Pioglitazone and alogliptin combination therapy in type 2 diabetes: a pathophysiologically sound treatment

Insulin resistance and islet (beta and alpha) cell dysfunction are major pathophysiologic abnormalities in type 2 diabetes mellitus (T2DM). Pioglitazone is a potent insulin sensitizer, improves pancreatic beta cell function and has been shown in several outcome trials to lower the risk of atherosclerotic and cardiovascular events. Glucagon-like peptide-1 deficiency/resistance contributes to islet cell dysfunction by impairing insulin secretion and increasing glucagon secretion. Dipeptidyl peptidase-4 (DPP-4) inhibitors improve pancreatic islet function by augmenting glucose-dependent insulin secretion and decreasing elevated plasma glucagon levels. Alogliptin is a new DPP-4 inhibitor that reduces glycosylated hemoglobin (HbA1c), is weight neutral, has an excellent safety profile, and can be used in combination with oral agents and insulin. Alogliptin has a low risk of hypoglycemia, and serious adverse events are uncommon. An alogliptin–pioglitazone combination is advantageous because it addresses both insulin resistance and islet dysfunction in T2DM. HbA1c reductions are significantly greater than with either monotherapy. This once-daily oral combination medication does not increase the risk of hypoglycemia, and tolerability and discontinuation rates do not differ significantly from either monotherapy. Importantly, measures of beta cell function and health are improved beyond that observed with either monotherapy, potentially improving durability of HbA1c reduction. The alogliptin–pioglitazone combination represents a pathophysiologically sound treatment of T2DM.

[1]  R. Unger,et al.  Pancreatic glucagon secretion in normal and diabetic subjects. , 1969, The American journal of the medical sciences.

[2]  W. A. Müller,et al.  Studies of pancreatic alpha cell function in normal and diabetic subjects. , 1970, The Journal of clinical investigation.

[3]  W. A. Müller,et al.  Abnormal alpha-cell function in diabetes. Response to carbohydrate and protein ingestion. , 1970, The New England journal of medicine.

[4]  R. Unger.  Glucagon physiology and pathophysiology. , 1971, The New England journal of medicine.

[5]  R. DeFronzo,et al.  The Disposal of an Oral Glucose Load in Healthy Subjects: A Quantitative Study , 1985, Diabetes.

[6]  R. DeFronzo,et al.  Effect of chronic hyperglycemia on in vivo insulin secretion in partially pancreatectomized rats. , 1987, The Journal of clinical investigation.

[7]  D. Drucker,et al.  Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[8]  R. DeFronzo.  Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. , 1988, Diabetes.

[9]  R. DeFronzo.  The Triumvirate: β-Cell, Muscle, Liver: A Collusion Responsible for NIDDM , 1988, Diabetes.

[10]  Yii-Der I. Chen,et al.  Measurement of Plasma Glucose, Free Fatty Acid, Lactate, and Insulin for 24 h in Patients With NIDDM , 1988, Diabetes.

[11]  J. Habener,et al.  Insulinotropic hormone glucagon-like peptide-I(7-37) stimulation of proinsulin gene expression and proinsulin biosynthesis in insulinoma beta TC-1 cells. , 1992, Endocrinology.

[12]  J. Habener,et al.  Galanin inhibits proinsulin gene expression stimulated by the insulinotropic hormone glucagon-like peptide-I(7-37) in mouse insulinoma beta TC-1 cells. , 1992, Endocrinology.

[13]  B. Göke,et al.  Glucagon-like peptide-1(7–37)/(7–36)amide is a new incretin , 1992, Molecular and Cellular Endocrinology.

[14]  C. McMahan,et al.  Rapid gastric emptying of an oral glucose solution in type 2 diabetic patients. , 1992, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[15]  J. Holst,et al.  Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. , 1993, The Journal of clinical investigation.

[16]  J. Puschett.  Pharmacological classification and renal actions of diuretics. , 1994, Cardiology.

[17]  J. Holst,et al.  Both Subcutaneously and Intravenously Administered Glucagon-Like Peptide I Are Rapidly Degraded From the NH2-Terminus in Type II Diabetic Patients and in Healthy Subjects , 1995, Diabetes.

[18]  P. Libby,et al.  Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. , 1995, The Journal of clinical investigation.

