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Original Studies |
Department of Medicine, Division of Endocrinology and Diabetology, University of Helsinki (H.Y.-J., M.-R.T.), Helsinki; Kymenlaakso Central Hospital (L.R.), Kotka; the Department of Medicine, University of Turku (M.K., P.S., J.V.), Turku; Hatanpää Hospital (E.K., S.R.), Finnish Diabetes Center (S.S.), Tampere; Kuopio City Hospital (J.L., L.N.), Kuopio; Äänekoski Health Center (T.M.), Äänekoski; and Lappi Central Hospital (T.T.), Rovaniemi, Finland
Address all correspondence and requests for reprints to: Prof. Hannele Yki-Järvinen, M.D., University of Helsinki, Department of Medicine, Division of Endocrinology and Diabetology, Haartmanin-katu 4, FIN-00290 Helsinki, Finland. E-mail: ykijarvi{at}helsinki.fi
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Abstract |
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Introduction |
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One of the striking features of NIDDM, however, is its heterogeneity with respect to physical characteristics such as body weight and metabolic characteristics such as the degree of insulin resistance and residual insulin secretion (5). The impact of such features on the response to various insulin treatment regimens is unknown, although clinical experience and scattered case reports (6) would favor the view that obese patients with NIDDM are more difficult to treat with insulin than are nonobese subjects. Regarding the choice of the insulin regimen, one might hypothesize that lean, insulin-sensitive patients benefit from insulin regimens resembling those used for patients with IDDM, whereas obese patients might be treated with less intense insulin regimens. However, no systematic study testing the validity of these or other beliefs regarding the individual factors underlying the treatment response to insulin has been performed. It is also unknown whether factors such as body weight should be considered in choosing the insulin regimen.
In the present study, we report the 1-yr treatment results from the Finnish Multicenter Insulin Study comparing insulin regimens in NIDDM (2). Analysis of the treatment response after 1 yr revealed significant deterioration in glycemic control, particularly in the obese patients. We, therefore, analyzed the 1 yr data by comparing the treatment results in nonobese and obese patients treated with either combination therapy with insulin or insulin alone.
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Subjects and Methods |
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FINMIS had two specific aims regarding insulin therapy in NIDDM. First, we wished to determine the optimal insulin treatment regimen for patients with NIDDM by comparing two combination and two insulin therapy regimens with each other and with a control group who continued oral agents. Data from this comparison have been reported previously (2). This part of the trial was discontinued at 3 months, as it was considered unethical not to treat overt hyperglycemia in the control group after 3 months. The second aim of the FINMIS study was to determine the roles of individual factors, especially body weight on the long term treatment response to combination therapy with insulin vs. insulin therapy alone during a 12-month period. Data addressing this aim form the basis of the present report.
Patient selection. The study consisted of a 6-week run-in
period and 12 months of insulin therapy. The patients were recruited in
six centers using the following criteria: inclusion criteria: 1) age
40–70 yr, 2) body mass index (BMI) less than 35 kg/m2, 3)
fasting plasma glucose more than 144 mg/dL (8 mmol/L), 4) duration of
diabetes more than 3 yr, 5) previous oral therapy with a maximal dose
of either glipizide (
15 mg/day) or glibenclamide (10.5 mg/day)
alone or in combination with metformin, and 6) fasting serum C-peptide
more than 0.33 nmol/L (reference range, 0.33–0.69 nmol/L). The
exclusion criteria were serious macro- or microvascular complications
or other diseases (2).
Randomization. After a 6-week run-in period (see Ref. 2 for
details), the patients were originally randomized, using minimization
as the method of randomization (7), into combination [100 IU/mL NPH;
Protaphan Human Pen (Novo Nordisk, Espoo, Finland) before breakfast or
at 2100 h and continued oral agents] and insulin [100 IU/mL
70/30 NPH/regular insulin; Demiphan Human Pen, Novo-Nordisk) before
breakfast and dinner, or NPH (ProtaphanR Human Pen) at
2100 h and regular insulin (100 IU/mL; Actrapid Human Pen,
Novo/Nordisk) before breakfast, lunch, and dinner] therapy groups (2).
The patients who continued insulin or combination therapy after 3
months until 1 yr formed the present study population (see
"drop-outs" in Results). As baseline BMI was the most
significant predictor of changes in glycemic control during the
follow-up (see Results), the patients were subdivided into
groups based on their mean baseline BMI into obese and nonobese
subjects treated with either combination or insulin therapy (Table 1
). This method of analysis was chosen
because of its clarity, although similar conclusions regarding the
impact of body weight on the response to insulin therapy could also be
obtained using regression analyses. Those with BMIs below and above the
mean (28.1 kg/m2) were called nonobese and obese,
respectively. The baseline physical and clinical characteristics of the
study groups are shown in Table 1.
