1. Insulin Toxicity in Type 2 Diabetes
From:

2. How to Cure Type 2 Diabetes
“In individuals, insanity is rare; but in groups, parties, nations and epochs, it is the rule.” ― Friedrich Nietzsche

3. 33
It is Hard to Treat T2DM Adequately… Because T2DM is a Progressive Disease
ADOPT
8.0
7.6
Treatment difference (95% CI)
Rosiglitazone vs. metformin, 0.13 (0.22 to 0.05); p = 0.002
Rosiglitazone vs. glyburide, 0.42 (0.50 to 0.33); p < 0.001
7.2
A1C (%)
6.8
6.4
Annual curve (95% CI)
The data are from ADOPT , a double-blind, randomized, controlled trial designed to investigate the efficacy of rosiglitazone, as compared with other oral glucose-lowering medications, in maintaining long-term glycemic control in patients with recently diagnosed type 2 diabetes.
Rosiglitazone, metformin, and glyburide were evaluated as initial treatment in patients (n = 4,360) treated for a median of 4.0 years. Kahn SE, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006; 355:
Rosiglitazone, 0.07 (0.06 to 0.09)
Metformin, 0.14 (0.13 to 0.16)a
Glyburide, 0.24 (0.23 to 0.26)a
6.0 1 2 3 4 5
Time (years)
No. of patients
4012
3308
2991
2583
2197
822
aRosiglitazone vs. other treatments.
Kahn SE et al. N Engl J Med 2006; 355:

4. 34
It is Hard to Treat T2DM Adequately… Because T2DM has Multiple Pathophysiologic Abnormalities
Decreased insulin secretion
Decreased incretin effect
Increased lipolysis
Increased glucagon secretion
Islet-α cell
Increased glucose reabsorption
Hyperglycemia
Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009; 58(4):
Increased hepatic glucose production
Neurotransmitter dysfunction
Decreased glucose uptake
DeFronzo R. Diabetes 2009; 58:

5. Diabetes Does not alter disease process Disease Cause Treatment
Symptom
Symptomatic Treatment
Diabetes
Insulin Resistance
????
?????
High Blood Sugars
Insulin
OHA
Infection
Bacteria
Antibiotic
Fever
Acetominophen
Does not alter
disease process

6. What causes Insulin Resistance?
Leads to high insulin
levels
How do we develop resistance in a biological system?

7. What causes resistance to antibiotics ?
What causes resistance to viruses?
Prolonged exposure to antibiotics
Prolonged exposure to viruses

8. What causes resistance to addictive drugs?
Nicotine
Nitroglycerin
Alcohol
Benzodiazepines
Narcotics
Cocaine
Marijuana
Prolonged exposure to addictive drugs

9. Down-regulation of Receptors
Ritalin (Methylphenidate)
Stimulant
Down-regulation
Of receptors
Reduced activity
In ADHD
High, persistent levels of hormone cause down-regulation of receptors

10. Reinforcing cycles of Resistance
Persistent Exposure
What causes antibiotic resistance?
Prolonged high level exposure to antibiotics
What causes drug resistance?
Prolonged high level exposure to drugs
What causes nicotine resistance?
Prolonged high level exposure to nicotine
What causes psycho-stimulant resistance?
Prolonged high level exposure to psycho-stimulants
Resistance
What causes Insulin Resistance?
Does Insulin cause Insulin Resistance?

11. Insulinomas Surgical resection of adenoma reverses insulin resistance
Diabetologia :294-5
Patients with insulinoma show
insulin resistance in the
absence of arterial hypertension
16 patients with insulinoma
Increasing insulin resistance
Surgical resection of adenoma reverses insulin resistance
J Endocrinol Invest 13:241–245, 1990

12. Insulin causes insulin resistance
40 hour insulin infusions
12 non obese subjects
Insulin Resistance
Production of insulin resistance by hyperinsulinemia in man Diabetologia 28:70 –75, 1985 Rizza RA

13. Insulin causes insulin resistance
“These results demonstrate that chronic, physiologic hyperinsulinemia … leads to the development of insulin resistance”
15 healthy young men started on physiologic euglycemic hyperinsulinemia
After 4 days glucose disposal decreased by 20-40%
P<0.001
Before and after
96h constant insulin infusion
Effect of sustained physiologic hyperinsulinemia and hyperglycemia on insulin secretion and insulin sensitivity in man
Diabetologia Oct1994, Vol37, Iss 10, Del Prato S

