,126 citations