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ORIGINAL ARTICLE

Rationale for the Use of Insulin Therapy Alone As the Pharmacological Treatment of Type 2 Diabetes

Michael Berger, MD
Viktor Jörgens, MD
Ingrid Mühlhauser, MD

Before any treatment of type 2 diabetes in accordance with the principles of evidence-based medicine can be generally recommended, the considerable disease heterogeneity must be taken into account, and randomized controlled intervention trials directed to cardiovascular and microangiopathic organ damage end points must be performed for the various subgroups of patients. Until then, it appears prudent to treat the typical Caucasian type 2 diabetic patient primarily by nondrug therapies, and if they fail to achieve the patient's individual treatment goals, then insulin treatment should be initiated. Treatment of type 2 diabetic patients with insulin alone, aimed at the patient's individual therapeutic goals, is effective and safe when conducted as an integral part of specific and structured treatment and teaching programs. Insulin treatment can be safely used to achieve near-normal HbA_1c levels (<7.0–7.5%) if prevention of diabetic microangiopathy is indicated, or to maintain HbA_1c levels <8.5–9.0% if catabolic symptoms due to insulin deficiency are to be prevented.

Diabetes Care 22 (Suppl. 3):C71–C75, 1999

What follows is a dialogue between two renowned diabetologists after one of them (M.B.) had remarked during a session of a scientific symposium that he considered the use of oral antidiabetic drugs to be incompatible with the principles of evidence-based medicine, because he was not convinced of their efficacy and worried about their safety.

Waiting for the hotel elevator:
P.G.: Hi, M.—I hear that you don't treat type 2 diabetics anymore!
M.B.: No, that's not true! I only use treatments that are truly beneficial for the patients. Admittedly, this may be something new.
P.G.: Yes, this is pretty innovative.
In the elevator:
M.B.: Seriously, P., I am concerned about the safety of sulfonylureas in type 2 diabetes.
P.G.: Oh, we have been through stages of this discussion all along. I believe all that matters is the control of glycemia.
M.B.: Yes, but this is true for microangiopathy—not for macroangiopathy, which is the main problem for type 2 diabetic people.
P.G.: I admit there is no hard evidence. But still, I believe that even with regard to atherosclerosis, the main thing is to lower blood sugar—no matter by which method or drug.
M.B.: During the past few years, there has been interesting new information forthcoming from animal experimentation indicating a negative effect of sulfonylureas on perfusion injury and hypoxemic reconditioning of the myocardium. This should stop us from using the sulfonylureas in all type 2 diabetic patients with coronary artery disease.
P.G.: I don't buy this.
Departing into different directions after leaving the elevator:
P.G.: Let me know when you change your mind, M., will you?

(Verbatim transcript of a non–consensus-developing discussion held in Nice, France, on 25 October 1997, as witnessed and put together by I.M.)

In introducing the subject of this article, we should clearly state that in this department type 2 diabetic patients are treated by non-drug therapy, as the first choice of treatment, or by insulin therapy—i.e., there was absolutely no use of oral antidiabetic agents until September 1998. This policy—which was not unusual among leading diabetes centers in the U.S. in the 1970s—is based on several lines of evidence, the description of which will take up most of this article. We first present our interpretation of the current status of the sulfonylurea controversy and of the debate on potential risks of hyperinsulinemia, followed by a paragraph on the justification of near-normalization of glycemic control in type 2 diabetic patients. We then describe the necessity of defining individual therapeutic goals for a given patient with type 2 diabetes, and, finally, we present some preliminary data on the medium-term follow-up of type 2 diabetic patients on two different strategies of insulin treatment.

