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Pioglitazone

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  • Slide 2-4 Plasma Insulin After Oral Glucose: Effects of Obesity and Diabetes Following a glucose challenge after overnight fasting, plasma insulin levels are dependent upon obesity as well as diabetes. Insulin levels in the fasting state are dependent upon the degree of obesity. Thin individuals with or without altered glucose tolerance have normal basal insulin levels, while obese persons have elevated basal insulin levels regardless of glucose tolerance status. After a glucose challenge, both thin and obese individuals with type 2 diabetes demonstrate reduced early insulin responses when compared with their respective control groups. However, obese individuals with type 2 diabetes have higher post-glucose insulin levels than do thin individuals with normal glucose tolerance, thus demonstrating the persistence of the effect of obesity on insulin secretion. Bagdade JD, Bierman EL, Porte D Jr. The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest . 1967;46: 1549-1557.
  • Slide 2-4 Plasma Insulin After Oral Glucose: Effects of Obesity and Diabetes Following a glucose challenge after overnight fasting, plasma insulin levels are dependent upon obesity as well as diabetes. Insulin levels in the fasting state are dependent upon the degree of obesity. Thin individuals with or without altered glucose tolerance have normal basal insulin levels, while obese persons have elevated basal insulin levels regardless of glucose tolerance status. After a glucose challenge, both thin and obese individuals with type 2 diabetes demonstrate reduced early insulin responses when compared with their respective control groups. However, obese individuals with type 2 diabetes have higher post-glucose insulin levels than do thin individuals with normal glucose tolerance, thus demonstrating the persistence of the effect of obesity on insulin secretion. Bagdade JD, Bierman EL, Porte D Jr. The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest . 1967;46: 1549-1557.
  • Slide 2-4 Plasma Insulin After Oral Glucose: Effects of Obesity and Diabetes Following a glucose challenge after overnight fasting, plasma insulin levels are dependent upon obesity as well as diabetes. Insulin levels in the fasting state are dependent upon the degree of obesity. Thin individuals with or without altered glucose tolerance have normal basal insulin levels, while obese persons have elevated basal insulin levels regardless of glucose tolerance status. After a glucose challenge, both thin and obese individuals with type 2 diabetes demonstrate reduced early insulin responses when compared with their respective control groups. However, obese individuals with type 2 diabetes have higher post-glucose insulin levels than do thin individuals with normal glucose tolerance, thus demonstrating the persistence of the effect of obesity on insulin secretion. Bagdade JD, Bierman EL, Porte D Jr. The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest . 1967;46: 1549-1557.
  • Slide 2-4 Plasma Insulin After Oral Glucose: Effects of Obesity and Diabetes Following a glucose challenge after overnight fasting, plasma insulin levels are dependent upon obesity as well as diabetes. Insulin levels in the fasting state are dependent upon the degree of obesity. Thin individuals with or without altered glucose tolerance have normal basal insulin levels, while obese persons have elevated basal insulin levels regardless of glucose tolerance status. After a glucose challenge, both thin and obese individuals with type 2 diabetes demonstrate reduced early insulin responses when compared with their respective control groups. However, obese individuals with type 2 diabetes have higher post-glucose insulin levels than do thin individuals with normal glucose tolerance, thus demonstrating the persistence of the effect of obesity on insulin secretion. Bagdade JD, Bierman EL, Porte D Jr. The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest . 1967;46: 1549-1557.
  • Slide 2-4 Plasma Insulin After Oral Glucose: Effects of Obesity and Diabetes Following a glucose challenge after overnight fasting, plasma insulin levels are dependent upon obesity as well as diabetes. Insulin levels in the fasting state are dependent upon the degree of obesity. Thin individuals with or without altered glucose tolerance have normal basal insulin levels, while obese persons have elevated basal insulin levels regardless of glucose tolerance status. After a glucose challenge, both thin and obese individuals with type 2 diabetes demonstrate reduced early insulin responses when compared with their respective control groups. However, obese individuals with type 2 diabetes have higher post-glucose insulin levels than do thin individuals with normal glucose tolerance, thus demonstrating the persistence of the effect of obesity on insulin secretion. Bagdade JD, Bierman EL, Porte D Jr. The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest . 1967;46: 1549-1557.
  • Slide 2-4 Plasma Insulin After Oral Glucose: Effects of Obesity and Diabetes Following a glucose challenge after overnight fasting, plasma insulin levels are dependent upon obesity as well as diabetes. Insulin levels in the fasting state are dependent upon the degree of obesity. Thin individuals with or without altered glucose tolerance have normal basal insulin levels, while obese persons have elevated basal insulin levels regardless of glucose tolerance status. After a glucose challenge, both thin and obese individuals with type 2 diabetes demonstrate reduced early insulin responses when compared with their respective control groups. However, obese individuals with type 2 diabetes have higher post-glucose insulin levels than do thin individuals with normal glucose tolerance, thus demonstrating the persistence of the effect of obesity on insulin secretion. Bagdade JD, Bierman EL, Porte D Jr. The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest . 1967;46: 1549-1557.
