HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Extract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yki-Järvinen, H. Search for Related Content PubMed PubMed Citation Articles by Yki-Järvinen, H. Social Bookmarking                What's this?

Combination Therapies With Insulin in Type 2 Diabetes

¹ Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland

	INTRODUCTION

TOP INTRODUCTION GLYCEMIC CONTROL AND INSULIN... WEIGHT GAIN HYPOGLYCEMIAS CHANGES IN SERUM TRIGLYCERIDES... BLOOD PRESSURE SPECIAL QUESTIONS PREDICTION OF INSULIN... PREDICTORS OF A GLYCEMIC... PRACTICAL ALGORITHM TO INITIATE... CONCLUDING REMARKS References

 
The U.K. Prospective Diabetes Study (UKPDS) demonstrated that intensive glucose control with insulin or sulfonylureas markedly reduces the risk of microvascular complications (1). For myocardial infarction, the reduction in risk (16% for a 0.9% decrease in HbA_1c) was of borderline significance but corresponded closely to epidemiological predictions (14% decrease for a 1% drop in HbA_1c) (2). These data demonstrated that neither insulin nor sulfonylureas, despite causing hyperinsulinemia and weight gain, have adverse effects on cardiovascular outcome. Glycemic control deteriorated continuously, however, even in intensively treated patients in the UKPDS (1).

In the UKPDS, the worsening of glycemic control has been attributed to the natural course of type 2 diabetes and lack of efficacy of current antihyperglycemic therapies (1). Insulin therapy consisted of a single injection of ultralente or isophane insulin. If the daily dose exceeded 14 U, regular insulin was added and home-glucose monitoring was encouraged (1). Combination therapy regimens with insulin and oral agents were not used. We now know that 14 U of long-acting insulin is insufficient to control fasting glycemia in most type 2 diabetic patients (3). Since 1977, when the UKPDS was started, several studies have tried to define the optimal insulin treatment regimen for type 2 diabetic patients. These studies are the focus of this review and include studies comparing insulin alone to combination therapy with insulin and sulfonylureas (subject to meta-analyses in 1991 and 1992) (4,5) and more recent trials using metformin, glitazones, or acarbose in insulin combination therapy regimens. They do not contain data on cardiovascular end points but only on surrogate markers of risk of micro- and macrovascular complications, mostly data on glycemia, body weight, insulin doses, lipids, and in a few studies, also accurate data on the frequency of hypoglycemias.

According to a Medline search (1966–2000), insulin alone has been compared with insulin combination therapy in a total of 34 prospective studies that lasted at least 2 months and reported data on HbA₁ or HbA_1c in type 2 diabetic patients. Studies comparing glycemic control, weight gain, hypoglycemias, and insulin requirements between the two modes of treatment in insulin-naïve patients are listed in Table 1 and in previously insulin-treated patients are listed in Table 2. The studies have been ranked according to glycemic control at the end of the trial.

	GLYCEMIC CONTROL AND INSULIN REQUIREMENTS

TOP INTRODUCTION GLYCEMIC CONTROL AND INSULIN... WEIGHT GAIN HYPOGLYCEMIAS CHANGES IN SERUM TRIGLYCERIDES... BLOOD PRESSURE SPECIAL QUESTIONS PREDICTION OF INSULIN... PREDICTORS OF A GLYCEMIC... PRACTICAL ALGORITHM TO INITIATE... CONCLUDING REMARKS References

	WEIGHT GAIN

TOP INTRODUCTION GLYCEMIC CONTROL AND INSULIN... WEIGHT GAIN HYPOGLYCEMIAS CHANGES IN SERUM TRIGLYCERIDES... BLOOD PRESSURE SPECIAL QUESTIONS PREDICTION OF INSULIN... PREDICTORS OF A GLYCEMIC... PRACTICAL ALGORITHM TO INITIATE... CONCLUDING REMARKS References

 
What determines weight gain during insulin therapy?
Although most patients with type 2 diabetes are overweight, weight loss precedes the diagnosis of type 2 diabetes (7). This weight loss is due to hyperglycemia-induced wasting of energy, as glucosuria and as energy used to overproduce glucose (8). When glucose control is improved with insulin and/or sulfonylureas, energy loss in the urine decreases or ceases, weight increases, and basal metabolic rate (kJ/min) (8–10) and dietary intake (11) remain unchanged. The increase in body weight increases basal metabolic rate, but this is counterbalanced by improved glycemic control, which decreases basal metabolic rate because less energy is needed for glucose overproduction. Because dietary intake remains unchanged (11), weight gain is proportional to reduction of glucosuria and can indeed be predicted based on fasting glucose concentrations (11). Because glucosuria appears when the fasting glucose concentration exceeds 10–12 mmol/l, weight gain is inevitable if insulin therapy is postponed until significant glucosuria occurs. In our experience, a 5-mmol/l (90-mg/dl) decrease in fasting glucose or a decrease in HbA_1c by 2.5% from a baseline of 15 mmol/l (270 mg/dl) is associated with a 5-kg weight gain during 1 year (or 2 kg/1% decrease in HbA_1c) (11). Thus, the main predictors of weight gain are initial glycemia and its response to treatment (11). The patient with poor glycemic control before initiation of insulin therapy but with a good treatment response is at greatest risk for weight gain.