SULFONYLUREA CONTROVERSY— It is a matter of unchallenged consensus that macroangiopathy represents the major threat to people with type 2 diabetes; excess cardiovascular morbidity and mortality determine the prognosis of these patients. Considering such unanimity, it appears bewildering that only two studies have ever attempted to reduce the excess cardiovascular morbidity and mortality of type 2 diabetes by antidiabetic therapy. In contrast, literally thousands of studies were performed to describe the effects of blood glucose lowering therapies on surrogate markers rather than cardiovascular disease end points. Furthermore, almost all of these studies as carried out to describe the effects of oral antidiabetic agents were underpowered and of too short a duration to be able to render any clinically relevant results. The amount of money and manpower, of energy of (young) colleagues and efforts on the part of patients that went into such studies during the past 40 years appears to be a shameful waste of valuable resources. Of the only two studies directed to the essential question of whether antidiabetic therapy influences the development and progression of macroangiopathy in type 2 diabetes, the University Group Diabetes Program (UGDP) was completed some 25 years ago, with the results published in a number of reports, mainly during the 1970s. Completely unexpectedly, this study showed that the use of tolbutamide was associated with a significant increase of cardiovascular and total mortality when compared with insulin treatment or diet alone (1–3); similar findings were reported with regard to the use of phenformin (4).

The UGDP study's verdict indicating a cardiotoxic effect of sulfonylureas has become the center of one of the most heated controversies in the history of modern medicine, a controversy that has involved physicians, investigators, medical associations, regulating agencies, the public and—in increasing amounts—representatives and lawyers acting on behalf of pharmaceutical companies. Inasmuch as the validity and relevance of the UGDP data implementing sulfonylurea drugs in the excess cardiovascular mortality in type 2 diabetic patients were debated over the decades, it is unexplainable why—with the one exception of the U.K. Prospective Diabetes Study (UKPDS)—no subsequent studies were performed to confirm or refute the alleged cardiotoxic effect of sulfonylureas. All along, one important point put forward by the critics of the UGDP study has been the lack of any pathophysiological plausibility of the lethal side effects of sulfonylurea treatment. During recent years, however, a number of side effects of sulfonylurea drugs on cardiac vasculature and functions have become apparent, initially based on animal experimentation. In particular, sulfonylureas have been shown to block ATP-dependent potassium channels, thus interfering with the preconditioning of the myocardium by hypoxemia and enlarging the areas of necrosis after experimental coronary occlusion (5). In fact, a number of recent findings in animals and humans have provided a pathophysiological plausibility for alleged cardiotoxic effects of sulfonylureas, as these drugs appear to aggravate the hypoxemic damage to the myocardium in the case of coronary occlusion/artery disease (6–9). Such a pathophysiological scenario fits well with the observations that the alleged cardiotoxic effect of sulfonylureas appears to exert itself in an increased lethality of myocardial (re)infarctions or cardiac death rates, rather than by increasing cardiac events or the incidence of cardiovascular morbidity (2,6). We have suggested that this phenomenon represents the explanation for the results of the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) Study: the difference in mortality between the insulin-treated group and the control group was mainly due to the incidence rates of sudden death and fatal reinfarction, whereas potential indicators of progression of coronary artery disease (such as the frequency of percutaneous transluminal coronary angioplasty or coronary bypass surgery intervention) and also the total reinfarction rate were virtually identical (6,10). Our hypothesis is further strengthened by the fact that those patients in the DIGAMI Study with noninsulin therapy before the myocardial infarction in whom oral antidiabetic treatment was discontinued in the insulin-infusion group experienced a particular prognostic benefit in comparison with those patients in the control group in whom sulfonylurea treatment was presumably continued. Actually, this hypothetical phenomenon could also have been operative in the Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type 2 Diabetes (VACSDM), in which intensified insulin therapy, which comprised the use of glipizide for some patients, was associated with a tendency toward increased cardiovascular event rates despite a substantial improvement of HbA_1c (11). In this situation, appropriate studies directed at the efficacy and safety of sulfonylurea drugs with particular emphasis on type 2 diabetic patients with coronary heart disease have recently been demanded (6,9,14).