  • Slide 2-4 Plasma Insulin After Oral Glucose: Effects of Obesity and Diabetes Following a glucose challenge after overnight fasting, plasma insulin levels are dependent upon obesity as well as diabetes. Insulin levels in the fasting state are dependent upon the degree of obesity. Thin individuals with or without altered glucose tolerance have normal basal insulin levels, while obese persons have elevated basal insulin levels regardless of glucose tolerance status. After a glucose challenge, both thin and obese individuals with type 2 diabetes demonstrate reduced early insulin responses when compared with their respective control groups. However, obese individuals with type 2 diabetes have higher post-glucose insulin levels than do thin individuals with normal glucose tolerance, thus demonstrating the persistence of the effect of obesity on insulin secretion. Bagdade JD, Bierman EL, Porte D Jr. The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest . 1967;46: 1549-1557.

Pioglitazone Pioglitazone Presentation Transcript

  • Emerging trends in the therapy of DM Better clarity, Better outcomes Dr. B. K. Iyer
  • Diabetes – evolving status as of today Stem cell therapy Therapy based on Glucokinase Therapy based on GLP1 [EXENATIDE] Insulin sensitizers Insulins & OHAs Inhaled insulins Bariatric Surgery Therapy based on Amylin [PRAMILINTIDE] The growing epidemic of type 2 diabetes is prompting the need for a lot of of new therapies
  • Diabetes – evolving understanding today
    • But, the main problem in diabetic patients is - an increased level of blood glucose,
    Free Radicals in Biology and Medcine, J. R. Pffafly, Spring 2001.
    • Poor circulation,
    • Platelet adhesion / aggregation
    • Atherosclerotic heart disease,
    • Renal / Ocular problems
    Formation of free radicals All contributing to diabetic complications Not always be due to lack of insulin but due to lack of effective insulin action This increased glucose level, in majority of diabetics gives rise to Formation of advanced glycation end products (AGE )
  • Diabetes – evolving therapies today Insulin sensitizers, thus, play a key role in the therapy of diabetes, since they not only help to tackle insulin resistance but also manage the components of metabolic syndrome. Hence, insulin sensitization is the key to effective insulin action
  • Diabetes – roadmap of today What we know What we may not know What we need to know
    • IR
    • Metabolic Syndrome
    • PPAR receptors
    • The close link of CAD & diabetes
    • The many facets of pioglitazone
    Add- vantage of pioglitazone over rosiglitazone Today’s review
  • What Is Known?
  • Insulin Resistance [IR]
    • Concept of insulin resistance [IR] is not new but more than 50 yrs old.
    • In IR, abnormally large amounts of exogenous and endogenous insulin is required for normal biologic response.
    • IR is suggested by fasting insulin concentrations of > than 15 micro U/ml. [?]
    • IR leads to:
      • Clinical manifestations and
      • Biochemical abnormalities.
  • Insulin Resistance: Manifestations Hypertension, Atherosclerosis, POS Disturbed glucose tolerance Acanthosis Nigricans, Central obesity. Clinical manifestations Dyslipidaemia Glucose intolerance Biochemical abnormalities Vascular abnormalities High TG, Low HDL-C; Small, dense LDL Insulin resistance, Hyperinsulinaemia Abnormal thrombolysis, ED & VSC dysfunction INSULIN RESISTANCE
  • Metabolic Syndrome – what is it?
    • Complex interrelationship of metabolic abnormalities = Metabolic Syndrome
    Hyperinsulinaemia Central obesity Glucose intolerance Dyslipidaemia Hypertension associated with an increased risk of atherosclerotic cardiovascular disease
    • Pro-inflammatory state (  C-reactive protein)
    • Pro-coagulant changes (  fibrinogen and  plasminogen activated inhibitor-1)
    • Premature atherosclerosis
  • Metabolic Syndrome – clinical identification Fasting Glucose Waist circumference Triglycerides HDL - C Hypertension >110 mg/dL (>6.1 mmol/L) Men = >94 cm (>36.7 in) Women = >80 cm (>31.2 in) >150 mg/dL (>1.69 mmol/L) Men = <40 mg/dL (<1.03 mmol/L) Women = <50 mg/dL (<1.29 mmol/L) >130/>85 mm Hg.
    • Metabolic syndrome usually diagnosed when 3 or more of these risk factors are present.
    • Recently changes to the International Diabetes Federation consensus worldwide definition of the metabolic syndrome = central obesity + any 2 of the other 4 factors .