14. Insulin causes insulin resistance
Intensive Conventional Insulin Therapy for Type II Diabetes
Diabetes Care :23-31 Henry RR
Increasing insulin resistance!
8.7 kg weight gain!
14 DM2 patients given intensive glucose control over 6 months
100 units/ day at 6 months

15. High insulin secretion is primary
Non-obese
Non-obese
Does high insulin come first or insulin resistance?
Early Changes in Postprandial Insulin Secretion, not in Insulin Sensitivity Characterize Juvenile Obesity
Diabetes 43: ; 1994 Le Stunff C

16. High insulin secretion is primary
Increasing resistance with duration of obesity
Diabetes 43: ; 1994 Le Stunff C
Time Sequence of Juvenile Obesity
Increased
insulin
Insulin
Resistance
Genetics
Obesity

17. Pulsatile Release Prevents Tolerance
Endogenous Insulin
Cortisol, PTH, gonadotropins, growth hormone etc. also released in pulsatile fashion

18. Insulin causes diabetes!
Conclusions
Insulin causes insulin resistance
Insulin resistance causes hyperinsulinemia
Resistance requires high, persistent level
The Glycemic Index – Physiological Mechanisms Relating to Obesity, Diabetes, and Cardiovascular Disease
David Ludwig JAMA May 8, 2002 – Vol 287 No 18
Insulin causes diabetes!

19. Complications of Diabetes

20. Complications of Diabetes
Type 1 and 2 Diabetes
High Blood Sugars
(Oxidative Stress)
(Advance Glycation
End Products)
Problem is that this is simply NOT TRUE
Complications of Diabetes

21. ACCORD
Hazard Ratio 1.22
Randomized 10,251 diabetic patients to tight vs. less tight glycemic control
After 3.5 years, study stopped early due to increased deaths
27.8% of patients in aggressive group gained > 10 kg
Kaplan-Meier Curves for the Primary Outcome and Death from Any Cause
The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:

22. Cumulative Incidences of Events, According to Glucose-Control Strategy
ADVANCE
Figure 3. Cumulative Incidences of Events, According to Glucose-Control Strategy. The hazard ratios for intensive glucose control as compared with standard glucose control were as follows: for combined major macrovascular or microvascular events, 0.90 (95% confidence interval [CI], 0.82 to 0.98) (Panel A); for major macrovascular events, 0.94 (95% CI, 0.84 to 1.06) (Panel B); for major microvascular events, 0.86 (95% CI, 0.77 to 0.97) (Panel C); and for death from any cause, 0.93 (95% CI, 0.83 to 1.06) (Panel D). The vertical dashed lines indicate the 24-month and 48-month study visits, at which additional data on microvascular events were collected, specifically the ratio of urinary albumin to creatinine and results of a retinal examination. For events relating to these data, the event time was recorded as the date of the visit. The curves were truncated at month 66, by which time 99% of the events had occurred. The effects of treatment (hazard ratios and P values) were estimated from unadjusted Cox proportional-hazard models that used all the available data.
Randomized 11,140 diabetic patients to tight vs. less tight glycemic control
After 5 year follow up, no significant benefit on major macrovascular event or death
Cumulative Incidences of Events,
According to Glucose-Control Strategy
The ADVANCE Collaborative Group. N Engl J Med 2008;358:

23. What about hyperinsulinemia?
Type 2 Diabetes
Increased
Insulin
High Blood Sugars
Complications of Diabetes
Diabetes is disease of insulin resistance
Current treatment is directed at high blood sugars

24. Insulin treatment has toxicity
“significant and graded association between
mortality risk and insulin exposure level”
12,272 new diabetics Saskatchewan
Insulin use and increased risk of mortality in type 2 diabetes: a cohort study
Diabetes, Obesity and Metabolism 12: 47–53, 2010 Gamble JM

25. Insulin treatment has toxicity
in UK
84,622 incident Type 2 DM cases Hyperinsulinemia or insulin resistance?
Mortality and Other Important Diabetes-Related Outcomes With Insulin vs Other Antihyperglycemic Therapies in Type 2 Diabetes
J Clin Endocrinol Metab 98: 668–677, 2013 Currie CJ