The UKPDS is not helpful in this context, as patients with clinically relevant coronary artery disease were excluded during the recruitment process: the entire cohort included only 3% patients with a history of angina pectoris (excluding those with present angina) and 2% with a history of myocardial infarction (prior to 1 year before recruitment). Patients with heart failure were excluded (15,16). Furthermore, the study does not have the power to rule out clinically relevant differences concerning cardiovascular morbidity and mortality between the four treatment arms represented under "intensive therapy"(15).

In summary, faced with the recently strengthened hypothesis that sulfonylureas may exert a cardiotoxic side effect in type 2 diabetic patients with coronary heart disease, we do not recommend the general use of this class of drugs—until sulfonylureas have been proven to be safe and effective with regard to relevant clinical end points, as has been the case for glibenclamide in a specified subgroup of type 2 diabetic patients (15) and for metformin monotherapy in obese type 2 diabetic patients—if HbA_1c levels can be lowered to ~7.0% over a period of 10 years (16). The use of metformin in combination with sulfonylureas, however, was associated with increased mortality (16). As there are no proofs of the safety and efficacy of acarbose or troglitazone with regard to the relevant clinical end points of cardiovascular disease (or microangiopathy), general recommendations to use these drugs are unjustified.

NO PROOF OF EXOGENOUS INSULIN'S ATHEROGENEITY— In the context of recent pathophysiological speculations focusing on the metabolic syndrome, some authors have advanced the hypothesis that hyperinsulinemia might be a promoter of macroangiopathy. The evidence for this hypothesis was, if anything, remarkably thin (17). Nevertheless, as a consequence, people have argued against the use of insulin treatment in type 2 diabetes so as not to advance the incidence and progression of cardiovascular diseases. Such a recommendation is purely hypothetical and lacks any support by clinical intervention trials. In contrast, the UGDP study has clearly demonstrated that treatment with exogenous insulin (independent of the improvement of control which was achieved) did not lead to any increase in cardiovascular morbidity or mortality (3). Similar findings can be extracted from the 10-year follow-up data of the UKPDS (15).

PREVENTION OF VASCULAR DISEASES BY NEAR-NORMOGLYCEMIA IN TYPE 2 DIABETES— A further unexpected result of the UGDP study and of the UKPDS was that the improved degree of metabolic control achieved by the variable insulin group and the intensive blood glucose control when compared with the other treatment arms was not associated with a decrease in the incidence rates of macroangiopathy (3,15). In the UKPDS cohort of younger (mean age 53 years; mean BMI 27.5 kg/m²), newly manifest type 2 diabetic patients, an improvement of ~1% HbA_1c over a period of 10 years (mean values 7.9 vs. 7.0%) led to a significant decrease of microvascular complications, with a relative risk reduction of 25%. Expressed in other terms, however, this benefit appeared rather modest: an absolute risk reduction of 2.8%, with a value for the numbers needed to treat of ~36 (15,16). In the framework of the VACSDM, no clear-cut message as to the end-point benefits of near-normalization of glycemia in type 2 diabetes became apparent (11). The randomized controlled study on Japanese diabetic patients, which has reported beneficial effects of tightening metabolic control, has been criticized because the individuals recruited for this rather small study can hardly be called representative of type 2 diabetic patients (12).

In conclusion, the case for aiming to near-normalize glycemic control in type 2 diabetic patients is considerably weaker than for type 1 diabetes. In type 2 diabetes, there is no proof that normoglycemia can prevent the macroangiopathic late complications that represent the major clinical problem of the disease; in fact, several circumstantial pieces of evidence have recently been interpreted against such a hypothesis (18,19). In contrast, the cases for control of hypertension (20,40) and hypercholesterolemia (21) and for the prescription of aspirin (22) in patients with type 2 diabetes, especially when associated with coronary heart disease, appear to be most convincing.