  • Insulin Resistance: Mechanisms
    • Pre receptor
      • (abnormal insulin or insulin antibodies)
    • Receptor
      • (decreased receptor number or affinity)
    • Glucose transporter
      • (decreased GLUT 4 molecule)
    • Post-receptor
      • (abnormal signal transduction & phosphorylation)
  • Insulin Resistance: Cellular
    • 2 major signalling pathways occur in the cell in response to insulin binding to receptor.
    Defect in this signalling pathway regulates the cycling or translocation of GLUT4 [glucose transporter subtype 4]
    • PI3K [phosphatidylinositol-3’-kinase] pathway; &
    • MAP [mitogen-activated protein] kinase pathway
  • Insulin Resistance: pathway effects
    • Under normal conditions, insulin is antiatherogenic via the PI-3 kinase pathway in VSMC & endothelial cells:
      • Stimulates NO production and thereby
      • antagonises the effects of VEGF on expression of adhesion molecules;
  • Insulin Resistance: pathway effects
    • In insulin resistance, there is inhibition of PI-3 kinase activity, but insulin will continue its unimpaired Erk MAP kinase signalling.
    • Via the unimpaired MAP kinase pathway, Insulin is no longer antiatherogenic but contributes to create pro-atherogenic environment.
  • Insulin Resistance: pathway effects
  • IR: common clinical manifestation
    • IR is present in more than 90% of patients with ACANTHOSIS NIGRICANS [AN] and hence [AN] is a said to be a clinical marker of IR;
    • The postulated mechanism mediating the association of insulin resistance with AN is that -
      • Hyperinsulinemia leads to binding of insulin to insulin-like growth factor receptors on keratinocytes and fibroblasts, with resultant hyperplasia of the skin.
  • IR and AN “ Velvety, mossy, verrucous, hyperpigmented skin change often found over the nape of the neck, in the axillae or beneath the breasts.”
  • IR and AN more than 90% of patients with IR 21% of diabetic patients 55% of obese patients ?? % of obese, diabetic patients Microscopic acanthosis nigricans in type 2 diabetes, j Cutan med Surg 2001 sep-Oct;5(5):390-3 by manus RM, Gottschalk R, Alanen K, Shum DT, Grundy P I Packianathan, O Stevenson & N finer , Centre for obesity research, Luton and Dunstable hospital NHS trust, Luton, UK, diabetes care 1999 Oct 22 (10) : 1655-9 Studies have revealed that AN is present in
  • IR and dyslipidaemia Elevated Triglycerides Reduced HDL- cholesterol Normal or Slightly elevated LDL – C
    • IR impairs the normal suppression of FFA release from adipose tissue in the PP state.
    • IR impairs insulin mediated skeletal muscle uptake of FFAs;
    • Increased FFA release from abdominal adipose tissue and delivery to the liver by portal circulation offers  hepatic secretion of large triglyceride-rich VLDL.
    • IR downregulates the activity of Lipoprotein lipase, an enzyme important for VLDL - C metabolism.
    • Reduced LDL receptor affinity and susceptibility to oxidation
    Characteristic lipid abnormality in IR is Small dense LDL particles
  • IR and Obesity
    • Distribution of body fat has great prognostic significance.
    • Abdominal obesity is a better predictor of IR, DM, IGT.
    • Waist-to-Hip Ratio is vital
      • > 94 cms. for males
      • > 80 cms. for females
  • IR and hypertension Direct vasodilator Increases sympathetic outflow Increases renal sodium reabsorption Counter the vasodilatory effects and result in elevations of BP in the IR individuals Insulin VSMC hypertrophy Endothelial dysfunction &  production of NO Thus, IR Increases chances of atherogenesis & CAD Insulin resistance
  • The approach to tackle IR
  • Insulin resistance - management
    • Insulin resistance can be managed by employing the following approaches:
      • Lifestyle modifications
      • Metformin
      • Thiazolidinediones
      • ACE Inhibitors
    Thiazolidinediones constitute the most effective way by their action on PPARs.
  • PPAR receptors
    • Peroxisome proliferator-activated receptors (PPARS) are ligand activated transcription factors (members of the nuclear receptor family) that are the molecular target of the Thiazolidinediones [TZDs];
    • PPARs heterodimerize with the retinoid X receptor and modulate the function of many target genes.
    • 3 PPARs are known:
      •  ,  , and  .
  • PPARs - Peroxisome proliferator-activated receptors
    • The better known are PPAR-   and PPAR-  .
    • Both have been shown to be present in variable amounts in cardiovascular tissues including:
      • Endothelium,
      • Vascular smooth muscle cells,
      • Macrophages, and the
      • Heart.