26. Hyperinsulinemia
Increased adhesion molecule expression on endothelial cells
Increased trans-endothelial migration of leukocytes
Stimulation of smooth muscle cell proliferation
Pro-inflammatory effects

27. References
(1) Madonna R, De Caterina R. Prolonged exposure to high insulin impairs the endothelial PI3-kinase/Akt/nitric oxide signalling. Thromb Haemost 2009;101:345–50. (2) Okouchi M, Okayama N, Imai S, et al. High insulin enhances neutrophil transendothelial migration through increasing surface expression of platelet endothelial cell adhesion molecule-1 via activation of mitogen activated protein kinase. Diabetologia 2002;45:1449–56. (3) Pfeifle B, Ditschuneit H. Effect of insulin on growth of cultured human arterial smooth muscle cells. Diabetologia 1981;20:155–8. (4) Stout RW, Bierman EL, Ross R. Effect of insulin on the proliferation of cultured primate arterial smooth muscle cells. Circ Res 1975;36:319–27. (5) Iida KT, Shimano H, Kawakami Y, et al. Insulin up-regulates tumor necrosis factor-alpha production in macrophages through an extracellular-regulated kinase-dependent pathway. J Biol Chem 2001;276:32531–7.

28. Insulin receptor staining in human plaque
Endothelial insulin receptor expression in human atherosclerotic plaques: Linking micro- and macrovascular disease in diabetes?
Atherosclerosis 222 (2012) 208– 215, Rensing KL

29. Insulin stimulates angiogenesis
Insulin may stimulate angiogenesis within atherosclerotic plaques
In vitro angiogenic sprouting assay.
Endothelial insulin receptor expression in human atherosclerotic plaques: Linking micro- and macrovascular disease in diabetes? Atherosclerosis 222 (2012) 208– 215, Rensing KL

30. Insulin causes salt and water retention
“Elevation of plasma insulin concentration within the physiological range has a marked anti-natriuretic action”
Renal effect of insulin to increase sodium retention in the kidney
Parving H DIABETOLOGIA,Volume 32, Number 9 (1989), 

31. Insulin Toxicity in Diabetes
Basic science evidence suggests that insulin itself is a toxic agent

32. Low A1C is NOT good for you
Oral Combination
Insulin
UK General Practice Research Database
20,005 patients changed regimens to include insulin
Mean follow up 4.5 years
Adjusted Hazard Ratios by A1c
27,965 patients intensified from oral monotherapy to combination therapy
Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study
Lancet 2010; 375:481-89, Currie CJ

33. Low A1C is a risk factor
A1C and Cardiovascular Outcomes in Type 2 Diabetes
Diabetes Care 34:77–83, 2011, Colacayo et al
Nested case control study of 11,157 cases of DM2

34. Not the case in non-diabetics
11,092 patients in ARIC study
Glycated Hemoglobin, Diabetes, and Cardiovascular Risk in Nondiabetic Adults
N Engl J Med 2010;362:800-11, Selvin E

35. Metformin versus Sulfonylurea
Retrospective cohort study of 253,690 patients initiating treatment
(98,665 sulfonylurea and 155,025 with metformin)
Comparative Effectiveness of Sulfonylurea and Metformin Monotherapy on Cardiovascular Events in Type 2 Diabetes Mellitus
Ann Intern Med. 2012;157: Roumie CL

36. Metformin versus sulphonlyurea
40% increased risk of MI and death
using UK general practice research database
Retrospective cohort study 91,521 patients with DM
Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs Tzoulaki I. BMJ 2009; 339:b4731

