The CIIIT procedure itself is not just IV insulin in high doses in a physician’s office. It is high doses of insulin given intravenously using a complex patented algorithm of  geometric pulses together with oral glucose, all given in a defined pattern over 4 to 6 hours together with glucose monitoring.  (The original CIIIT procedure, well described in the MPQCT review, has been streamlined so it no longer requires  9 hours.) 

Besides the 11 nationwide locations mentioned in the review, CIIIT has been and is  currently used in clinical practices in Wichita, KS, Denver CO, New Bedford MA, and Seoul, Korea

Response to Criterion 3, 4, 5

1.      Experimental Metabolic Studies.

Initial experimental studies (Foss et al, 1982, Diabetes 31(1):46-52) indicated a more favorable metabolic effect of intravenous(IV) administration of insulin compared to subcutaneous(s.c.) and also more favorable effects when administered IV in a pulsatile rather than a continuous infusion pattern.  The initial studies documented two metabolic effects - increased capability of the liver to store and metabolize glucose.

There are no  “conflicting studies” regarding the metabolic effects.  All the published studies support the model and benefits we proposed in the 1980s.   The  Levy-Marchal  study which the MCPQT review reported as “showing no metabolic advantage of pulsatile insulin administration”  was in fact a study of  the use of  subcutaneous insulin in either a pulsed or continuous infusion fashion.  As noted above, subcutaneous insulin cannot produce the metabolic effects that CIIIT does.  The Levy-Marchal paper is not relevant to the discussion of CIIIT.

The reviewer noted a study by  Heinemann that assessed the effects of a very brief period (2 consecutive days) of CIIIT (Heinemann et al, 1989).  This study  did indeed  fail to show  improved glycemic control in a small group of well-controlled type I DM patients.  This study documented CIIIT’s enhancement of the glucose handling ability of liver and muscle.  In general, type 1 diabetic patients are very insulin sensitive. The 2 day exposure of the participants’ muscles and livers to very high insulin levels (200-1000uU/ml) and large (~300 grams/day} glucose ingestion resulted in a very rapid (9 hours) maximal expansion of muscle and liver glycogen stores. Not surprisingly, study subjects displayed impaired glucose tolerance after a glucose load the following day simply because muscle glycogen stores were already at maximal capacity prior to the glucose tolerance test and the ingested glucose had simply no where to go. (Parenthetically, patients who note high blood glucose levels the day after receiving CIIIT, are now routinely asked to exercise (e.g. brisk walk) immediately after their CIIIT session to partially deplete their maximally expanded muscle glycogen stores. The increased activity has consistently resulted in a drop in blood glucose levels to the target range the following day.)

2.       Clinical Case Series.

In a  prospective clinical study (Aoki et al, Am J Med, 1995), we reported the correction of severe postural hypotension in three type 1 diabetic patients after 3 months of CIIIT.  The patients served as their own controls (historical control design.) They had previously failed to improve their severe postural symptoms on an intensive 4 - injection insulin program together with conventional therapy for orthostatic hypotension, including fluorinef and  salt tablets.  After adding CIIIT to their intensive insulin therapy, they all experienced improvement in their orthostatic hypotension symptoms after about one month and became asymptomatic in that regard by 3 months. Furthermore, following the deliberate discontinuation of CIIIT after 3 months, the postural symptoms reoccurred within 1-2 months. Resumption of CIIIT 3 months later again resolved the problem.  Therefore, contrary to MPCQT interpretation, this study was controlled (had a historical control design).   Since 1995, similar good outcomes in resistant-to-treatment  orthostatic hypotension have been reproduced by another endocrinologist, elsewhere, with a larger group of patients.

3.    Retrospective Clinical Studies.

1)      Aoki et al, ( Lancet, 1993)

 In a study of the long term effects of CIIIT on 20 “brittle” type I diabetic patients, we reported improved glycemic control as well as a dramatic decrease in the incidence of both major and minor hypoglycemic events.  Again, the patients served as their own controls, i.e. historical control design), to avoid  the clearly unacceptably risky and unethical utilization of a "true" control group (i.e. sham CIIIT using saline rather than insulin pulses together with the ingestion of ~300 grams of glucose by a brittle type I DM subject.)  A similar degree of glycemic control (HbA1c ~7%) was achieved in relatively recently diagnosed type I DM subjects, intensively treated, with mild or no complications, in the DCCT study, but at the cost of a three fold increase in hypoglycemic events.

