Irl B. Hirsch, MD, Guest Editor

The data and comments presented in this From Research To Practice section suggest that, although we have exciting new tools for the treatment of diabetes, we need clarification on many issues concerning these technologies.

Dr. John White presented a balanced overview of the pharmacologic treatment of hyperglycemia for those with type II diabetes. (p. 227) He concluded with a treatment algorithm, which he prefaced by noting the lack of comparative clinical trials of different classes of agents. But despite this and the fact that his algorithm is based in part on opinion only, this is an excellent guide for the pharmacologic management of type II diabetes with the currently available agents.

Dr. White’s algorithm is not in conflict with the American Diabetes Association’s recently published consensus,¹ since the former goes into much more detail for a given clinical scenario. The problem, I believe, is the complexity of algorithms developed with so many different new classes of agents, as well as new agents in the same class, such as glimiperide and lispro. Although Dr. White asked us to use this algorithm as a framework for discussion and debate, how are busy family physicians going to decipher the available material? How much more complicated will this type of algorithm be when troglitazone and other new drugs become available?

We also know from the United Kingdom Prospective Diabetes Study that monotherapy for hyperglycemia is successful only for the short term.² This means that after 3–6 years, following Dr. White’s algorithm, most patients will need to begin Step 3, combination oral therapy. Dr. White did not add triple oral agent therapy to his algorithm due to lack of data. But I can envision that as a Step 3A, given the number of people with diabetes now on triple therapy, often because they have refused insulin and their well-intentioned health-care providers are grasping for any help they can find. It thus appears unlikely that there will be unanimous enthusiasm for the regimens in Steps 4 and 5 that require lispro three times per day.

Space does not allow a more detailed discussion of this algorithm. I think it is reasonable to expect, however, that there will be heated debate on this topic in the future, especially as newer and probably more expensive agents are developed.

It is hard to believe that we have discussed continuous subcutaneous insulin infusion (CSII) as one of our older therapies. Most of us now understand the major benefits and drawbacks of pump therapy.^3-4

The fact that CSII use appears to be increasing suggests that more health-care providers are recommending this for their patients with type I diabetes. Historically, one of the major problems of pump therapy has been that it has had relatively few physician supporters. Without a physician advocate, external pumps would not be prescribed.

Progress has been made in teaching health-care providers about pump therapy. This has truly been on-the-job training, at least for physicians. This aspect of diabetes therapy is not routinely taught during endocrine fellowship training (based on an informal survey at an National Endocrine Fellows meeting, 1995), let alone during internal medicine or family medicine residencies.

The report Ms. Farkas-Hirsch reviewed (p. 237) describes how nurses from a high-risk obstetrical program participated in a pump program protocol. Although fewer centers now admit their patients to the hospital for CSII initiation, it would be interesting to obtain follow-up on the women in this report, since these are the patients who are more likely to be admitted for this indication. Description of programs such as this one can have a much greater impact only if appropriate outcomes are measured. These would include not only the maternal and fetal outcomes, but also those pertaining to satisfaction of the nursing staff involved with the program.

Dr. Neil White (p. 235) discussed the issue of CSII altering the risk of severe hypoglycemia. Some have argued that using only regular insulin with CSII avoids the erratic absorption that occurs with all insulins. But in terms of absolute time, this variation will be less with insulin programs using all short-acting insulin.

One problem with the literature to date is that study designs and patient baseline rates of severe hypoglycemia differ. As Dr. White noted, subjects in the Bode report were selected for a high rate of severe hypoglycemia during multiple daily injection (MDI) therapy. There was no control with either a switch back to MDI or a similar group of patients remaining on MDI for the 4 years of the study.

On the other hand, one has to be cautious comparing this group of patients to the cohort in the Diabetes Control and Complications Trial (DCCT). The Bode group had a mean (± SD) age and duration of diabetes of 39.2 ± 12.9 and 22.2 ± 9.7 years, respectively. At randomization of the DCCT patients, primary prevention patients had a mean (±SE) age and duration of diabetes of 27 ± 0.4 and 2.6 ± 0.08 years, while the secondary intervention subjects had a mean age and duration of 27 ± 0.4 and 8.9 ± 0.2 years, respectively.⁵ It is quite possible that an older group of people with a longer mean duration of diabetes would have an increased risk of severe hypoglycemia, particularly since duration of diabetes is an independent risk for severe hypoglycemia.⁶ What does seem clear is that there is a subgroup of patients who may do better with CSII than MDI.