37. Risk of Mortality: SU vs. Metformin57
A) Entire cohort
B) Subgroup w/ documented CAD 10 10
Survival probability
Survival probability
0.9
0.9
0.8
0.8
0.7
Metformin
Glimepiride
Glipizide
Glyburide
Metformin
Glimepiride
Glipizide
Glyburide
0.7
0.6
0.6
0.5 12 24 36 48 60 72 12 24 36 48 60 72
Months on study
Months on study
The purpose of this study was to assess the overall mortality risk of individual sulfonylureas vs. metformin in a large cohort of patients with type 2 diabetes. This was a retrospective cohort study involving the records of 23,915 patients with type 2 diabetes who initiated monotherapy with metformin (n = 12,774), glipizide (n = 4,325), glyburide (n = 4,279) or glimepiride (n = 2,537). Subjects were all at least 18 years of age, with and without a history of CAD, and not on insulin or a non-insulin injectable at baseline.
The primary outcome was all-cause mortality. An increase in overall mortality risk was observed in the entire cohort (left panel) with glipizide (HR 1.64; 95% CI ), glyburide (HR 1.59; 95% CI ), and glimepiride (HR 1.68; 95% CI ) vs. metformin. However, in patients with documented CAD (right panel), a statistically significant increase in overall mortality risk was only found with glipizide (HR 1.41; 95% CI ) and glyburide (HR 1.38; 95% CI ) vs. metformin.
It is important to note that since the patients were not randomly assigned to one therapy or the other, there may have been biases introduced in terms of which medications they were started on (i.e., perhaps sicker patients were not started on metformin).
Reference:
Pantalone KM, Kattan MW, Yu C, et al. Increase in overall mortality risk in patients with type 2 diabetes receiving glipizide, glyburide or glimepiride monotherapy versus metformin: a retrospective analysis. Diabetes Obes Metab 2012; 14(9):803-9.
Retrospective cohort study of 23,915 DM2 patients initiated with metformin or SU 40-60% increase risk of MI/ death
Pantalone KM, et al. Diabetes Obes Metab 2012; 14(9):803-9.

38. Sulfonylurea versus Metformin
Multicenter, randomized, double-blind, placebo-controlled trial
of 304 DM2 with CAD
Mean age 63.3 years
3 year follow up
Effects of Metformin Versus Glipizide on Cardiovascular Outcomes in Patients With Type 2 Diabetes and Coronary Artery Disease
Diabetes Care, epub Dec 10, 2012 Hong Jie

39. Insulin infusion post MI increases mortality
Experiences from an extended follow-up of the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) 2 Study
Diabetologia. 2011 Jun;54(6): , Mellbin et al
4 – 8 year follow up, 1,145 patients

40. Long acting insulin increases risk

41. Cancer

42. Diabetes increases cancer risk
Mechanism:
Hyperinsulinemia?
Hyperglycemia?
Diabetologia (2012) 55:1607–1618
Diabetes and cancer: evaluating the temporal relationship between type 2 diabetes and cancer incidence

43. Metformin reduces risk of cancer
of Record linkage databases – diabetes clinical information system and database of dispensed prescriptions
983 cases, 1846 controls
Case control trial 983 cases
Metformin and reduced risk of cancer in diabetic patients
BMJ VOLUME JUNE 2005,

44. Metformin reduces risk of cancer
Observational cohort study
4,085 patients
Adjusted hazard ratio 0.63 ( )
Started metformin
from UK
New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes
Diabetes Care Sep;32(9): Libby G

45. Insulin increases cancer risk
Relative risk compared to metformin mono-therapy
in UK since 2000
2051 events
Retrospective cohort of patients newly started on diabetes medications
The influence of glucose-lowering therapies on cancer risk in type 2 diabetes
CJ Currie Diabetologia (2009) 52:

46. Insulin increases cancer mortality
Average age 64.3 years
Average follow up 5.4 years
Population based cohort study from Saskatchewan
10,309 new diabetics
Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin
Diabetes Care Feb;29(2):254-8 Bowker SL

47. Common pathway of insulin sensitivity, obesity and cancer risk
“persons susceptible to cancer owing to a constitutive mutation in the tumor-suppressor gene PTEN also have heightened sensitivity to insulin and are obese”
Weight Gain
Decreased HgA1C
Increased Cancer
PTEN
Mutation
Insulin
Effect
PTEN Mutations as a Cause of Constitutive Insulin Sensitivity and Obesity
N Engl J Med Volume 367(11): September 13, 2012

48. TZDs worked too well!
“the increase in % fat mass correlated with the decrease in HbA1C during rosiglitazone treatment”
Predictors of improved glycaemic control with rosiglitazone therapy in type 2 diabetic patients
Br J Diab Vasc Dis Jan/Feb 2005; 5:
Decreased HgA1C
Weight Gain
Increased MI
Increased Cancer
Insulin
Effect
Insulin
Rosigliazone