  • PPARs - Peroxisome proliferator-activated receptors
    • PPAR-  is involved in fatty acid oxidation & found in liver, kidney, and skeletal muscle;
    • PPAR-  is mainly expressed in the adipocyte and is involved in fat cell differentiation, lipid storage, and insulin sensitivity.
    • Activation of PPAR-  induces adipocyte genes responsible for:
      • Lipoprotein Lipase, adipocyte FABP, fatty acyl-CoA synthase, malic enzyme, glucokinase,
      • GLUT4 transporter protein & fatty acid transporter.
  • PPAR receptors and cholesterol
  • PPARs and Thiazolidinediones Action on PPAR  Action on PPAR  Impacts glucose metabolism mainly Thiazolidinediones [TZDs] are insulin sensitizing compounds that  insulin resistance and enhance the biological response to endogenously produced insulin. Affects lipid metabolism mainly
    • Thus, thiazolidinediones [TZDs] exert effects on muscle / liver cells to  insulin sensitivity & ↓ plasma glucose.
    • TZDs  lipogenesis in adipocyte thus lowering serum FFA and TG levels.
    • TZDs  subcutaneous adipose tissue mass and body weight.
    Saltiel & Olefsky. Diabetes 1996;45:1661–9
  • Thiazolidinediones and their role
  • Thiazolidinediones and their role
  • Thiazolidinediones and their role
  • What May Be Unknown? What is the new thiazolidinedione - Pioglitazone?
  • Pioglitazone - introduction
    • Relatively newer insulin sensitizer or thiazolidinedione that specifically reduces insulin resistance in type 2 diabetes;
    • is an add-on oral, once-daily therapy to metformin and sulphonylurea therapy
    • improves and maintains glycaemic control in patients with type 2 diabetes and is also atheroprotective over the long-term.
    • has additional favourable lipid effects in dyslipidaemic patients (  TG,  HDL-C,  LDL-C)
  • Pioglitazone – Mechanism of action
  • Pioglitazone - Pharmacokinetics
    • Rapidly & completely absorbed and measurable in serum within 30 mts., with Cmax observed < 2 hrs.
    • Food slightly delays Tmax to 3 - 4 hours, but does not alter the extent of absorption.
    • Pioglitazone is extensively protein bound (>99%) in human serum, principally to serum albumin.
    • Extensively metabolized by hydroxylation and oxidation.
    • Metabolites are pharmacologically active.
    • Steady state concentrations reached within 7 days.
  • Pioglitazone – Caution
    • No known drug interactions
    • No adequate studies in pregnancy and lactation .
    • Not evaluated adequately in patients on OCPs;
    • Contraindicated for use:
    • in patients with hepatic impairment,
    • in patients with cardiac failure (NYHA I-IV cardiac status) ,
    • in patients with known hypersensitivity to pioglitazone.
  • Pioglitazone – The little known facts Pioglitazone exhibits a characteristic delay of 4-12 weeks in the onset in response – due to their activity in the nucleus / fat redistribution. A major side effect is wt. gain due to  lipogenesis in adipose tissue which ↓ FFA levels &  subcutaneous adipose tissue mass and body wt. [2-3 Kg. for every 1% decrease in HbA1C]. Unlike Rosiglitazone, which produces inactive metabolites, the metabolites of pioglitazone are active Another side effect of pioglitazone is fluid retention and plasma volume expansion, affecting the hematocrit -> dilutional anemia [Pedal edema in 4-6% of patients].
    • With pioglitazone, there is altered transcription of lipogenic and lipid storage genes such as
    • PEPCK-C – enzyme critical for glyceroneogenesis;
    • CAP – important component required for GLUT-4 translocation
  • Pioglitazone – what needs to be known?
    • The significant benefits of pioglitazone
    • Pioglitazone has proven characteristics:
    • Targets insulin resistance, a core defect; and improves glycemic control without causing hypoglycemia [except with SUs]
    • Improves lipid profile with good anti-atherogenic effects.
    • What are the other potential benefits of pioglitazone?
    • Pioglitazone provides other potential benefits:
    • Preservation of pancreatic beta-cell function
    • Prevention of progression from IGT to type 2 diabetes
    • Improvement in cardiovascular outcomes – How?
  • Pioglitazone –effects on cardiovascular risk factors Effect on lipids Effects on clotting factors
    • ↓ Triglycerides
    • Increased HDL
    • ↓ small, dense LDL
    • ↓ LDL oxidation
    Effects on vascular factors Effects on inflammation
    • ↓ Plasminogen activator inhibitor-1 (PAI-1) levels
    • ↓ Fibrinogen levels
    • ↓ Carotid intima-media thickness
    • ↓ PWV
     C-reactive protein levels
  • Studies on Pioglitazone
  • Pioglitazone studies
    • Anti-diabetic studies
      • Monotherapy of Pioglitazone vs. metformin
      • Combination therapy comparison of Pioglitazone + SU vs. Metformin + SU
      • Monotherapy of Pioglitazone vs. metformin vs. SU and their combinations - comparisons
    • Anti-atherogenic studies
      • Pioglitazone and cardiac risk factors
      • PROactive.