The MPCQT interpretation of the dramatic reduction in frequency of hypoglycemic events reported with CIIIT (compared to the DCCT) was that "the increased attention to participants" contributed to "the avoidance of hypoglycemic reactions".  I believe the DCCT patients were contacted weekly or more frequently.   CIIIT patients are seen weekly.   The true explanation for our  study results, however, was implied but not fully articulated in the article.   All the patients in our study presented with  hypoglycemia unawareness, many with  severe hypoglycemic episodes while sleeping.  All were on intensive insulin therapy and despite this had at least 3 severe hypoglycemic episodes per month requiring intervention by someone other than themselves.  After 6 months of CIIIT, 100% of these patients regained partial or total awareness of impending hypoglycemic events.  

The results achieved with CIIIT in this study were superior to those reported in the DCCT.  Thus, we do not understand how the MPCQT finds it "difficult to conclude that CIIIT improves net health outcomes as much as or more than the established alternatives".    In this group of patients who were already on intensive insulin therapy, and whose average HBA1c was still  8.5 % and who still had major problems with hypoglycemic events, the addition of CIIIT led to a ~ 97% reduction of major hypoglycemic events combined with a reduction in HbA1c from 8.5 to 7%.  CIIIT provided two improved outcomes:

a)      In “brittle” type 1 diabetic patients the ability to pursue intensive insulin therapy without the risk of serious hypoglycemic events.  

b)      The reduction of HBA1c to normal levels (as shown by the DCCT to predict improved health outcomes in diabetes.)

CIIIT is not an alternative to the many insulin regimens currently available, CIIIT is a totally different therapy with different pharmacologic effects than subcutaneous insulin and is used as an additional therapy when intensive insulin alone does not  prevent complications or when intensive insulin therapy puts the patient at risk for severe hypoglycemic reactions.

2)             Aoki et al, (The Online J Curr Clin Trials, 1995)

Our clinical observation that CIIIT lowered the blood pressure in hypertensive diabetics led to this investigation.  In this randomized controlled study, three months of CIIIT on 74 type 1 diabetic subjects resulted in a significant improvement in glycemic control (HbAIc) and reversal of the abnormal circadian BP pattern seen in hypertensive diabetic patients, The MPCQT finds that "the clinical significance of the effect on circadian BP pattern is unclear".  Unlike MPCQT, we feel that the reversal of an abnormality in a disease process is a favorable and desirable net health outcome. We believe that a significant decrease in blood pressure at night should result in decreased end organ damage over the long term.  Furthermore, just as in the Lancet paper above, CIIIT again proved clearly superior in reducing HbAIc compared to intensive subcutaneous insulin therapy alone (control group) despite an identical amount of "attention to participants" (all patient were seen weekly by the same physician.)   

The  MPCQT review comments on the fact that in this study the effects on hypoglycemic episodes were not reported. As you might expect, when an intervention normalizes a very basic metabolic activity such as fuel metabolism, many different outcomes in many different organ systems are affected.  This is both the joy and the grief of researching CIIIT – we cannot afford to measure and report the entire list of parameters that CIIIT affects in other systems that are not the focus of the current study.  This brief (3 months) study focused on restoration of the normal circadian blood pressure rhythm and glycemic control.  

3)             Aoki et al, (Endocrine Practice, 1999)

Finally, in the multi-center, retrospective, longitudinal study assessing the effects of CIIIT on progression of overt diabetic nephropathy in 31 patients, we reported the stabilization of progression of overt nephropathy.  Stabilization consisted of no significant change in 1.)  creatinine clearance, 2.) the reciprocal of the serum creatinine, or 3.)  proteinuria over a mean period of 37 months.  The MPCQT review felt it was a point against the therapy that there was no significant change in the 24-hr urinary protein".   That comment seemed very illogical to us since, no change in the protein excretion is to be expected when no change in CrCl or in reciprocal serum creatinine were noted during the observation period.  (Parenthetically, the literature would have predicted an increase in  daily urinary protein excretion at the rate of 300-500 mg/day/year. Thus, the lack of a significant increase in proteinuria we reported is very significant since it is in accord with the stabilization of the creatinine clearance.) The point of this paper is that CIIIT halted the progression of the nephropathy.  Diabetic renal disease is a relentlessly progressive disease with patients experiencing a 12-15 ml/min/year loss in creatinine clearance each year once it starts.   All the findings in this paper are consonant with the interpretation of arrested progression of overt diabetic nephropathy with CIIIT. 