Choice of oral agent and weight gain in insulin-naïve patients.
Only one trial has compared the combination of insulin with that of insulin and metformin alone in previously insulin-naïve patients (12). In this study, which lasted 12 months, the bedtime insulin-metformin regimen was superior to three other bedtime insulin regimens with respect to glycemic control, weight gain, and hypoglycemias (Table 1) (12). The ability of metformin to counteract weight gain and improve glycemia, when combined with insulin, has been confirmed in abstract reports (13,14). In these studies, weight gain was less despite comparable glycemia (13) or weight gain was similar despite better glycemic control (14) in patients using metformin and insulin compared with those using insulin and sulfonylureas or insulin alone. Data are heterogenous regarding the ability of metformin to influence weight gain when combined with both insulin and sulfonylureas, compared with regimens containing insulin alone (Table 1). In two comparisons, weight gain was less with the combination regimen than with insulin alone (15,16), whereas two other comparisons revealed no difference (12,15) (Table 1, Fig. 1). The ability of metformin to counteract weight gain during insulin combination therapy has been attributed to a decrease in dietary intake (11).

View larger version (20K): [in this window] [in a new window]   Figure 1 — Weight gain in previously insulin-treated patients during treatment with insulin combination regimens containing metformin (MET) (24,42,43), various sulfonylureas (SU) (26,44–51), and glitazones (GLIT) (52–54) and in insulin-naïve patients treated with insulin and MET (12), SU+MET (12,15,16), and SU (12,25,27–29).

	HYPOGLYCEMIAS

TOP INTRODUCTION GLYCEMIC CONTROL AND INSULIN... WEIGHT GAIN HYPOGLYCEMIAS CHANGES IN SERUM TRIGLYCERIDES... BLOOD PRESSURE SPECIAL QUESTIONS PREDICTION OF INSULIN... PREDICTORS OF A GLYCEMIC... PRACTICAL ALGORITHM TO INITIATE... CONCLUDING REMARKS References

 
Frequency of hypoglycemias in type 1 versus type 2 diabetes.
In both patients with type 1 (22) and type 2 (12) diabetes, the frequency of hypoglycemias is inversely proportional to glycemic control. In the Diabetes Control and Complications Trial, in patients with HbA_1c between 7 and 8%, the frequency of severe hypoglycemias requiring assistance in the provision of treatment was 0.62 per patient per year (22). In contrast, in the FINFAT study (12), the Kumamoto study (23), or other studies of type 2 diabetes in which comparable glycemic control was achieved (24,25), there were no severe hypoglycemias. The frequency of biochemical hypoglycemias (blood glucose <3.5 mmol/l) was 1.9 per patient per year in patients treated with insulin plus metformin and approximately twice as high in the other groups in the FINFAT study (12). In the latter study, HbA_1c averaged between 7 and 8% in all groups for 1 year. These data, although derived from separate studies, suggest that hypoglycemias are much less of a problem in type 2 diabetic patients than in type 1 diabetic patients.

Does the oral agent influence the occurrence of hypoglycemias independent of glycemic control?
The occurrence of hypoglycemia has been sparsely reported [eight comparisons in insulin-naïve patients (Table 1) and five comparisons in previously insulin-treated patients (Table 2)]. In insulin-naïve patients, use of insulin combination therapy with metformin has been associated with less hypoglycemias than with insulin alone, despite better glycemic control with the insulin-combination regimen (12). No difference was observed between insulin-alone and insulin-sulfonylurea regimens in five of seven studies; in two studies (25,26), there were more cases of hypoglycemia with insulin and sulfonylurea than with insulin alone (Tables 1 and 2). No difference in the incidence of hypoglycemia was observed between insulin alone compared with insulin plus sulfonylurea and metformin regimens (Tables 1 and 2). In the latter studies, there was also no difference in glycemic control. In all three studies comparing insulin-glitazone combination therapy to insulin alone, the frequency of hypoglycemia was higher and glycemic control was better with the insulin-combination regimen. These data suggest that with the possible exception of metformin, use of insulin combination therapy is accompanied by a similar frequency of hypoglycemia than is use of insulin alone.