For younger type 2 diabetic patients (such as <60–65 years of age), it appears justified to extrapolate the findings from the Diabetes Control and Complication Trial, which clearly relate the degree of metabolic control to incidence and progression of microangiopathy. Respective recommendations to strive for near-normal HbA_1c levels in these patients, though broadly supported (13,18,19), have only recently been supported by appropriate evidence (15,16).

DEMOGRAPHIC CHARACTERISTICS OF TYPE 2 DIABETES AND NEED FOR INDIVIDUALIZED TREATMENT GOALS— In clinical practice, one needs to primarily consider the demographic characteristics of type 2 diabetic patients; they might differ quite profoundly depending on the country or the genetic background, reflecting the enormous heterogeneity of the disease. As far as Germany (and most probably central and northern Europe) is concerned, the comprehensive data collected by Ratzmann (23) on the entire cohort of 48,104 diabetic patients living in East Berlin on 31 December 1988 (comprising 4% of the total population) appear to be representative. With type 1 diabetic patients representing <5% of the total diabetic population, it is clear that the majority of patients with type 2 diabetes are above 65–70 years of age, i.e., in a geriatric age range. In most of these patients (>75% of whom had predominantly been diagnosed in the course of state-organized population screening procedures [24]), diabetes represents but one facet of the multimorbidity of the old and the very old. Ratzmann (23) estimated for the East German population that some 65% of type 2 diabetic patients are diagnosed at an age of 65 years and older, under the conditions of a health care system where a significant delay between the onset of asymptomatic hyperglycemia and the diagnosis of type 2 diabetes could practically be excluded.

Faced with such a heterogeneity of type 2 diabetes in the context of demographic characteristics, it follows that for each patient, individual therapeutic goals need to be defined for any preventive treatment plan. If at all possible, the definition-making process must involve patients directly in order to facilitate their acceptance of the treatment goals.

The majority of clinicians seem to accept that near-normalization of HbA_1c levels (e.g., <7.0–7.5%) represents a rational goal for younger type 2 diabetic patients (in general, <60 to 65 years of age), which is supported by recent evidence. For the vast majority of type 2 diabetic patients who are older than 65 years (at least in central and northern Europe), the prevention of diabetes-related symptoms becomes the main therapeutic goal. This goal includes treatment and prevention of the classic (but sometimes not immediately apparent) symptoms of insulin deficiency and hyperglycemia but also the avoidance of symptomatic side effects of antidiabetic drugs (such as metformin and acarbose) and the discontinuation of unnecessary dietary regulations. In fact, the scientific evidence for most dietary prescriptions for type 2 diabetic patients is rather weak or nonexistent if scrutinized for a potential benefit to the individualized therapeutic goals for a given patient (25). Diabetes-related symptomatology appears to develop at levels of >8.5–9%. HbA_1c values below this range in an elderly patient free of diabetes-related symptoms should therefore be quite acceptable and not lead to any foreseeable vascular damage. At levels above this range of 8.5–9.0% HbA_1c, patients usually become symptomatic; hence, an intensification of treatment, preferably the initiation of insulin therapy, is indicated. Thus, the indications for insulin therapy differ in relation to the treatment objectives: if the prevention of microangiopathy is the treatment goal, insulin therapy should be started once HbA_1c levels increase >7.0–7.5%; if the prevention (and treatment) of diabetes-related symptoms is the therapeutic goal for a given patient, insulin therapy usually becomes indicated at HbA_1c levels >8.5–9.0%. Needless to add, the prevention of acute diabetic complications of diabetes, such as hyperosmolar or ketoacidotic comata and severe hypoglycemia, as well as complications resulting from the diabetic foot syndrome, remain a primary therapeutic objective for every diabetic patient (26–28).