[19]  G. Berglund,et al.  Glucose modulation of insulin and glucagon secretion is altered in impaired glucose tolerance. , 1995, The Journal of clinical endocrinology and metabolism.

[20]  B. Ahrén.  Insulinotropic action of truncated glucagon-like peptide-1 in mice. , 1995, Acta physiologica Scandinavica.

[21]  J. Egan,et al.  Glucagon-like peptide-1 affects gene transcription and messenger ribonucleic acid stability of components of the insulin secretory system in RIN 1046-38 cells. , 1995, Endocrinology.

[22]  P. J. Larsen,et al.  Central administration of GLP-1-(7-36) amide inhibits food and water intake in rats. , 1996, The American journal of physiology.

[23]  C. McMahan,et al.  Rapid Gastric Emptying of a Solid Pancake Meal in Type II Diabetic Patients , 1996, Diabetes Care.

[24]  D. Lloyd‐Jones,et al.  The vascular biology of nitric oxide and its role in atherogenesis. , 1996, Annual review of medicine.

[25]  J. Holst,et al.  Glucagon-Like Peptide I Receptors in the Subfornical Organ and the Area Postrema Are Accessible to Circulating Glucagon-Like Peptide I , 1996, Diabetes.

[26]  D. Smith,et al.  A role for glucagon-like peptide-1 in the central regulation of feeding , 1996, Nature.

[27]  J. Habener,et al.  Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor. , 1996, Endocrinology.

[28]  G. Boden.  Role of Fatty Acids in the Pathogenesis of Insulin Resistance and NIDDM , 1997, Diabetes.

[29]  J. Habener,et al.  Insulinotropic Glucagon-Like Peptide I Receptor Expression in Glucagon-Producing α-Cells of the Rat Endocrine Pancreas , 1997, Diabetes.

[30]  B. Yeğen,et al.  Glucagon-like peptide-1 inhibits gastric emptying via vagal afferent-mediated central mechanisms. , 1997, American journal of physiology. Gastrointestinal and liver physiology.

[31]  R. DeFronzo.  PATHOGENESIS OF TYPE 2 DIABETES: METABOLIC AND MOLECULAR IMPLICATIONS FOR IDENTIFYING DIABETES GENES , 1997 .

[32]  B. Ahrén.  Glucagon‐like peptide‐1 (GLP‐1): A gut hormone of potential interest in the treatment of diabetes , 1998, BioEssays : news and reviews in molecular, cellular and developmental biology.

[33]  R. Holman,et al.  Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) , 1998, The Lancet.

[34]  Uk-Prospective-Diabetes-Study-Group.  Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) , 1998, The Lancet.

[35]  J. Habener,et al.  The glucagon-like peptides. , 1999, Endocrine reviews.

[36]  B. Ahrén,et al.  Glucose intolerance is predicted by low insulin secretion and high glucagon secretion: outcome of a prospective study in postmenopausal Caucasian women , 2000, Diabetologia.

[37]  R. Holman,et al.  Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study , 2000, BMJ : British Medical Journal.

[38]  B. Ahrén,et al.  Impaired glucose tolerance (IGT) is associated with reduced insulin-induced suppression of glucagon concentrations , 2001, Diabetologia.

[39]  J. Holst,et al.  Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. , 2001, The Journal of clinical endocrinology and metabolism.

[40]  G. Striker.  Glucose toxicity. , 2001, Kidney International.

[41]  S. Kahn.  Clinical review 135: The importance of beta-cell failure in the development and progression of type 2 diabetes. , 2001, The Journal of clinical endocrinology and metabolism.

[42]  A. Astrup,et al.  A meta-analysis of the effect of glucagon-like peptide-1 (7-36) amide on ad libitum energy intake in humans. , 2001, The Journal of clinical endocrinology and metabolism.

[43]  J. McGarry.  Dysregulation of Fatty Acid Metabolism in the Etiology of Type 2 Diabetes , 2001 .

[44]  T. Shibasaki,et al.  Critical Role of cAMP-GEFII·Rim2 Complex in Incretin-potentiated Insulin Secretion* , 2001, The Journal of Biological Chemistry.

[45]  S. Kahn,et al.  The Importance of β-Cell Failure in the Development and Progression of Type 2 Diabetes , 2001 .

[46]  P. Brubaker,et al.  Glucagon-like peptide-1 treatment delays the onset of diabetes in 8 week-old db/db mice , 2002, Diabetologia.