  • Pioglitazone vs. Metformin
  • Pioglitazone and Metformin on Glycemic Control and insulin sensitivity indicators
    • 205 patients were analysed in the first head to head double blind clinical trial in recently diagnosed type2 diabetes patients [naive to OHA therapy] comparing pioglitazone and metformin over a 32 week period
    Imre Pavo et al, The Journal of clinical endocrinology & metabolism, vol. 88: No. 4, 1637-1645, 2003 Subjects were randomized to either 30 mg. pioglitazone daily, or 850 mg. metformin daily titrations upward to 45 mg. [77% pioglitazone patients], or titrations upward to 2550 mg. [73% metformin patients] to achieve fasting glucose levels of 7.0 mmol/ liter [126 mg. / 100 ml.]
  • Pioglitazone and Metformin on Glycemic Control Imre Pavo et al, The Journal of clinical endocrinology & metabolism, vol. 88: No. 4, 1637-1645, 2003
    • Effects of pioglitazone and metformin treatment on:
    • glycosylated haemoglobin; and
    • fasting glucose levels
  • Pioglitazone and Metformin on insulin sensitivity indicators Imre Pavo et al, The Journal of clinical endocrinology & metabolism, vol. 88: No. 4, 1637-1645, 2003
    • Effects of pioglitazone and metformin treatment on:
    • Fasting serum insulin levels
    • HOMA- S [ homeostasis model assessment of insulin sensitivity ] levels [indicator of insulin sensitivity]
  • Pioglitazone and Metformin on Glycemic Control and insulin sensitivity indicators
    • At end point of 32 weeks [8 months]:
    Imre Pavo et al, The Journal of clinical endocrinology & metabolism, vol. 88: No. 4, 1637-1645, 2003
      • Pioglitazone and metformin had similar effects on glycaemic parameters like glycosylated haemoglobin and FPG levels, with pioglitazone being slightly better;
      • Pioglitazone was significantly more effective than metformin in improving indicators of insulin sensitivity, as determined by:
        •  fasting serum insulin concentration [6.2% decrease with pioglitazone as compared to metformin]; &
        •  in homeostasis model assessment of insulin sensitivity [HOMA-S] levels.
      • Pioglitazone treatment resulted in weight gain, whereas metformin treatment resulted in weight loss. [0.9% over 8 months, markedly lower than 5% average wt. gain]
  • Pioglitazone and Metformin on lipid levels
    • At end point of 32 weeks [8 months]:
    Imre Pavo et al, The Journal of clinical endocrinology & metabolism, vol. 88: No. 4, 1637-1645, 2003 A significant increase in was observed with pioglitazone but no significant change was observed with metformin. Effect on apolipoproteins Both therapies significantly reduced TG levels Effect on TG levels Total cholesterol was unchanged in the pioglitazone group but decreased significantly in the metformin group Effect on Total-C levels Decreased significantly in the metformin group compared with pioglitazone [PIOGLITAZONE - shift from small, dense LDL paricles to large LDL particles] Effect on LDL-C levels Significantly greater in the pioglitazone group compared with metformin Effect on HDL-C levels
  • Pioglitazone or Metformin added to existing SU therapy
  • Impact of Pioglitazone or Metformin existing SU therapy
    • 319 patients were analysed to assess the efficacy and safety of the addition of pioglitazone or metformin to existing SU therapy in patients with inadequately controlled diabetes over 60 weeks.
    Markolf Hanefeld et al, Diabetes Care, 27: 141-147, 2004 Subjects were randomized to either 15 mg. pioglitazone daily, or 850 mg. metformin daily titrations upward to 45 mg., or titrations upward to 2550 mg.
    • 2 groups
    • Pioglitazone + SU group
    • Metformin + SU group
  • Impact of Pioglitazone + SU vs. Metformin + SU therapy Markolf Hanefeld et al, Diabetes Care, 27: 141-147, 2004
    • Effects of pioglitazone+SU vs. metformin+SU treatment on:
    • glycosylated haemoglobin; and
    • fasting glucose levels
  • Impact of Pioglitazone + SU vs. Metformin + SU therapy Markolf Hanefeld et al, Diabetes Care, 27: 141-147, 2004
    • Effects of pioglitazone+SU vs. metformin+SU treatment on:
    • Triglycerides; and
    • HDL-cholesterol levels
  • Impact of Pioglitazone + SU vs. Metformin + SU therapy Markolf Hanefeld et al, Diabetes Care, 27: 141-147, 2004
    • Effects of pioglitazone+SU vs. metformin+SU treatment on:
    • LDL- Cholesterol ; and
    • Total cholesterol: HDL-C ratio
  • Impact of Pioglitazone + SU vs. Metformin + SU therapy Markolf Hanefeld et al, Diabetes Care, 27: 141-147, 2004
    • Effects of pioglitazone+SU vs. metformin+SU treatment on:
    • Albumin / creatinine ratio; and
    • Log TG: HDL-C ratio
  • Impact of Pioglitazone or Metformin on existing SU therapy
    • Although the effects of pioglitazone+SU and metformin+SU are more or less similar on HbA1c and FBG, it is the impact on other parameters that decide the prognosis of the patient in the long run;
    • On prolonged use, pioglitazone arrests the decline in beta-cell function perhaps by protecting the beta-cell from lipotoxicity.