STRUCTURED TREATMENT AND TEACHING PROGRAMS AS IMPLEMENTED ON A NATIONAL BASIS IN GERMANY— In accordance with general World Health Organization policies and with the high prevalence of type 2 diabetes, this disease must remain the domain of the primary health care physician. To enable effective diabetes care at the level of the family doctor, we have developed, evaluated, and implemented a structured treatment and teaching program for non-insulin-treated type 2 diabetic patients. The program is primarily based on non-drug treatment (29–31) and on a group teaching approach mainly carried out by physicians' assistants (32); it includes systematic self-monitoring of glucosuria, flexible (if needed, hypocaloric) nutrition, and (if possible) increasing physical activity. One-year follow-up data of patients treated with this program by general practitioners have demonstrated moderate, but significant losses of weight; decreases of HbA_1c levels (if indicated as part of the individualized therapeutic goals); and a reduction of the use of oral antidiabetic agents by about two-thirds (26,33). Since 1991, this program has been remunerated for each participating patient to primary health care physicians who have participated in a specific postgraduate education course. To date, some 25% of all primary health care physicians in Germany have participated in such courses (34). With the growing interest by family physicians in initiating insulin therapy in their practices (rather than referring their patients to a hospital for that purpose), there was a demand for a similar treatment and teaching program for the initiation and improvement of insulin therapy in type 2 diabetic patients. Such a program had already been evaluated as part of inpatient diabetes care (35). At this point, the program as adapted to outpatient services and developed and evaluated for parameters of safety and effectiveness by Jörgens et al. (36,37) includes five group sessions and is presently being implemented on a national basis in Germany, including an adequate remuneration of primary health care physicians who have participated in the program's postgraduate education course.

STRATEGIES OF INSULIN TREATMENT IN TYPE 2 DIABETES— Various strategies of insulin treatment have been proposed for patients with type 2 diabetes. Respective alternative ways of insulin substitution depend to a large part on the endogenous insulin secretory capacity of a given patient and his/her individual therapeutic goal. The longer one waits to initiate insulin therapy, the less endogenous insulin will be mobilizable (e.g., in the case of the so-called sulfonylurea secondary failure), and the more sophisticated insulin substitution strategies will have to be. On the basis of pathophysiological and clinical plausibilities, we have hypothesized that the earlier in the natural history of type 2 diabetes insulin treatment is started, the more endogenous insulin reserve will be (and hopefully will remain) available; so that the insulin therapy can be carried out as an insulin supplementation, e.g., with preprandial injections of regular insulin only.

Presently, two main strategies of insulin treatment in type 2 diabetic patients are being pursued at this department (27,28). The first strategy is the injection of a combination insulin preparation (e.g., 30% regular plus 70% NPH human insulin) before breakfast and before dinner along with dietary recommendations and systematic metabolic self-monitoring aiming to achieve the individual therapeutic goals (conventional insulin therapy). The second strategy is the injection of regular insulin before main meals as a supplementary insulin therapy. Timing and carbohydrate contents of meals can be kept very flexible, as patients learn to adapt insulin dosages based on metabolic self-monitoring. If started early enough during the natural history of type 2 diabetes, endogenous insulin secretion might transiently and partly recover (similar to the remission phase of type 1 diabetes), and required doses and frequencies of injections might decrease. This type of insulin therapy has been used favorably in younger type 2 diabetic patients who are unable to reach their therapeutic goals (i.e., usually HbA_1c levels <7.0–7.5%) by non-drug treatment. More recently, we have begun using the strategy of preprandial regular insulin injections also to achieve the particular therapeutic goals in old and very old people, with the advantage being that—in theory—the risk of severe hypoglycemia is decreased (when compared with conventional insulin therapy or to glibenclamide therapy). However, very frequently, NPH injections at bedtime have to be added to regular insulin, as the endogenous insulin secretion does not suffice to achieve acceptable levels of fasting glycemia.