[47]  D. Drucker,et al.  Structure-function of the glucagon receptor family of G protein-coupled receptors: the glucagon, GIP, GLP-1, and GLP-2 receptors. , 2002, Receptors & channels.

[48]  R. Bergman,et al.  The evolution of β‐cell dysfunction and insulin resistance in type 2 diabetes , 2002, European journal of clinical investigation.

[49]  J. Hardies,et al.  Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. , 2002, The Journal of clinical endocrinology and metabolism.

[50]  J. McGarry.  Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. , 2002, Diabetes.

[51]  M. Nauck,et al.  Gastric Inhibitory Polypeptide: the neglected incretin revisited , 2002, Regulatory Peptides.

[52]  T. Buchanan,et al.  Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. , 2002, Diabetes.

[53]  Y. Miyazaki,et al.  Abdominal fat distribution and peripheral and hepatic insulin resistance in type 2 diabetes mellitus. , 2002, American journal of physiology. Endocrinology and metabolism.

[54]  B. Ahrén.  Gut peptides and type 2 diabetes mellitus treatment , 2003, Current Diabetes Reports.

[55]  D. Drucker.  Glucagon-like peptides: regulators of cell proliferation, differentiation, and apoptosis. , 2003, Molecular endocrinology.

[56]  R. DeFronzo,et al.  A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. , 2003, Diabetes.

[57]  S. Grundy,et al.  Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. October 7, 2003. , 2003, Circulation.

[58]  M. Matsuda,et al.  Beta-cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study , 2003, Diabetologia.

[59]  Dennis D. Kim,et al.  Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. , 2003, The Journal of clinical endocrinology and metabolism.

[60]  T. M. Hayes,et al.  The glucose dependent insulinotropic polypeptide response to oral glucose and mixed meals is increased in patients with Type 2 (non-insulin-dependent) diabetes mellitus , 2004, Diabetologia.

[61]  J. Holst,et al.  Incretins, insulin secretion and Type 2 diabetes mellitus , 2004, Diabetologia.

[62]  L. J. Hardies,et al.  Plasma resistin concentration, hepatic fat content, and hepatic and peripheral insulin resistance in pioglitazone-treated type II diabetic patients , 2004, International Journal of Obesity.

[63]  T. Elasy,et al.  Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association: response to Nesto. , 2004, Diabetes care.

[64]  R. DeFronzo,et al.  A meta-analysis comparing the effect of thiazolidinediones on cardiovascular risk factors. , 2004, Archives of internal medicine.

[65]  J. Wishart,et al.  Relationship between oral glucose tolerance and gastric emptying in normal healthy subjects , 1993, Diabetologia.

[66]  G. Nichols,et al.  The burden of treatment failure in type 2 diabetes. , 2004, Diabetes care.

[67]  S. Grundy,et al.  Thiazolidinedione Use, Fluid Retention, and Congestive Heart Failure: A Consensus Statement From the American Heart Association and American Diabetes Association , 2003, Diabetes care.

[68]  R. DeFronzo,et al.  Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. , 2004, The Journal of clinical endocrinology and metabolism.

[69]  S. Saydah,et al.  Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. , 2004, JAMA.

[70]  D. Mikhailidis.  Disordered gastric motor function in diabetes mellitus , 1995, Diabetologia.

[71]  S. Bowlin,et al.  Glycemic control from 1988 to 2000 among U.S. adults diagnosed with type 2 diabetes: a preliminary report. , 2004, Diabetes care.

[72]  M. Hanefeld,et al.  Long-term efficacy and tolerability of add-on pioglitazone therapy to failing monotherapy compared with addition of gliclazide or metformin in patients with type 2 diabetes , 2005, Diabetologia.

[73]  Erland Erdmann,et al.  Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial , 2005, The Lancet.

[74]  R. DeFronzo,et al.  Dose-response effect of elevated plasma free fatty acid on insulin signaling. , 2005, Diabetes.

[75]  H. Krumholz,et al.  Thiazolidinediones, Metformin, and Outcomes in Older Patients With Diabetes and Heart Failure: An Observational Study , 2005, Circulation.

[76]  R. Urquhart,et al.  Comparison of pioglitazone and gliclazide in sustaining glycemic control over 2 years in patients with type 2 diabetes. , 2005, Diabetes care.