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Analytical methods
Home blood glucose measurements were performed using the Hypocount Home Blood Glucose Monitor (Oriola, Espoo, Finland). HbA1c concentrations were determined at the Helsinki University Central Hospital using high pressure liquid chromatography (8). Serum C-peptide concentrations were measured by RIA (9). Serum lipoprotein fractions were separated by sequential flotation in an ultracentrifuge (L8–70, Beckman, Palo Alto, CA) as previously described (10). Cholesterol and triglyceride concentrations were measured enzymatically using kits 187313 and 297771 from Boehringer Mannheim (Mannheim, Germany). Liver enzymes, serum creatinine, and blood glucose were measured using standard techniques in the local treatment center. All other measurements were assayed centrally at the University of Helsinki Research Laboratories.
Statistical analysis
Analysis of data distribution and comparison of changes between
the groups were performed using BMDP programs (11) for detailed data
description (program 2D) and ANOVA (program 7D) followed by the
Bonferroni test. Changes within a group were calculated using ANOVA for
repeated measures (program 2V). Data regarding drug use were analyzed
using multiway tables (program 4F) followed by Pearson’s
2 statistic for comparison between groups. Linear
regression analyses were performed using simple (program 8D) and
multiple (program 1R) linear regression analyses. Results are shown as
the mean ± SE.
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Results |
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In the entire study group (n = 100), HbA1c averaged 9.7 ± 0.2% at 0 months and 8.0 ± 0.1%, 8.0 ± 0.1%, 8.2 ± 0.1%, and 8.5 ± 0.2% at 3, 6, 9, and 12 months, respectively (P < 0.001 for each time point vs. 0 months). Glycemic control at 12 months was significantly worse than that at 3 (P < 0.001), 6 (P < 0.001), or 9 months (P < 0.02). In simple regression analysis, the change in HbA1c between 12 and 3 months (0.64 ± 0.18%) was significantly correlated with weight gain (P < 0.02) and initial weight (P < 0.02), but not with other parameters such as fasting glycemia, C-peptide, duration of diabetes, age, blood pressure, lipid or lipoprotein concentrations, use of metformin, diuretics, ß-blockers, or other drugs. In multiple linear regression analysis, initial weight (P < 0.05), but not the change in weight (P = 0.58), was an independent predictor of deterioration of glycemic control.
Nonobese patients. HbA1c decreased significantly
by -2.0 ± 0.2% (P < 0.001, 3 vs. 0
months) during the first 3 months of insulin therapy. This decrease was
maintained throughout the 12-month treatment period (Fig. 1). The decrease in HbA1c was
similar in the combination and insulin therapy groups (Fig. 1).
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). At 12 months, HbA1c was not significantly lower than
that at baseline (change, -0.5 ± 0.4%). The worsening of
glycemic control was similar in the combination and insulin therapy
groups (Fig. 1). The decrease in HbA1c at 6, 9, and 12, but
not that at 3 months, was significantly greater in the nonobese than in
the obese group (Fig. 1; P < 0.05 or less at all time
points). This was true for both the combination and the insulin therapy
groups and even after adjusting for the slightly lower baseline
HbA1c in the obese compared to the nonobese group using
analysis of covariance. Changes in body weight
Nonobese patients. Body weight increased significantly
compared to 0 months in both the combination and insulin therapy groups
(Fig. 2). Patients treated with
combination therapy gained significantly less weight throughout the
12-month period than those treated with insulin alone (Fig. 2). Weight
gain averaged 3.5 ± 0.6 kg in the combination and 5.1 ± 0.7
kg in the insulin-treated group at 12 months.
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Insulin doses
In the nonobese patients, the mean daily insulin dose averaged 0.2 ± 0.1 and 0.6 ± 0.1 IU/kg in the combination and insulin therapy groups at 12 months. In the obese patients, the mean daily insulin doses, expressed in terms of kilograms of body weight, were identical to those in the nonobese patients and averaged 0.2 ± 0.1 and 0.6 ± 0.1 IU/kg in patients treated with combination and insulin therapy, respectively.