It is difficult to know at this time the impact lispro will have on diabetes therapy. I agree with Dr. Schade (p. 238) that the addition of this new insulin should be considered just one of many small advances in our ability to treat diabetes in the last half century. However, after listening to many of my patients (and lurking on the Internet), I believe there are many who have much greater expectations of this new insulin analog.

It is interesting that most studies have not found differences in HbA1c when lispro is compared to regular insulin. However, an abstract presented by Zinman at the American Diabetes Association’s 56th Annual Meeting and Scientific Sessions⁷ showed improved HbA_1c levels in CSII users receiving lispro as compared to those using regular insulin.

It is becoming clear that basal insulin delivery is a critical component to overall glycemia. Compared with a typical multiple injection regimen, preprandial glucose levels with lispro are significantly higher, thus reducing the impact of the postprandial glucose improvements.⁸

As Dr. Schade pointed out, the early studies raise further questions, and it may be that we will need more studies to understand how to best use this new tool. Perhaps using lispro in combination with new long-acting insulin analogs or combining lispro with regular insulin will be helpful for some patients. Alternatively, some people now doing well with regular insulin may simply want to use small doses of lispro to better correct premeal (or for that matter, postprandial) hyperglycemia. I look forward to studies exploring these possibilities. I also hope to see studies examining how lispro can be used effectively for hospitalized patients. It will also be interesting to see how the higher price of the new insulin affects patient use.

Another technology, implantable insulin pump (IIP) therapy, continues in its evolution. It is interesting that IIP has proceeded with testing for more than a decade without much recent fanfare.

Dr. Saudek summarized a report (p. 242) showing a lower frequency of hypoglycemia with IIP compared to subcutaneous therapy. After reviewing the insulin curves from this study, it is not at all unexpected that hypoglycemia would be less frequent with the IIPs. However, Dr. Saudek raised an important question that merits repeating: how would IIP therapy compare to subcutaneous insulin therapy with insulin lispro? The insulin curves appear similar, but any conclusions would be premature without appropriate clinical trials. Based on preliminary results,⁷ a randomized protocol comparing IIP with CSII using lispro would be welcomed.

Dr. Haire-Joshu (p. 244) raised important points about how patients adjust to IIP therapy and to technological advances in general. Like many studies examining the psychosocial impact of a new therapy, the Barrett report had a biased population. Besides being self-selected to participate in this study, the subjects were, generally, college-educated, female, married, and employed full time. How to extrapolate our new treatment tools to different patient populations is a question all health-care providers must address.

Finally, as exciting as all of these new tools are, how are we going to pay for them? For that matter, can we pay for our current technologies? The article by Stern and Levy (reviewed by Dr. Vinicor, p. 246) raises some provocative questions.

One could certainly raise some concerns with their economic model, such as the fact that few patients practicing intensive therapy will require 12 glycated hemoglobin tests each year, or that the frequency of CSII use in this model is too little, or for that matter, too great. I also suspect that, with improved screening for albuminuria and the greater use of angiotensin-converting enzyme inhibitors, the costs of nephropathy and end-stage renal disease is overestimated. Most importantly, indirect costs of complications (such as early disability due to visual impairment or lower extremity amputation) were not included in the calculation.

Despite these concerns, though, the fundamental question remains: should all individuals with type I diabetes have access to intensive therapy, including at least four daily self-monitoring of blood glucose (SMBG) tests, a certified diabetes educator for between-visit communication, CSII, and now lispro? Stern and Levy conclude that, even in the long run, intensive therapy is more expensive than standard therapy. Although we are still awaiting publication of the final DCCT data on this point, Stern and Levy’s point that not everyone should be considered for this therapy is reasonable.

My difference of opinion with them relates to where the line is drawn and to what constitutes intensive therapy. This may vary for different communities and different groups of patients within a community. For example, while most would agree with Stern and Levy that tight control generally is not indicated for children younger than 10 years old, few would deny the parents of these children enough blood glucose strips to prevent devastating hypoglycemia, even if that required more than four glucose tests per day. And what about adult patients with hypoglycemia unawareness, where frequent SMBG and CSII may be beneficial?