[77]  M. Hanefeld,et al.  Long‐term therapy with addition of pioglitazone to metformin compared with the addition of gliclazide to metformin in patients with type 2 diabetes: a randomized, comparative study , 2005, Diabetes/metabolism research and reviews.

[78]  A. Baron,et al.  Exenatide (exendin-4) improves insulin sensitivity and {beta}-cell mass in insulin-resistant obese fa/fa Zucker rats independent of glycemia and body weight. , 2005, Endocrinology.

[79]  Giovanni Pacini,et al.  Improved meal-related beta-cell function and insulin sensitivity by the dipeptidyl peptidase-IV inhibitor vildagliptin in metformin-treated patients with type 2 diabetes over 1 year. , 2005, Diabetes care.

[80]  K. Petersen,et al.  Decreased Insulin-Stimulated ATP Synthesis and Phosphate Transport in Muscle of Insulin-Resistant Offspring of Type 2 Diabetic Parents , 2005, PLoS medicine.

[81]  Dennis D. Kim,et al.  Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus. , 2005, American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.

[82]  Alfonso T. Perez,et al.  A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. , 2005, Diabetes care.

[83]  B. Zinman,et al.  Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. , 2006, The New England journal of medicine.

[84]  Y. Miyazaki,et al.  The Effect of Pioglitazone on the Liver , 2006, Diabetes Care.

[85]  D. Wingate,et al.  Role and integration of mechanisms controlling gastric emptying , 1994, Digestive Diseases and Sciences.

[86]  J. Hardies,et al.  A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. , 2006, The New England journal of medicine.

[87]  D. Drucker,et al.  The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes , 2006, The Lancet.

[88]  R. Buckingham,et al.  Effect of various diuretic treatments on rosiglitazone-induced fluid retention. , 2006, Journal of the American Society of Nephrology : JASN.

[89]  M. Hanefeld,et al.  Glycemic control and treatment failure with pioglitazone versus glibenclamide in type 2 diabetes mellitus: a 42-month, open-label, observational, primary care study* , 2006, Current medical research and opinion.

[90]  M. Nauck,et al.  Reduced incretin effect in Type 2 (non-insulin-dependent) diabetes , 2006, Diabetologia.

[91]  S. Haffner,et al.  Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial. , 2006, JAMA.

[92]  J. Rosenstock,et al.  Effect of early addition of rosiglitazone to sulphonylurea therapy in older type 2 diabetes patients (>60 years): the Rosiglitazone Early vs. SULphonylurea Titration (RESULT) study , 2006, Diabetes, obesity & metabolism.

[93]  R. DeFronzo,et al.  Insulin Secretion and Action in Subjects With Impaired Fasting Glucose and Impaired Glucose Tolerance , 2006, Diabetes.

[94]  M. Matsuda,et al.  Thiazolidinediones improve beta-cell function in type 2 diabetic patients. , 2007, American journal of physiology. Endocrinology and metabolism.

[95]  M. Hanefeld,et al.  Anti-inflammatory effects of pioglitazone and/or simvastatin in high cardiovascular risk patients with elevated high sensitivity C-reactive protein: the PIOSTAT Study. , 2007, Journal of the American College of Cardiology.

[96]  M. Massi-Benedetti,et al.  PROactive 06: cost‐effectiveness of pioglitazone in Type 2 diabetes in the UK , 2007, Diabetic medicine : a journal of the British Diabetic Association.

[97]  C. Deacon.  Incretin‐based treatment of type 2 diabetes: glucagon‐like peptide‐1 receptor agonists and dipeptidyl peptidase‐4 inhibitors * , 2007, Diabetes, obesity & metabolism.

[98]  S. Nissen,et al.  Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. , 2007, The New England journal of medicine.

[99]  R. DeFronzo,et al.  Relationship between vascular reactivity and lipids in Mexican-Americans with type 2 diabetes treated with pioglitazone. , 2007, The Journal of clinical endocrinology and metabolism.

[100]  A. Lincoff,et al.  Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. , 2007, JAMA.

[101]  D. Kassel,et al.  Discovery of alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV. , 2007, Journal of medicinal chemistry.

[102]  M. Falagas,et al.  Effect of thiazolidinedione therapy on restenosis after coronary stent implantation: a meta-analysis of randomized controlled trials. , 2007, American heart journal.

[103]  M. Hanefeld,et al.  Rosiglitazone RECORD study: glucose control outcomes at 18 months , 2007, Diabetic medicine : a journal of the British Diabetic Association.