Hypoglycemias
The number of reported symptomatic hypoglycemic episodes averaged 1.6 ± 0.6 and 2.1 ± 0.5 episodes/patient·yr in the nonobese patients treated with combination and insulin therapy (NS). In the obese patients, the number of hypoglycemic episodes averaged 0.4 ± 0.2 and 1.7 ± 0.8 episodes/patient·yr, respectively (P = NS). The number of hypoglycemic episodes in the obese subgroup treated with combination therapy (0.4 ± 0.2) was significantly lower than the frequency in the nonobese group using insulin alone (2.1 ± 0.5; P < 0.05).
Changes in blood pressure and serum lipids and lipoproteins
Systolic blood pressures in the entire study population were
1 ± 2 (P = NS), 6 ± 2 (P <
0.01), 8 ± 2 (P < 0.001), and 8 ± 2
(P < 0.001) mm Hg higher at 3, 6, 9, and 12 months,
respectively, than at baseline. A progressive increase was observed in
both the nonobese and obese patients and in both combination and
insulin therapy groups (Fig. 3). The
increase in systolic blood pressure was weakly positively correlated
with weight gain in the entire study group (r = 0.22;
P < 0.02). Diastolic blood pressure did not change
significantly during the study period (data not shown).
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). The
decrease in serum triglycerides was mainly due to a decrease in the
triglyceride content of very low density lipoprotein (VLDL) particles
(Table 2 and Fig. 4). Serum total
cholesterol remained unchanged. However, the cholesterol content of
lipoprotein subfractions was slightly altered. The serum low density
lipoprotein cholesterol exhibited a small increase, which was
counterbalanced by slight decreases in the cholesterol content of both
VLDL and high density lipoprotein subfractions (Table 2).
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In addition to the control group, which was discontinued after 3 months, a total of 20 patients discontinued the study. In 5 patients this was due to a medical problem (renal carcinoma, foot infection and toe amputation, psychiatric problem, and 2 myocardial infarctions). Two patients moved outside their hospital district. Thirteen patients (10% of the patients who started insulin therapy) discontinued the study prematurely because of noncompliance. Of these patients 7 were in the multiple insulin therapy group, 2 were in the 2-injection group, 2 were in the evening NPH, and 2 were in the morning NPH combination therapy groups.
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Discussion |
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The participating centers represented locations at which patients with NIDDM are usually treated. The doctors and nurses at the participating centers were highly motivated and experienced, and also specialized in the treatment of diabetic patients. Despite this, however, the glycemic targets were not achieved. Although the goal was to increase the insulin dose, if fasting plasma glucose exceeded 7 mmol/L or postprandial glucose exceeded 10 mmol/L, this clearly did not happen. This resulted in suboptimal glycemic control in all groups and a marked deterioration in glycemia in the obese patients with NIDDM. Several factors could explain the use of insufficient insulin doses. We believe that the major reason was that the adjustment of the insulin dose was performed at 3-month intervals at the treatment center, rather than by the patient. The recommended average starting doses in the combination and insulin therapy groups (see Materials and Methods) were 10 and 20 IU at a fasting plasma glucose concentration of 10 mmol/L. The insulin dose was then, as is usually done, increased by 4–6 IU/visit. Considering this rate of increase in the insulin dose, it is not surprising that the daily insulin doses were not higher than 20 and 45 IU in the combination and insulin therapy groups at 12 months. The insulin dose required to achieve normo- or near normoglycemia varies considerably in NIDDM. In the present study, the individual bedtime doses of NPH ranged from 8–99 IU in the evening insulin combination therapy group. This implies that self-adjustment of the insulin dose, based on home glucose monitoring, is necessary for proper adjustment of the insulin dose. Self-adjustment may speed up achievement of glycemic targets and avoid abandoning insulin therapy prematurely. This approach has now been successfully used in a new multicenter study comparing four different combination therapy regimens, all including bedtime NPH (13).
Worsening of glycemic control over time in obese NIDDM patients has often been attributed to weight gain (14, 15). In the present study, the obese patients did not gain more weight than the nonobese subjects, yet their glycemic control deteriorated after an initial improvement. Weight gain per se, therefore, cannot explain worsening of glycemic in obese patients with NIDDM. On the other hand, obese patients may not tolerate weight gain as well as nonobese subjects. In the present, as in previous studies (16), the obese patients had higher C-peptide and triglyceride concentrations than the nonobese subjects, consistent with greater hepatic or peripheral insulin resistance (17). It is, therefore, possible that the insulin dose needed to counteract the additional effects of weight gain on insulin sensitivity are greater, per kg BW, in the obese than the nonobese patients. It is also well known that NIDDM is a disease characterized by gradual loss of ß-cell function, insulin sensitivity, and an increase in blood glucose concentrations (12) due to factors such as glucose toxicity (18). This natural course of NIDDM is, however, unlikely to explain worsening of glycemic control in the obese patients with NIDDM because these patients had, if anything, better glycemic control at baseline than the nonobese patients.
