Stepwise and Combination Drug Therapy for the Treatment of NIDDM

M M E N T A R Y

Stepwise and CombinationDrug Tiierapy for tiieTreatment of KIDDMHAROLD E. LEBOVITZ, MD

P harmacological tberapy for patientswith non-insulin-dependent diabe-tes mellitus (NIDDM) is finally ma-

turing into a rational discipline in whichits primary goal is to prevent markedmorbidity and increased mortality, whichhave been the hallmarks of this ubiqui-tous disease. Several major scientific ad-vances have been responsible for thischange. It has been unequivocally dem-onstrated that the level of glycémie con-trol has a direct and perhaps linear rela-tionship to the development andprogression of retinopathy in both insu-lin-dependent diabetes mellitus (IDDM)and NIDDM patients (1-3) and to the de-velopment and progression of nephropa-thy and neuropathy in IDDM patients.We now know that the level of HbAj^ is ayardstick by which to estimate the likeli-hood that microvascular and neuropathiccomplications will occur and progress ( 1-3). The Diabetes Control and Complica-tions Trial study provides us with thequantitative data shown in Table 1 (2).Similar data from the Wisconsin EyeStudy in NIDDM patients provide quan-titatively different but qualitatively similardata (3).

Therefore, we are able to concludethat every incremental improvement in

the level of HbAj , benefits patients withall types of diabetes and will reduce mi-crovascular and neuropathic complica-tions. As the contemporary strategy, theimplication of this for the management ofglycemia should be stepwise and multipledrug treatment to lower the HbAj^ to-ward normal as much as possible withoutcausing significant side effects.

While microvascular and neuro-pathic complications in NIDDM patientsare quite important, there are overwhelm-ing data that in western society the majordevastating chronic complications arethose attributed to macrovascular disease(4-6). Between 50 and 60% of NIDDMpatients' deaths are due to coronary arterydisease. The reasons for the increased ma-crovascular disease in NIDDM patientscannot be explained solely by hyperglyce-mia because individuals with impairedglucose tolerance and newly diagnosedNIDDM show significant increases in ma-crovascular disease (7-9). This has led tothe recognition tbat many individualshave an antecedent metabolic diseasesyndrome that is characterized by centralobesity, hypertension, dyslipidemia (in-creased very-low-density lipoprotein, tri-glycéride [TG], and decreased high-den-sity lipoprotein cholesterol), insulin

• • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • a

From the Department of Medicine, Division of Endocrinology, State University of New York,Health Science Center, Brooklyn, New York.

Address correspondence and reprint requests to Harold E. Lebovitz, MD, SUNY HealthScience Center at Brooklyn, 451 Clarkson Ave., Box 1205, Brooklyn, NY 11203.

Received for publication 6 July 1994 and accepted in revised form 22 September 1994.NIDDM, non-insulin-dependent diabetes mellitus; IDDM, insulin-dependent diabetes melli-

tus; TG, triglycéride; FDA, Food and Drug Administration.

resistance, hyperinsulinemia, abnormallevels of circulating coagulation factors(fibrinogen, PAl-1), and hyperuricemia(10,11). It is unclear how all the variouscardiovascular risk factors interact tocause accelerated atherosclerosis inNIDDM patients, but it is clear that eachidentifiable factor should be improved ifpossible.

In this context of treating glyce-mia and the other metabolic defects inNIDDM patients, we can examine what isavailable now and in the near future toallow us to achieve our therapeutic goals.While diet and exercise are uniformlyheralded as the panacea for the treatmentof NIDDM, large long-term studies haveconsistently achieved adequate glycémieand metabolic control in no more than10% of the populations treated only withdietary intervention and increased physi-cal activity (12,13). The remainder of thepatients have required pharmacologicaltreatment.

For glycémie regulation, fourclasses of drugs are available worldwide.They are sulfonylurea compounds, bi-guanide compounds, a-glucosidase in-hibitors, and insulins (14,15). Theseclasses have different modes of actions asdescribed in Table 2 and Eig. 1. There-fore, they can be used individually for cer-tain types of patients or can be combinedin a stepwise fashion to provide moreideal glycémie control for most patients.Additionally, each of these classes ofdrugs have different effects on bodyweight, serum lipid levels, plasma insulinlevels, and perhaps even insulin resis-tance (16). Thus, they have the potentialto alter cardiovascular risk factors as wellas glycemia.

Hermann et al. (13) and Jeppesenet al. (17) are excellent examples of thepoints that I have discussed. Both studiesconfirm and extend observations that aremore than 25 years old that showed thatthe combination of metformin and sulfo-nylurea compounds is able to achieve ex-cellent glycémie control in NIDDM pa-tients who are not adequately controlled

1542 DIABETES CARE, VOLUME 17, NUMBER 12, DECEMBER 1994

Lebovitz

Table 1—Glycémie control and complications in IDDM: DCCT Study

Rate/100 patient-years

-7.2 t . -9 .2

DevelopmentS:3-step sustained retinopathy

MicroalbuminuriaClinical proteinuriaClinical neuropathy

ProgressionSevere nonproliferative or

proliferative retinopaihyLaser treatmentClinical proteinuriaClinical neuropathy

1.2

2.20.23.1

1.1

0.90.67.0

4.7

3.40.39.8

2.4

2.31.4

16.1

on either drug alone. Hermann et al.showed equal efficacy of metformin andglyburide in mildly hyperglycémie pa-tients. More severely hyperglycémie pa-

tients experienced HbAjj, levels reducedby slightly >2% when the drugs werecombined. An advantage of metforminover glyburide was no weight gain and no