Both strategies of insulin treatment must be integral parts of structured treatment and teaching programs during which the patients understand and accept the reasoning for the initiation of insulin treatment. Under those conditions, the therapeutic safety and effectiveness can easily be evaluated. Systematic prospective evaluation studies are presently in progress. Except for the risks of severe hypoglycemia and excessive increases in body weight, there are no side effects of insulin treatment of type 2 diabetes (see above). These variables can easily be determined in the framework of follow-up studies, along with HbA_1c levels and the incidence of acute complications. We have compiled some data from a number of follow-up evaluations (35,37–39), part of which is as yet unpublished, describing the medium-term therapeutic effects of the structured treatment and teaching program for insulin-treated type 2 diabetic patients.

Thus, in an multicenter attempt, we have reexamined some 550 type 2 diabetic patients (initial mean values: age 64 years, duration of diabetes 10 years, HbA_1c 9.6%, BMI 28.3 kg/m²) for up to 2 years after the initiation of conventional insulin therapy. Mean HbA_1c values dropped to 8.1%, BMI remained almost constant at 28.8 kg/m²; the incidence of severe hypoglycemia was relatively low at 0.04 cases per patient per year; and there were no cases of ketoacidotic or hyperosmolar diabetic coma. In a preliminary follow-up of 80 consecutive patients (mean age 52 years) for a mean of 2 years following the initiation of supplementary insulin therapy, mean HbA_1c levels fell from 9.4 to 7.5%, and BMI remained constant at 25.9 (vs. 25.7) kg/m²; and during >160 patient-years, there was no case of severe hypoglycemia.

Those are just observational data, such as any diabetes center should feel necessary to gather for quality assurance reasons. They are hardly meaningful concerning the principal outcomes variables—but they are proving the efficacy and safety of insulin therapy in type 2 diabetic patients based on conventional surrogate parameters.

CONCLUDING REMARKS— In conclusion, insulin treatment of type 2 diabetic patients aiming at individual therapeutic goals is effective and safe if conducted as an integral part of specific and structured treatment and teaching programs. Avoiding the (potential) hazards and risks of oral antidiabetic agents, insulin treatment can safely be used to achieve near-normal HbA_1c levels (<7.0–7.5%) if prevention of diabetic microangiopathy is indicated or to lower HbA_1c levels below 8.5–9.0% if catabolic symptoms due to insulin deficiency are primarily to be prevented. To carry out the treatment of type 2 diabetes in accordance with the principles of evidence-based medicine, randomized controlled intervention trials directed to cardiovascular and microangiopathic organ end points need to be conducted over and above the available data on certain subgroups of patients. Until then, it appears justified to treat the majority of patients with type 2 diabetes primarily by non-drug therapies; and, if they fail, to initiate insulin therapy aiming to achieve the patients' individual treatment goals. Furthermore, there is ample evidence to call for the normalization of arterial hypertension and hypercholesterolemia and to justify the prescription of aspirin in type 2 diabetes.

Acknowledgments— This study has been generously supported by the Peter Klöckner Stiftung, Duisburg/Germany (to M.B.).

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From the Department of Metabolic Diseases and Nutrition (WHO Collaborating Center for Diabetes Treatment and Prevention) (M.B., V.J., I.M.), Heinrich-Heine University, Düsseldorf; and the Professorial Unit for Health Science and Education (I.M.), University of Hamburg, Hamburg, Germany.

Address correspondence and reprint requests to Professor Michael Berger, Department of Metabolic Diseases and Nutrition, Heinrich-Heine University, Moorenstrasse 5, D-40225 Düsseldorf, Germany. E-mail: bergermi@uni-duesseldorf.de.

Received for publication 6 July 1998 and accepted in revised form 29 October 1998.

Abbreviations: DIGAMI, Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction; UGDP, University Group Diabetes Program; UKPDS, U.K. Prospective Diabetes Study; VACSDM, Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type 2 Diabetes.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

This article is based on a presentation at a conference organized by the Indiana University Diabetes Research and Training Center. The conference and the publication of this article were made possible by an unrestricted educational grant from Eli Lilly and Company.

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