    Imre Pavo et al, The Journal of clinical endocrinology & metabolism, vol. 88: No. 4, 1637-1645, 2003
  • Pioglitazone vs. Metformin vs. SU
  • Comparison of Effects of Pioglitazone with Metformin or SU & combination
    • 940 patients were analysed in 4 multicenter, randomized, double blind, double-dummy, parallel group clinical trials:
    Antonio Ceriello et al, Diabetes Care 28: 266-272, 2005
      • Pioglitazone versus metformin;
      • Pioglitazone versus gliclazide;
      • Pioglitazone + SU versus metformin + SU;
      • Pioglitazone + metformin versus metformin + SU.
  • Comparison of Pioglitazone with Metformin or SU & combination on CISI Antonio Ceriello et al, Diabetes Care 28: 266-272, 2005
  • Comparison of Effects of Pioglitazone with Metformin or SU & combination
    • In monotherapy trials of
      • Pioglitazone versus metformin;
      • Pioglitazone versus gliclazide;
    • Pioglitazone reduced postload glycaemia and enhanced CISI [ insulin sensitivity index] more than metformin and gliclazide;
    Antonio Ceriello et al, Diabetes Care 28: 266-272, 2005
  • Comparison of Effects of Pioglitazone with Metformin or SU & combination
    • In combination therapy trials of
      • Pioglitazone + SU, reduced postload glycaemia and increased CISI [composite insulin sensitivity index] more than metformin + SU;
      • Pioglitazone + metformin also reduced postload glycaemia and enhanced CISI [composite insulin sensitivity index] more than metformin and gliclazide;
    Antonio Ceriello et al, Diabetes Care 28: 266-272, 2005
  • Anti-inflammatory and Anti-atherogenic studies
  • Pioglitazone - impact on cardiovascular risk factors
    • Pioglitazone, by its effect on cardiovascular risk markers, shows that it has 2 additional vital effects:
      • Anti-inflammatory effect;
      • Anti-atherogenic effect
    • Improvement of cardiovascular risk markers by pioglitazone is independent from glycaemic control and may be attributed to PPAR-  activation in the vascular tissues; viz. Endothelium, Vascular smooth muscle cells, Macrophages, and the Heart
  • Anti-inflammatory and Anti-atherogenic studies Pioglitazone vs. Control
  • Pioglitazone & C-Reactive Protein (CRP)
    • 136 Japanese type 2 diabetic patients were divided into 2 groups for therapy of 3 months:
      • The pioglitazone group [70]; and
      • The untreated group [66 patients].
    • Changes in CRP and PWV were monitored to analyse the relationship between the antidiabetic and anti-atherogenic effects of pioglitazone.
    It was seen that CRP is significantly decreased in patients with type 2 diabetes, irrespective of their blood glucose response. Noriko Satohi et al, Diabetes Care 26, 9,: 2493-2499, 2003
  • Pioglitazone & pulse wave velocity [PWV]
    • Pulse wave velocity [PWV] is a direct parameter of arterial distensibility [reflection of advanced sclerotic changes and vascular stiffness] ;
    • Pulse wave velocity [PWV] is not only a marker of vascular changes but also a prognostic predictor of mortality in diabetes;
    • Hence, combined with other markers such as high-sensitivity CRP, PWV is a reliable marker for the evaluation of the anti-atherogenic effect of pioglitazone.
    Noriko Satohi et al, Diabetes Care 26, 9,: 2493-2499, 2003
  • Pioglitazone - Reduces PWV
    • PWV is significantly decreased by 3 months of pioglitazone therapy in patients with type 2 diabetes;
    • It is also well known that there is a good correlation between carotid arterial IMT and PWV in type 2 diabetic patients
    Noriko Satohi et al, Diabetes Care 26, 9,: 2493-2499, 2003
  • Anti-inflammatory and Anti-atherogenic studies Pioglitazone vs. SU
  • Pioglitazone - CRP, MMPs and IMT
    • 173 type 2 diabetic patients of duration 7.2  7.2 years were divided into 2 groups for therapy of 6 months:
      • The pioglitazone group [89]; and
      • The SU group [66 patients].