Until this report by Aoki, there was no known way to halt the progression of diabetic nephropathy. As the MPCQT review notes (page11, paragraph 1), “once diabetic nephropathy has progressed to the stage of hypertension,  proteinuria, or early renal failure, glycemic control is not generally beneficial in influencing its course: instead, anti-hypertensive medications and restriction of dietary protein are recommended (Masharani and Karam, 2001.” In the Aoki  study, most participants were already on ACE inhibitors and other anti-hypertensive agents resulting in good BP control and were on dietary protein restriction prior to entering the study. It was the failure of these conventional modalities that prompted them to enroll in the CIIIT program.  The MPCQT review kept referring to “alternative” therapies that could be used instead of CIIIT, but in this situation, there are none.   The alternatives he mentions are already being  employed, and the disease is still relentlessly progressing. 

We therefore find it puzzling that the MPCQT review concludes that "it is possible it was the weekly adjustments in regimen rather than the CIIIT that were responsible for the apparent stability in renal function".   No researchers have ever reported stabilization of overt diabetic nephropathy with "weekly adjustments in therapeutic regimen."    In the report by Dailey reviewed below, a randomized controlled trial of CIIIT in nephropathy, the control group getting intensive insulin therapy was being monitored weekly, and their renal disease progressed significantly.  

4.    Prospective, Randomized, Controlled Clinical Trials

     1)             Aoki et al, (Diabetes Care, 1995)

 We had observed clinically that adding CIIIT to intensive insulin therapy (4 insulin injections/day or insulin pump) in hypertensive diabetic patients often led to a pronounced decrease in their blood pressure - requiring the physician to decrease the dose or reduce the number of anti-hypertensive agents during their months on CIIIT therapy.  That observation prompted this prospective study that showed a 46% reduction in anti-hypertensive medication requirements, for the same degree of BP control, at the end of 3 months of CIIIT in 26 patients with type I DM, hypertension, and nephropathy. 

The MPCQT review stated that because there was no change in glycemic control with CIIIT, the resultant improvement in blood pressure control seen with CIIIT could not have been due to improvement in the patient’s metabolism.  This statement is not correct.  As far as we know in humans, the regulation of blood sugar and the regulation of blood pressure are separate independent processes.  These patients were selected because they had hypertension, not problems with glycemic control.   During the 1 to 3 month stabilization period, efforts were made to optimize their blood pressure and glucose control prior to the initiation of the study.   In patients who achieved good glycemic control during the stabilization period, no further improvement in glycemic control was expected with the addition of  CIIIT.

The MPCQT review was incorrect in assigning caution to the study because of a high dropout rate "15 (31%) of the original 41  enrollees were excluded from the study.”  The drop out rate is actually much less .  All patients recruited for this study underwent an initial 1-3 month run-in/ stabilization period (intensive s.c. insulin therapy and lowering of BP to or below 140/90 mm Hg with medication). Only patients who successfully completed this run-in/ stabilization period were randomized and entered the actual study (randomized cross-over design).  Fifteen patients did not successful complete this run-in/stabilization period for various reasons (explained in the paper.)  All 26 patients stabilized and then randomized to the actual study completed this study.  Thus, the actual dropout rate for the study was 0%  during a 6-month study that involved a crossover at 3 months. 

The run-in period was necessary to determine medication doses required at steady state prior to actually beginning the study.  It then became possible to calculate the reduction in dosage during the randomized study.   By providing a more uniform population for the randomized study, the run-in actually strengthened the study by decreasing the likelihood that the significant difference in outcome detected was due to something other than CIIIT.   Those 15 excluded during the run-in period have no bearing on the acceptability by patients of the CIIIT procedure, since none of these patients were on CIIIT during the run-in.  

The MPCQT reviewer’s discussion regarding the lack of a significant decrease in proteinuria  (a parameter not monitored in this short term study ) (page 8, paragraph 3) is completely inappropriate in the context of this anti-hypertensive study.

 The MPCQT reviewer asks of all these prospective -randomized- controlled trials why intention-to-treat type of analysis was not done.  (A reminder to the reviewer, intention to treat analysis begins at the point of randomization, not prior to the run in period.)  Intention–to-treat is not the best analysis to use in initial studies of a therapeutic modality in which the point of the study is to ascertain whether or not the treatment is effective.  In these studies, there is a great requirement for internal validity.  Later, after the therapy has been proven effective, larger studies using intention to treat can be used to pinpoint more exactly the acceptability of the therapy in a diverse population.   Besides these issues, in the case of our anti-hypertensive medication study, intention-to-treat is not recommended  because this was a crossover study involving a relatively small number of patients.   