The present data and recent reports by others (3, 4) confirm, in nonobese patients with NIDDM, our original report showing that combination therapy with insulin induces less weight gain than the use of insulin alone. This difference could be caused by "eating because of an insulin injection," i.e. greater dietary intake in those taking multiple rather than single insulin injections, differences in the degree of peripheral hyperinsulinemia during the various insulin regimens, prevention of weight gain by use of metformin in the combination therapy groups (19), or other factors. The exact reason for this difference, however, awaits studies specifically examining this question.
We observed a significant increase in systolic blood pressure in the entire study population, which was weakly correlated with weight gain over 12 months. This result differs from our previous finding of an unchanged blood pressure after 3 months of insulin therapy (2). Lindström et al. found no increase in blood pressure despite a mean weight gain of 8.6 kg over 27 months. The lack of an increase in blood pressure in the latter study could be a type 2 error, as only 21 patients were studied (20). The same reason may explain why Bruce et al. found no significant increase in blood pressure during 12 months of insulin therapy in 22 patients with NIDDM (16). In keeping with the large variability in blood pressure measurements, we observed a similar increasing trend in blood pressure over 12 months in all groups, but the increase was not statistically significant at each time point. Obesity is known to be associated with hypertension (21). This was also true in the present study, in which the obese patients had higher systolic blood pressure at baseline and also used more diuretics for the treatment of hypertension. The correlation between weight gain and the increase in blood pressure, therefore, could reflect a causal relationship between the 2 parameters. These data further emphasize the need to treat patients with NIDDM with treatment regimens that improve glycemic control without inducing weight gain.
The decrease in serum and VLDL triglycerides in the present study were similar in the obese and nonobese patients, suggesting that the ability of insulin to decrease triglycerides does not parallel its effect on glycemia. Whether this is because antilipolysis or insulin stimulation of lipoprotein lipase (LPL) activity are not subject to insulin resistance or to other factors is presently unclear. Regarding the effect of various insulin regimens on lipid changes, Chow et al. (4) recently reported that serum triglycerides decreased significantly in the patients treated with insulin alone, but remained unchanged in those treated with bedtime NPH and oral agents. A similar pattern can be discerned in the present data. We have previously shown that adipose tissue LPL activity increases more than 2-fold during 4 weeks of multiple insulin injection therapy (10) and suggested that this increase contributes to the fall in VLDL. As insulin concentrations are higher during multiple insulin injection than during combination therapy (2), it is possible that the tendency toward a greater fall of triglycerides during insulin than combination therapy was due to a greater stimulation of LPL by insulin.
The frequency of reported symptomatic hypoglycemias was significantly lower in the obese patients treated with combination therapy (0.4 episodes/patient·yr) than in the nonobese subjects treated with insulin alone (2.1 episodes/patient·yr). This finding is consistent with worse glycemic control in the obese than the nonobese group. The frequency of hypoglycemic episodes was low, as during the first 3 months (2), and comparable to that reported by Taylor et al. in patients with NIDDM treated with insulin (0.4 episodes/patient·yr) (22).
In conclusion, the present study shows that obesity predicts a poor treatment response to insulin, regardless of the insulin treatment regimen, in patients with NIDDM. In obese patients, weight gain per se cannot explain the poor glycemic response, but it may induce a disproportionately large increase in insulin requirements because of greater insulin resistance in the obese than in the nonobese. To ensure adequate titration of insulin doses in the obese, we recommend intense education of patients to learn self-adjustment of the insulin dose based on home glucose monitoring. If insulin doses are adjusted only at out-patient visits every 3 months, glycemic targets are unlikely to be achieved. In nonobese patients, glycemic control improves equally during 1 yr with combination therapy with insulin and insulin alone, but combination therapy with insulin is associated with less weight gain than treatment with insulin alone. Even a slight increase in body weight appears harmful, as it is associated with an increase in blood pressure and low density lipoprotein cholesterol.
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Acknowledgments |
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Received April 16, 1997.
Revised August 29, 1997.
Accepted September 11, 1997.
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; Comb)
or insulin (•; Ins) therapy for 12 months. x, P
< 0.05; xxx, P < 0.001 (for decrease
vs. 0 months). For differences in changes in
HbA1c between the treatment groups, see text.