49. Current Treatment Paradigm
Give more and more insulin to control blood sugars
Insulin Resistance
(Diabetes)
Increase
Insulin

50. Current Treatment Paradigm
Treatments to reduce glucose often increase insulin levels
Investigators considered only gluco-toxicity but not insulin toxicity
The disease is insulin resistance but the treatment is hyperglycemia
Insulin cures type I diabetes Insulin causes type II diabetes

51. Current Treatment Paradigm is Idiotic
Like treating alcoholism with alcohol!
If you have a type 2 DM patient treated with Insulin – it is almost certainly wrong!
Increasing insulin resistance!
Diabetes Care :23-31 Henry RR
You can’t treat a hyperinsulinemic state with insulin!

52. Diabetes is getting worse!
Metformin
Glyburide
More
Insulin
More
Insulin
Metformin
Insulin
Consider this: pts start on metformin then more drug and more drug – then insulin then more and more – their diabetes is not getting better over the years it is getting WORSE!
Our treatment makes diabetes worse, but sugars better – then we wonder why pts are getting worse so we call it a chronic progressive disease – when in fact, the only thing chronic about it is our own stupidity!
Over Time

53. Diabetes Screening is Useless
20 184 individuals aged 40–69 years (mean 58 years), at high risk of prevalent undiagnosed diabetes
During 184 057 person-years of follow up (median duration 9·6 years), there were 1532 deaths in the screening practices and 377 in control practices (mortality hazard ratio [HR] 1·06, 95% CI 0·90–1·25) – if anything – increased mortality
Screening useless if treatment is incorrect!
Screening for type 2 diabetes and population mortality over 10 years (ADDITION-Cambridge): a cluster-randomised controlled trial Lancet November 17; 380(9855): 1741–1748 Simmons RK

54. Glucose Lowering without Hyperinsulinemia

55. Proportion of Participants with Events over Time.
ORIGIN
Randomized 12,537 with CV risk factors and type 2 diabetes to tight control with insulin or less tight control
Proportion of Participants with Events over Time.
No measureable difference in outcomes
The ORIGIN Trial Investigators. N Engl J Med 2012;367:

56. Lowering glucose without raising insulin improves outcomes
Randomized 1,429 patients
3.3 year follow up
49% RRR
2.5% ARR
12 MI Acarbose 1 MI Placebo
32 events Acarbose 15 events Placebo
Acarbose Treatment and the Risk of Cardiovascular Disease and Hypertension in Patients with Impaired Glucose Tolerance JAMA 2003; 290:

57. Hypertension
17%
11%
HR 0.66 P= 0.006

58. Treatment considerations
Insulin causes diabetes
Insulin increases cancer and CV events
**Decreasing insulin** reduces diabetes, CV events, and cancer
How to decrease insulin without raised blood sugars?
Insulin is the problem, not the solution

59. Diabetes – Medical treatment
Good
Metformin
Onglyza
Acarbose
Bad
Insulin
Sulphonylureas
TZDs

60. Surgical Options Roux-En-Y Gastric Bypass Sleeve Gastrectomy
Laparoscopic banding
>90% cure rates for diabetes

61. Diabetes is a Reversible Disease!
Hepatic Glucose Production
Changes of insulin sensitivity and beta cell function are reversible
Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol
Diabetologia 2011 Oct;54(10): , Lim EL
11 patients, BMI 33 – 8 week dietary intervention
But in follow up 12 weeks – weight regain 3 kg and 3 developed diabetes again

62. Food Rationing decreases Diabetes

63. Surgery cures diabetes
Bariatric Surgery versus Intensive Medical Therapy in Obese Patients with Diabetes
N Engl J Med 2012;366: Schauer PR
Basically surgically enforced fasting regimens

64. Fasting vs. Bariatric Surgery
10 patients serving as own control
10 day inpatient using diet alone or diet and post surgery separated by 6 weeks
7.3 kg wgt loss (diet) vs 4.0 kg (surgery + diet) (p=0.01)
Daily glycemia in the presurgery period was significantly lower (1, mg/dL*day [1, ,490.33) vs. 1, mg/dL*day [1, ,680.13]) compared with the postsurgery period (P = 0.02 between periods)
Glucose control better with fasting alone vs bariatric surgery
Rapid Improvement of Diabetes After Gastric Bypass Surgery: Is It the Diet or Surgery? Diabetes Care Mar 25, Lingvay I