    • Changes in HOMAs, CRP, MMPs and carotid IMT were monitored to assess the anti-atherogenic effects of pioglitazone
    It was seen that CRP, MMPs and IMT were all significantly decreased in patients with type 2 diabetes, as compared to SU. Andreas Pfutzner et al, Journal of the American college of cardiology, 45,:1925-1931, 2005
  • Pioglitazone - Independent effects
    • Like the other trials, this study also showed that the anti-atherogenic effect of pioglitazone is independent of its metabolic / antidiabetic effects.
    • In addition, adiponectin levels were also increased by pioglitazone.
    Andreas Pfutzner et al, Journal of the American college of cardiology, 45,:1925-1931, 2005
  • Pioglitazone - HOMAs and IMT
    • HOMA-S levels were improved only in the pioglitazone group;
    Pioglitazone M.R. Langenfeld et al, Circulation, 2005: 2525
    • There was substantial regression of the Carotid IMT after 24 weeks of pioglitazone treatment.
    • All these findings are of important prognostic implications for the use of pioglitazone.
    HOMA-S levels Carotid IMT
  • Pioglitazone – significance of these markers
    • Despite all these studies, there in one important question!
    Andreas Pfutzner et al, Journal of the American college of cardiology, 45,:1925-1931, 2005
    • Can the findings of improvements in these surrogate cardiovascular markers actually translate into substantial clinical outcome improvements?
    • Answering this vital question is the trial called - Proactive - ( PRO spective A ctos C linical T rial I n macro- V ascular E vents) in which 5328 High-risk type 2 diabetic patients with a history of macrovascular events have been monitored for 3 years for various primary and secondary endpoints.
    • Multicentric - 321 centers in 19 European countries.
  • PROactive - ( PRO spective A ctos C linical T rial I n macro- V ascular E vents)
  • Proactive - ( PRO spective A ctos C linical T rial I n macro- V ascular E vents)
    • High-risk patients with a history of macrovascular events were reviewed for baseline lipids, glycaemia and blood pressure to confirm inclusion selection criteria in PROactive.
    • They were then analysed in a randomised, placebo-controlled outcome study to assess whether pioglitazone significantly reduces the number of macrovascular events.
    • Patients were given pioglitazone (15 mg/day increasing to a maximum dose of 45 mg/day) or placebo as add-on therapy to their existing diabetic management, which was optimised throughout the study according to the International Diabetes Federation (Europe) Guidelines.
  • Proactive - ( PRO spective A ctos C linical T rial I n macro- V ascular E vents)
    • Patients were assessed every 2 months for 3 years for:
      • all-cause mortality,
      • non-fatal myocardial infarction,
      • stroke,
      • acute coronary syndrome,
      • cardiac intervention [including CABG or percutaneous coronary intervention],
      • major leg amputation, etc.
  • Proactive - ( PRO spective A ctos C linical T rial I n macro- V ascular E vents)
    • The completed data study was presented at the 41st Annual Meeting of the European Association for the Study of Diabetes (EASD), 10-15 September 2005
    A primary combination endpoint of the different macrovascular events of varying clinical importance A principal secondary combination endpoint of the most serious events, namely death, stroke and heart attack The primary combination endpoint was reduced by 10% The results focused on 2 key endpoints The principal secondary combination endpoint was reduced by 16%
  • Proactive - ( PRO spective A ctos C linical T rial I n macro- V ascular E vents)
    • Other secondary endpoints observed were the individual components of the primary endpoint.
    A significant reduction in HbA1c levels compared with best available care A significant improvement in diabetic dyslipidaemia with Additional PROactive results with pioglitazone showed
    •  in HDL cholesterol (9% more than best available care) &
    •  in triglycerides (by 13% more than best available care)
    A significant improvement in the LDL/HDL cholesterol ratio with 2%  in LDL-C compared with the best available care) A significant reduction in the systolic blood pressure with Median reduction of 3 mm Hg. compared with best available care
  • Proactive - ( PRO spective A ctos C linical T rial I n macro- V ascular E vents)
    • In conclusion:
    Pioglitazone significantly improves cardiovascular outcomes by helping to delay or reduce heart attacks, strokes or death in high-risk patients in addition to helping to tackle insulin resistance Pioglitazone gives new hope to people with Type 2 diabetes who, despite their attempt to control blood glucose and take medications, risk these life-threatening events.