[104]  K. Takeuchi,et al.  Chronic administration of alogliptin, a novel, potent, and highly selective dipeptidyl peptidase-4 inhibitor, improves glycemic control and beta-cell function in obese diabetic ob/ob mice. , 2008, European journal of pharmacology.

[105]  D. Klonoff,et al.  Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. , 2008, Current medical research and opinion.

[106]  E. Tuzcu,et al.  Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. , 2008, JAMA.

[107]  R. DeFronzo,et al.  Effects of exenatide versus sitagliptin on postprandial glucose, insulin and glucagon secretion, gastric emptying, and caloric intake: a randomized, cross-over study. , 2008, Current medical research and opinion.

[108]  Q. Mekki,et al.  Pharmacokinetic, pharmacodynamic, and tolerability profiles of the dipeptidyl peptidase-4 inhibitor alogliptin: a randomized, double-blind, placebo-controlled, multiple-dose study in adult patients with type 2 diabetes. , 2008, Clinical therapeutics.

[109]  Y. Miyazaki,et al.  Rosiglitazone and pioglitazone similarly improve insulin sensitivity and secretion, glucose tolerance and adipocytokines in type 2 diabetic patients , 2008, Diabetes, obesity & metabolism.

[110]  R. DeFronzo,et al.  Efficacy and Safety of the Dipeptidyl Peptidase-4 Inhibitor Alogliptin in Patients With Type 2 Diabetes and Inadequate Glycemic Control , 2008, Diabetes Care.

[111]  C. Cobelli,et al.  Effect of sitagliptin, a dipeptidyl peptidase‐4 inhibitor, on beta‐cell function in patients with type 2 diabetes: a model‐based approach , 2008, Diabetes, obesity & metabolism.

[112]  J. Rosenstock,et al.  Alogliptin added to insulin therapy in patients with type 2 diabetes reduces HbA1c without causing weight gain or increased hypoglycaemia , 2009, Diabetes, obesity & metabolism.

[113]  G. Bray,et al.  Determinants of glucose tolerance in impaired glucose tolerance at baseline in the Actos Now for Prevention of Diabetes (ACT NOW) study , 2010, Diabetologia.

[114]  P. Sham,et al.  Diabetes prevalence and therapeutic target achievement in the United States, 1999 to 2006. , 2009, The American journal of medicine.

[115]  R. Pratley,et al.  Efficacy and safety of the dipeptidyl peptidase‐4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapy , 2009, Diabetes, obesity & metabolism.

[116]  Q. Mekki,et al.  Coadministration of Pioglitazone or Glyburide and Alogliptin: Pharmacokinetic Drug Interaction Assessment in Healthy Participants , 2009, Journal of clinical pharmacology.

[117]  Devjit Tripathy,et al.  Actos Now for the prevention of diabetes (ACT NOW) study , 2009, BMC endocrine disorders.

[118]  K. Takeuchi,et al.  A novel dipeptidyl peptidase-4 inhibitor, alogliptin (SYR-322), is effective in diabetic rats with sulfonylurea-induced secondary failure. , 2009, Life sciences.

[119]  R. Pratley,et al.  Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study , 2009, Current medical research and opinion.

[120]  M. Taskinen,et al.  One-Year Treatment With Exenatide Improves β-Cell Function, Compared With Insulin Glargine, in Metformin-Treated Type 2 Diabetic Patients , 2009, Diabetes Care.

[121]  Ralph A. DeFronzo,et al.  From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus , 2009, Diabetes.

[122]  S. Kaul,et al.  Thiazolidinedione drugs and cardiovascular risks: a science advisory from the American Heart Association and American College Of Cardiology Foundation. , 2010, Journal of the American College of Cardiology.

[123]  Q. Mekki,et al.  Pharmacokinetics of alogliptin when administered with food, metformin, or cimetidine: a two-phase, crossover study in healthy subjects. , 2010, International journal of clinical pharmacology and therapeutics.

[124]  S. Kaul,et al.  Thiazolidinedione drugs and cardiovascular risks: a science advisory from the American Heart Association and American College of Cardiology Foundation. , 2010, Circulation.

[125]  R. DeFronzo.  Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009 , 2010, Diabetologia.

[126]  K. Bestehorn,et al.  Vascular Health and Risk Management , 2022 .