65. Fasting – a time tested treatment
“Our food should be our medicine.  Our medicine should be our food.  But to eat when you are sick is to feed your sickness."             Hippocrates

66. Fasting reduces plasma insulin
Stable blood sugars
Alternate-day fasting in nonobese subjects: effects on body weight, body composition, and energy metabolism Am J Clin Nutr 2005;81:69 –73 Heilbronn LK
16 patients
Increased free fatty acids
Available for energy

67. Fasting improves insulin sensitivity
Euglycemic clamp
Glucose
Infusion
rate
8 healthy men on alternate day fasting over 14 days
“Insulin-mediated whole body glucose uptake rates increased from 6.3 to 7.3 mgkg/min (P 0.03)”
Effect of intermittent fasting and refeeding on insulin action in healthy men
J Appl Physiol 99: 2128–2136, 2005 Halberg N

68. Fasting increases norephinphrine
11 healthy lean volunteers average 28 years
Decreased insulin, increased norephinephrine, fatty acids and cholesterol
Resting energy expenditure in short-term starvation is increased as a result of an increase in serum norepinephrine Am J Clin Nutr 2000;71:1511–5 Zauner C

69. Fasting increases Growth Hormone
Growth Hormone: Increases availability and utilization of fats for fuel Preserves muscle mass
Integrated GH concentration
6 healthy subjects in 5 day fast
“known ability of GH to increase hepatic glucose output, to promote positive nitrogen balance, and to induce lipolysis”
Average weight loss 4.8 kg
Fasting enhances growth hormone secretion and amplifies the complex rhythms of growth hormone secretion in man J Clin Invest April; 81(4): 968–975 Ho KY

70. Intermittent caloric restriction is better than continuous
Randomized trial 25% caloric reduction
107 overweight women
over 6 months
IER 2 days out of 7
The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: a randomised trial in young overweight women
Int J Obes (Lond) May ; 35(5): 714–727 Harvie MN

71. Intermittent caloric restriction is better than continuous
Insulin
Int J Obes (Lond) May ; 35(5): 714–727 Harvie MN

72. Clinical Effects

73. Fasting reduces diabetes
20 weeks
54 patients
P<0.05
Obese DM2 patients randomized to standard calorie restriction or 5 day periodic fast or 1 day week fasting
The Effect of Short Periods of Caloric Restriction on Weight Loss and Glycemic Control in Type 2 Diabetes
Diabetes Care. 1998 Jan;21(1):2-8 Williams KV

74. Fasting associated with less DM and CAD
Prospective study 200 patients going for angiography
Relation of routine, periodic fasting to risk of diabetes mellitus, and coronary artery disease in patients undergoing coronary angiography
Am J Cardiol. 2012 Jun 1;109(11): Horne BD

75. How to Treat Type 2 Diabetes
Insulin causes diabetes
Diabetes is a curable disease
**Lower insulin levels**
Bariatric surgery without the surgery – Fasting!
Effects of Fasting
We are treating DM with the very agents causing it –
Restore insulin sensitivity by targeting persistent high insulin levels

76. How to Cure Type 2 Diabetes
Diabetes is a curable disease
Insulin causes diabetes
**Lower insulin levels**
Bariatric surgery without the surgery – Fasting!
We are treating DM with the very agents causing it –
Restore insulin sensitivity by targeting persistent high insulin levels

77. Can We Cure Type 2 Diabetes?
No Diabetes – no diabetic nephropathy, no diabetic foot ulcers, diabetic retinopathy, reduced stroke, MI, cancers No Drugs, no surgery, no cost to patients, no long term side effects 12 month intensive fasting regime to cure diabetes

78. Case 1- Richard 55 year old white male Diabetes since 2002
Retinopathy
Neuropathy
Nephropathy
Started in IDM program June 2013

79. Richard
Diabetes – Cured
Hgb A1c 6.5%

80. Case 2 - Balraj 45 yo Sri Lankan man Diabetes diagnosed 2003 ITP
Nephropathy
Retinopathy
ITP
Started IDM program Aug 27, 2013