Bedtime Insulin

IngestionAlpha Glucosidase

Inhibitors

HepaticGlucoseProduction

ExtracellularGlucose Pool

Beta BlockersDiuretics

Nicotinic Acid

SulfonylureasAlpha AdrenergicAntagonists

MetforminInsulin

Alpha Adrenergic

Antagonists

Glucose Utilization

Fig. 1—Sites of action of various antidiabetic, anlihyperlensive, and lipid-lowering agents on glucosemeiabolism in NÍDDM paíienís. ingestion and hepatic glueose production lead to increased flux ofglucose into the extracellular pool Diet and a-glucosidase inhibitors decrease the ejects of ingestion andlower postprar)dial plasma glucose. Insulin administered at bedtime decreases hepatic glueose produc-tion and lowers fasting plasma glucose, insuiin deficiency and/or insulin resistance expand the pool byreducing efflux. Sulfonylurea drugs and a-adrener^c receptor antagonists can increase insulin secre-tion. Oiureties and ß-blockers decrease insulin secretion. Metformin and a-adrener^e receptor antag-onists increase insulin action. Nicotinic acid interferes with insulin action through its metabolic effects.

rise in plasma insulin. Jepperson et al. notonly showed the efficacy of adding met-formin to maximal sulfonylurea treat-ment in decreasing HbA, from 10.8 to7.9%, but they also showed reductions infasting and postprandial TGs, postpran-dial plasma insulin, and free fatty acids.

Metformin, when approved bythe Food and Drug Administration (FDA)for use in the U.S., will provide physictanswith an important agent for controllingglycemia and lowering cardiovascularrisk factors in NIDDM patients. Its abilityto lower fasting and postprandial plasmaglucose alone or in combination withother agents will provide improvedHbAjj. levels for many patients(14-16,18). Its effects in decreasing bodyweight (1-3 kg), lowering plasma insulin,decreasing TGs and possibly low-densitylipoprotein cholesterol, and reducingplasminogen activator inhibitor 1 levelsmay have some beneficial effects on car-diovascular disease.

Another class of drugs that specif-ically lowers postprandial plasma glu-cose, insulin, and TGs is a-glucosidaseinhibitors. These drugs can be combinedwith sulfonylurea compounds, met-formin, or both because their effect inlowering HbAi ^ is additive (14-16,19).While approved for use in many coun-tries, they are still being evaluated by theFDA.

The use of various oral agentsalone or in combination with each otherand/or insulin provides clinicians withnumerous options for the treatment ofNIDDM patients. Patients with mild tomodest hyperglycemia who are not ade-quately controlled on diet and modest in-creases in physical activity can be treatedwith metformin or with a-glucosidase in-hibitors when they become available.Neither would cause weight gain, andboth would lower postprandial insulinand TG levels. For more severe hypeigly-cemia associated with modest insulin de-ficiency, sulfonylurea compounds mightbe appropriate because they increase in-sulin secretion. As the sulfonylurea com-pounds become less effective, combina-

DiABETES CARE, VOLUME 17, NUMBER 12, DECEMBER 1994 1543

Commentary

Table 2—Primary mode of action of anti-diabetic drugs

SulfonylureasIncrease ß-cell insulin secretion through

closing the ATP-sensitive potassium ionchannel

MetforminDecreases hepatic glucose productionIncreases intracellular glucose metabolism

a-glucosidase inhibitorsDecrease postprandial glycémie rise by

slowing carbohydrate digestionInsulin

Increases intracellular glucose oxidationand utilization

Decreases hepatic glucose production

tion therapy with metformin and/or ana-glucosidase inhibitor could restore gly-cemic control to the desired target range.As endogenous insulin deficiency in-creases, one could consider adding an in-termediate-acting insulin at bedtime tocontrol fasting byperglycemia and con-tinue oral agents during the day. And fi-nally, with severe endogenous insulin de-ficiency, multiple daily injections ofinsulin might be necessary.

This new era of stepwise and com-bination therapy for the control of hyper-glycemia and the other metabolic abnor-malities associated with NIDDM shouldsignificantly decrease morbidity and mor-tality from NIDDM.

The focus of this commentary hasbeen on antihyperglycemic agents andtheir associated metabolic activities.However, it is equally important to recog-nize that some antihypertensive and lip-id-lowering agents exert specific meta-bolic actions on glycémie control (Fig. 1).Thus, an appropriately designed treat-ment program must be a symphony thatplays in harmony rather than cacophony.

The main goal of treatment in patientswith NIDDM is to normalize as much aspossible glycemia and cardiovascular dis-ease risk factors. Only then can we reducemorbidity and mortahty to nondiabeticlevels.

References

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14. Lebovitz HE: Oral antidiabetic agents. InJosiin's Diabetes MelHtus 13th ed. KahnCR, Weir GC, Eds. Philadelphia, PA, Lea& Febiger, 1994, p. 508-529

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