I also question their suggestion that those with incipient complications “should be treated on a research program basis. . . .”⁹ p. 51 The DCCT showed in its secondary intervention group a 54% decrease in the progression of retinopathy, a 56% reduction for the risk of developing clinical nephropathy (300 mg albuminuria per day), and a 57% reduction in clinical neuropathy.¹⁰ Also, other studies have documented improvements in renal outcomes with intensive therapy and improved control when microalbuminuria is initially present.^{11, 12}

The question, therefore, is: who makes these difficult decisions? In reality, the decision is now usually made by patients’ insurance companies, not by a consensus of national experts. Those without insurance have an even greater dilemma, since few of them can afford the expense of this therapy.

We should not be dissuaded from providing intensive therapy, with the prospect of preventing diabetes-related complications, simply because it may prove more expensive, even in the long run. To me, this seems like a good way to spend our health-care dollars, although I am sure some economists and health-care administrators would disagree.

The price of diabetes and its therapies increased as soon as Banting and Best administered the pancreatic extract to Leonard Thompson in December 1921. We should not be fearful of our continued progress or dismiss it as too expensive.

References

¹American Diabetes Association: Consensus statement: The pharmacological treatment of hyperglycemia in NIDDM. Diabetes Care 19 (Suppl 1): S54-61, 1996.

²UK Prospective Diabetes Study Group: UK Prospective Diabetes Study 16: overview of 6 years’ therapy of type II diabetes: a progressive disease. Diabetes 44:1249-58, 1995.

³Farkas-Hirsch R, Hirsch IB: Continuous subcutaneous insulin infusion: a review of the past and its implementation for the future. Diabetes Spectrum 7:80-84, 136-38, 1994.

⁴Hirsch IB: Implementation of intensive diabetes therapy in IDDM. Diabetes Reviews 3:288-307, 1995.

⁵The DCCT Research Group: Diabetes Control and Complications Trial (DCCT): update. Diabetes Care 13:427-33, 1990.

⁶Cryer PE, Fisher JM, Shamoon H: Hypoglycemia. Diabetes Care 17:734-55, 1994.

⁷Zinman B, Chaisson JL, Tildesley H, Tsui E, Strack TR: Insulin lispro in CSII: results of a double-blind, cross-over study. Diabetes 45 (Suppl 2): 28A, 1996.

⁸Rowe R, Anderson, Jr. JH, Gale E: A double-blind comparison of insulin lispro and regular insulin in patients on a multiple injection regimen. Diabetes 45 (Suppl 2): 71A, 1996.

⁹Stern Z, Levy R: Analysis of direct cost of standard compared with intensive insulin treatment of insulin-dependent diabetes mellitus and cost of complications. Acta Diabetol 33:48-52, 1996.

¹⁰The DCCT Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977-86, 1993.

¹¹Dahl-Jorgensen K, Bjoro T, Kierulf P, Sandvik L, Bangstad H-J, Hanssen KF: Long-term glycemic control and kidney function in insulin-dependent diabetes mellitus. Kidney Int 41:920-23, 1992.

¹²Felt-Rasmussen B, Mathiesen ER, Jensen T, Lauritzen T, Deckert T: Effect of improved metabolic control on loss of kidney function in type 1 (insulin-dependent) diabetic patients: an update of the Steno studies. Diabetologia 34:164-70, 1991.

Irl B. Hirsch, MD, Guest Editor

Irl B. Hirsch, MD, is an associate professor of medicine at the University of Washington School of Medicine’s Division of Metabolism, Endocrinology, and Nutrition, and the medical director of the Diabetes Care Center at the University of Washington Medical Center. His interests have focused on numerous aspects of intensive diabetes management; diabetes management during hospitalizations, particularly surgery; and educating other health-care providers and patients about the treatment of diabetes. He is the author of the new book How to Get Great Diabetes Care, published in 1996 by the American Diabetes Association, and he has served on the association’s Professional Practice Committee. He is also an associate editor of Clinical Diabetes.

Note of disclosure: Dr. Hirsch is on the speaker’s bureau and is a consultant for Eli Lilly and Company, which manufactures lispro and other products for the treatment of diabetes. He is also a speaker and a member of the medical advisory board for MiniMed, Inc., which manufactures insulin pumps.