81. Balraj
Hgb A1C 6.3%

82. Case 3 - Armando 45 year old Philippine patient
Newly diagnosed with diabetes – not currently on medications and does not want to take medication
Starting HgB A1C 8.7% and rising over 6 months
Started IDM program June 2013

83. Armando
Hgb A1C 6.3%

84. Jason Fung’s Intensive Diabetes Dietary Management (IDDM) Clinic
Time to get started…
If you have T2 DM patients treated with current standard treatment especially insulin – you are not curing them, you are killing them
Jason Fung’s Intensive Diabetes Dietary Management (IDDM) Clinic

85. DPP-4 Inhibitors may reduce cardiovascular events
4,607 patients randomized
A Systematic Assessment of Cardiovascular Outcomes in the Saxagliptin Drug Development Program for type 2 Diabetes
Postgrad Med 2010 Vol122; 3: Frederich

86. Stratified Analyses of CV Events: Pooled Data from Registration Trials (DPP-4 Inhibitors)69
Risk ratio
95% CI
No.
Sitagliptin1
0.68a
[0.41–1.12] 64
Saxagliptin2
0.43b
[0.23–0.80]
40c
Linagliptin3*
0.34b
[0.16–0.70]
34d
This slide compares data from the cardiovascular meta-analyses at the time of registration for sitagliptin, saxagliptin and linagliptin.1-3
For sitagliptin (Januvia), the relative risk reduction of cardiovascular events was calculated to be 0.68 in a meta-analysis of over 10,246 patients, with confidence intervals of 0.41 and 1.12.
For saxagliptin (Onglyza), the relative risk reduction of cardiovascular events was calculated to be 0.43 in a meta-analysis of 4,607 patients, with confidence intervals of 0.23 and 0.80.
For linagliptin (Trajenta), the relative risk reduction was calculated to be 0.34 in a meta-analysis of 5,239 patients, with confidence intervals of 0.16 and It is important to note that the main contributor to the number of events was a head-to-head study of linagliptin vs. sulfonylureas. When linagliptin was compared to placebo, the comparison was not statistically significant (per Trajenta Canadian Product Monograph, July 2011).
Given the fact that the study program for each of the drugs varied considerably with regard to study population, comparator, duration of follow-up, etc., one should not compare the results of one drug vs. another.
References:
1. Williams-Herman D, Engel SS, Round E, et al. Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes. BMC Endocr Disord 2010; 10:7.
2. Frederich R, Alexander JH, Fiedorek FT, et al. A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Postgrad Med 2010; 122(3):16-27.
Johansen OE, Neubacher D, von Eynatten M, et al. Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated meta-analysis of a phase 3 programme. Cardiovasc Diabetol 2012; 11:3.
1.3
1.8
0.1 1 10
Risk ratio
DPP-4 inhibitor better
Comparator better
*The main contributor to the overall differences in the primary endpoint was the events in the head-to-head study of linagliptin vs. glimepiride. Comparisons with placebo were not statistically significant (Johansen et al 2012; Trajenta Canadian Product Monograph July 2011).
aCalculated using exact procedures for the Poisson processes; bCox hazard ratio; cPatients with events: n = 22, saxagliptin; n = 18, control; dPatients with events: n = 11, linagliptin; n = 23, comparator.
1. Williams-Herman D, et al. BMC Endocr Disord 2010; 10: Frederich R, et al. Postgrad Med 2010; 122: Johansen O-E, et al. Cardiovasc Diabetol 2012; 11:3.