     2)             Dailey et al, (Metabolism, 2000)

This multi-center, parallel group, prospective, randomized, controlled trial) re-affirms and reproduces the results of the retrospective multi-center study previously published by Aoki et al (Endocrine Practice, 1999).   CIIIT clearly significantly slows the progression of overt diabetic nephropathy. In reviewing this study, the MPCQT review makes a serious error in stating that: "the absence of a reduction in urinary protein excretion in both groups was also unexpected".  This study very clearly shows that the progression of overt nephropathy was slower (but continued nevertheless!) in the treated group (essentially identical treatment except for the added CIIIT)  compared with the attention control group.   In the face of progressing diabetic nephropathy in both groups (albeit slower in one group than the other), why anyone would expect a decrease in proteinuria? As noted previously, without intervention, urinary protein excretion is expected to increase 300-500 mg/day/year. 

The MPCQT discussion of the known relative effectiveness of anti-hypertensive therapy and dietary protein restriction in overt diabetic nephropathy is superfluous. Both patients groups (C and T) in the Dailey study underwent similar anti-hypertensive therapy, mild sodium restriction, moderate dietary protein restriction,  and DCCT type diabetic diets.  The patients in both the treatment and control groups were seen weekly.  However, the rate of decline in creatinine clearance was significantly reduced only in the CIIIT (T) group. 

The repeated statement by the MPCQT review that there was a 46 % dropout rate is also misleading.  This study was designed for 12 months but also was planned to be extended another 6 months if the treatment appeared effective but had not yet reached statistical significance.  There was only a 21% dropout rate with 71/ of f 90 patients completing the 12-month study.  Only 8 patients dropped out of the CIIIT group, while 11 dropped out of the control group.  This is very admirable considering the time-intensiveness of the study and the severity of the disease.  At the end of the 12-month study, an extension of the study for 6 more months was offered to participants.   The primary reason that 22 / 71 (31%) patients dropped out at that time was the time required for weekly clinic visits.  However, 1 dropped out of the treatment group when gangrenous cholecystitis led to dialysis. 

 The only significant difference between patients completing only 12 months and those who continued for 18 months was that those who chose to continue had a higher baseline serum creatinine and thus presumably more severe renal disease.  (see attached graph, Fig. 1)  

 Dialysis/transplant is usually required when creatinine clearance falls to 15 ml/min.  One is tempted to extrapolate the curves shown above.  Since both groups had an average of  approximately 60 ml/min creatinine clearance at baseline, one would anticipate the time-to-dialysis/transplant for the control group to average 6 1/2 years, but average 15 years for the CIIIT treatment group. 

 Because the MPCQT reviewer was troubled by the dropout rate in these studies, we reviewed other nephropathy papers to see what the “expected” or  “usual” drop out rate in 18-month time-intensive studies of chronic disease.   We show two studies on the next page. 

An important point regarding the acceptance of CIIIT therapy by the patients in our clinical studies does not appear in any of the published papers.   At the end of each clinical study, many patients on CIIIT wanted to continue CIIIT because in addition to the improved outcome mentioned in the study, they also experienced other improvements in quality of life such as more energy and improved or complete remission of other diabetic complications such as painful peripheral neuropathy,  gastroparesis,  or foot ulcers.  Patients also discovered that after several months without CIIIT, their previous complications gradually returned.  Because of this, many have continued on CIIIT for years (some are in their 15^th year) necessitating establishment of an off- campus CIIIT facility.

The MPCQT review discusses the DCCT results but these have no bearing on the CIIIT nephropathy studies because patients with overt diabetic nephropathy were excluded from the  DCCT!  DCCT enrollees were drawn from a much healthier patient population and thus cannot be compared to the enrollees in the Dailey study. 

 The MPCQT review speculates that the result of an intention-to-treat analysis of the Dailey study would be negative.   In fact, based on the information in the paper, there is no way to know what an intention-to-treat analysis would show!  It may be more favorable than the current analyses.

The MPCQT reviewer also speculates that it would take years of CIIIT to prevent progression of end-stage renal disease.  This speculation is incorrect.  Actually, this study showed CIIIT postponing the progression of renal disease even in the first few months of CIIIT therapy.   In fact, this study and the study by Aoki (Endocrine Practice, 1999) discussed above, suggest that CIIIT can stave off renal failure for years. Postponing dialysis/transplant for even one year is a significant health benefit! 

 The MPCQT reviewer raised a caution because hypoglycemic episodes were not an endpoint  measured in this study on nephropathy.  Since hypoglycemia is not known to have any influence on the progression of renal failure and was not a criterion for entry into the study, it is unclear what the reviewer’s caution is.  We thought that saving money by not measuring non-contributory data was a virtue in research.

Risks