  • Pioglitazone - Summary Tackles insulin resistance Inhibits Resistin Reduces inflammatory mechanisms Anti-atherosclerotic effect and beta-cell preservation
    •  glycation & AGE formation;
    •  insulin resistance
    •  Adiponectin levels
    •  CRP levels
    •  adhesion of monocytes to endothelium
    •  platelet aggregation
    •  secretion of TNF-  from macrophages
    The atheroprotective insulin receptor sensitizer
    •  Insulin receptor expression in adipocytes and hepatocytes
    •  expression of GLUT4
    •  intima- media thickness of carotid artery
    •  small, dense LDL.
    •  accelerated  cell apoptosis.
  • Pioglitazone - Summary Powers insulin Improves Lipids Confronts challenges of cardiovascular risks Prevents complications The Superior insulin receptor sensitizer Doubly benefits diabetics Reduces small, dense LDL LDL Min. +12.8% HDL Min. -10.1% TG Result Lipid
  • What Needs to Be Known? What is different about Pioglitazone as compared to Rosiglitazone?
  • Second Generation thiazolidinediones – what is known? Yes No Active metabolites 24 16-24 Duration of action High 4 15 / 30 Pioglitazone Low 3 2 / 4 Rosiglitazone Activity on PPAR-  Plasma Peak Doses [mg.] Thiazolidinediones
  • Rosi vs. Pio study A Comparison of Lipid and Glycemic Effects of Pioglitazone and Rosiglitazone in Patients With Type 2 Diabetes and Dyslipidemia [Diabetes Care. 2005;28(7): 1547-1554.
  • Rosi vs. Pio study A Comparison of Lipid and Glycemic Effects of Pioglitazone and Rosiglitazone in Patients With Type 2 Diabetes and Dyslipidemia [Diabetes Care. 2005;28(7): 1547-1554.    
  • Rosi vs. Pio study A Comparison of Lipid and Glycemic Effects of Pioglitazone and Rosiglitazone in Patients With Type 2 Diabetes and Dyslipidemia [Diabetes Care. 2005;28(7): 1547-1554.
  • Rosi vs. Pio study Data presented at the American Heart Association’s 2004 scientific session in New Orleans by Ronald Goldberg, University of Miami school of medicine. Rosiglitazone [% changes] Pioglitazone [% changes] LDL- Cholesterol [Mg. ‘ dl.] HDL-cholesterol [Mg. / dl.] Triglycerides [Mg./ dl.] +23.3% +13.7% +7.8% +14.9% +14.0% -12.0% Week 24 changes from baseline
  • Rosi vs. Pio in dyslipidaemia   
  • How does all this affect our knowledge? Which of the 2 currently available thiazolidinediones is the better option? 2 vital questions on Thiazolidinediones Is there a role for thiazolidinedione in regular therapy of diabetes Multi-point fuel injection Carburretor
  • How does all this affect our knowledge? Is there a role for thiazolidinedione in regular therapy of diabetes Which of the 2 currently available thiazolidinediones is the better option? 2 questions with regard to Thiazolidinediones
    • Pioglitazone has dual mechanisms as an antidiabetic and alters disease progression:
      • Targets IR
      • Targets beta-cell function early.
    • Pioglitazone is an insulin sensitizer that functions as:
      • Antidiabetic
      • Antiatherogenic.
    • Rosiglitazone seems to be a pure PPAR  agonist.
    • Pioglitazone seems to act like a partial PPAR  agonist in addition to its PPAR  activity
    Pioglitazone the better Thiazolidinedione - Why? Action on Hba1c Impact on lipid parameters Improvement In FBS, PPBG Impact on Insulin Levels [FSI & HOMA-S] Increased Adiponectinaemia Action on blood pressure Impact on Cardiovascular Risk factors Impact on CRP and PWV Impact on carotid Intima Media Thickness Lesser risks of atherosclerosis
  • Pionorm - the better Thiazolidinedione – Action on Hba1c Impact on lipid parameters Improvement In FBS, PPBG Impact on Insulin Levels [FSI & HOMA-S] Increased Adiponectinaemia Action on blood pressure Impact on Cardiovascular Risk factors Impact on CRP and PWV Impact on carotid Intima Media Thickness Lesser risks of atherosclerosis New drugs like Muraglitazar and tesaglitazar, non-TZD drugs that inhibit the PPAR-  & -  receptors, are in late stage clinical trials and appear to have greater effect in reducing CV risk factors
  • Indications
    • Early Stages
      • Monotherapy for patients who have problems in OGTT or who are newly diagnosed and are failing non-pharmacologic therapies (diet and exercise).
    • Middle Stages
      • Combination therapy with other oral agents such as sulfonylurea and metformin when they show inadequate glycaemic control;
    • Late Stages
      • Combination therapy with insulin
    • Pioglitazone may be of greater use to:
    • Patients with metabolic syndrome,
    • Patients with diabetes and cardiovascular risk factors,
    • Patients with diabetes and known CAD episode.