87. Mean duration of these trials was only about 1 year71
Treatment with DPP-4 Inhibitors is Associated with Significant Reduction in MACE & Mortality in T2DM
Meta-analysis: 70 trials; 41,959 patients; mean follow-up of 44.1 weeks
# trials
# trials w/ events
# events (DPP-4)
# events (Comparator)
MH-OR [95%, CI] p
MACE 70 63
263
232
0.71 [0.59;0.86]
<0.001
Sitagliptin 27 24 77 67
0.86 [0.60;1.24]
0.43
Vildagliptin 16 15 75 74
0.61 [0.43;0.86]
0.005
Saxagliptin 13 12 62 46
0.67 [0.45;0.99]
0.047
Linagliptin 9 8 37 41
0.72 [0.45;1.16]
0.18
Alogliptin 5 4
0.86 [0.25;2.93]
0.81
AMI 61 59
0.64 [0.44;0.94]
0.023
Stroke 29 33
0.77 [0.48;1.24]
0.29
Mortality 53 30 50 51
0.60 [0.41;0.88]
0.008
CV Mortality 48 20 26
0.67 [0.39;1.14]
0.14
Mean duration of these trials was only about 1 year
These data come from a meta-analysis of published and unpublished trials comparing DPP-4 inhibitors to placebo or other drugs, with a duration of at least 24 weeks. The primary outcome investigated was major cardiovascular events (MACE, reported as serious adverse events) together with death from any cause.
The analysis included a total of 70 trials enrolling 41,959 patients. Mean follow-up was 44.1 weeks.
Overall, the odds ratio (OR) for MACE was reported to be 0.71, a statistically significant result vs. comparators (95% CI 0.59 to 0.86, p < 0.001).
Significant reductions in risk of acute myocardial infarction (MI) and all-cause mortality were also reported (OR 0.64 for MI and 0.60 for all-cause mortality).
For the primary endpoint, two individual DPP-4 inhibitors, saxagliptin (Onglyza; 13 studies) and vildagliptin (16 studies), were also associated with significant reductions in risk vs. comparators. The ORs for sitagliptin (Januvia; 27 studies), linagliptin (Trajenta; 9 studies) and alogliptin (5 studies), while all numerically in favor of these treatment agents, did not reach statistical significance.
Again, given the fact that the study program for each of the drugs varied considerably with regard to study population, comparator, duration of follow-up, etc., one should not compare the results of one drug vs. another.
The reductions in risk were seen early (the duration of most of the trials was only about 1 year).
Reference:
Monami M, Ahrén B, Dicembrini I, et al. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 2012 Aug 23 [Epub ahead of print].
0.0
1.0
10.0
MH-OR: Mantel–Haenzel odds ratio
Monami M, et al. Diabetes, Obesity and Metabolism 2012; Aug 23 [epub ahead of print].

88. SU is BAD for you

89. Ongoing CV Outcome Trials: DPP-4 Inhibitors72
Ongoing CV Outcome Trials: DPP-4 Inhibitors
Trial
Therapies #
Population
Primary endpoint
End Date
CAROLINA
Linagliptin/ Glimepiride
6000
CVD or ≥ 2 RF
Non-inferiority: time to first occurrence of any component of MACE composite outcome
Sept 2018
EXAMINE
Alogliptin/ Placebo
5400
ACS days before
Non-inferiority: time to occurrence of MACE
Dec 2014
SAVOR-TIMI 53
Saxagliptin/ Placebo
16,500
Superiority efficacy, non-inferiority safety: composite CV death, NF MI, NF stroke
July 2013
TECOS
Sitagliptin/ Placebo
14,000
Established CVD
Non-inferiority: time to first occurrence of composite CV outcome
Each of the DPP-4 inhibitors shown here (alogliptin, linagliptin [Trajenta], saxagliptin [Onglyza] and sitagliptin [Januvia]) is currently being investigated in a prospective, randomized, controlled trial to determine the impact of these therapies on cardiovascular events.1-3
As shown in the table, there are differences between these studies with respect to the comparator, the population and the primary endpoint.
References:
1. Golden SH. Emerging therapeutic approaches for the management of diabetes mellitus and macrovascular complications. Am J Cardiol 2011; 108(3 Suppl):59B-67B.
2. Fonseca VA. Ongoing clinical trials evaluating the cardiovascular safety and efficacy of therapeutic approaches to diabetes mellitus. Am J Cardiol 2011; 108(3 Suppl):52B-8B.
3. Clinicaltrials.gov
CVD = cardiovascular.
Adapted from: 1. Golden SH. Am J Cardiol 2011; 108(Suppl):59B-67B. 2. Fonseca V. Am J Cardiol 2011; 108(Supp):52B–58B. 3.

90. Yes, we can
45 years old Diabetes for 20 years On 100 units/ day of insulin After 2 months – off all insulin CURED of diabetes