	CHANGES IN SERUM TRIGLYCERIDES AND OTHER LIPIDS AND LIPOPROTEINS

TOP INTRODUCTION GLYCEMIC CONTROL AND INSULIN... WEIGHT GAIN HYPOGLYCEMIAS CHANGES IN SERUM TRIGLYCERIDES... BLOOD PRESSURE SPECIAL QUESTIONS PREDICTION OF INSULIN... PREDICTORS OF A GLYCEMIC... PRACTICAL ALGORITHM TO INITIATE... CONCLUDING REMARKS References

 
Insulin-naïve patients.
Data on changes in serum triglycerides and glycemia in insulin-naïve patients are summarized in Table 3. As judged from the weighted means of insulin-alone regimens, a decrease in HbA_1c from 10 to 8% (i.e., by 2%) is associated with a 0.7- to 0.8-mmol/l decrease in serum triglycerides from an initial concentration of 2.4–2.7 mmol/l. With insulin combination therapy regimens, a decrease of HbA_1c by 2% decreases serum triglycerides by 0.4–0.6 mmol/l (Table 3). In all except one study, insulin alone lowered serum triglycerides slightly more than insulin combination therapy, although there was no significant difference in the lowering of serum triglycerides with the two modes of therapy in any of the studies (Table 3). LDL and HDL cholesterol concentrations remained unchanged in all studies, with no differences between regimens (12,15,16,25,27–29).

	BLOOD PRESSURE

TOP INTRODUCTION GLYCEMIC CONTROL AND INSULIN... WEIGHT GAIN HYPOGLYCEMIAS CHANGES IN SERUM TRIGLYCERIDES... BLOOD PRESSURE SPECIAL QUESTIONS PREDICTION OF INSULIN... PREDICTORS OF A GLYCEMIC... PRACTICAL ALGORITHM TO INITIATE... CONCLUDING REMARKS References

	SPECIAL QUESTIONS

TOP INTRODUCTION GLYCEMIC CONTROL AND INSULIN... WEIGHT GAIN HYPOGLYCEMIAS CHANGES IN SERUM TRIGLYCERIDES... BLOOD PRESSURE SPECIAL QUESTIONS PREDICTION OF INSULIN... PREDICTORS OF A GLYCEMIC... PRACTICAL ALGORITHM TO INITIATE... CONCLUDING REMARKS References

 
Choice of insulin regimen during insulin combination therapy: NPH insulin or insulin glargine?
Regarding basal insulinization, the commonly used intermediate-acting insulin (NPH) is not ideal for once-daily use. In the FINMIS study, in patients with type 2 diabetes with a mean BMI of 29 kg/m², injection of NPH insulin at 9:00 P.M. resulted in maximal glucose lowering between 4:00 and 8:00 A.M., but the effect was gone by 3:00 P.M., i.e., 18 h after the injection, and dinnertime glucose concentrations were unnecessarily high. The recently approved long-acting insulin analog insulin glargine seems to overcome these problems. In a study comparing NPH plus oral agents to insulin glargine plus oral agents in 423 insulin-naïve type 2 diabetic patients for 1 year, all hypoglycemias were 35% lower and nocturnal hypoglycemias were 56% lower with insulin glargine than with NPH (Fig. 2). Dinnertime glucose levels were also significantly lower with insulin glargine than with NPH (Fig. 2).

View larger version (22K): [in this window] [in a new window]   Figure 2 — Upper panel: Diurnal glucose profiles after 52 weeks of treatment of 423 patients using oral hypoglycemic agents with either insulin glargine (•) or NPH (). Lower panel: The percentage of patients experiencing any symptomatic hypoglycemia (ALL) or nocturnal hypoglycemia (NOCTURNAL) in the same study (40).

	PREDICTION OF INSULIN REQUIREMENTS

TOP INTRODUCTION GLYCEMIC CONTROL AND INSULIN... WEIGHT GAIN HYPOGLYCEMIAS CHANGES IN SERUM TRIGLYCERIDES... BLOOD PRESSURE SPECIAL QUESTIONS PREDICTION OF INSULIN... PREDICTORS OF A GLYCEMIC... PRACTICAL ALGORITHM TO INITIATE... CONCLUDING REMARKS References

 
Variation in hepatic insulin sensitivity seems to be much more important than insulin absorption in determining insulin requirements during combination therapy with NPH insulin (3). Hepatic insulin sensitivity cannot be routinely measured but correlates with various indexes of obesity (3). In type 2 diabetic patients with a mean BMI of 29 kg/m², to achieve an average HbA_1c of 7.5% from a baseline value of 10%, the mean bedtime NPH insulin dose for body weights of 70, 80, 90, and 100 kg has been 0.2, 0.3, 0.4, and 0.5 IU/kg (3,11). However, interindividual variation is large and has varied 20-fold between 8 and 168 IU per day (12), which implies that these average predictions are not accurate enough to be used on an individual level.

Autoantibodies to glutamic acid decarboxylase (GADA) predict an increased likelihood of insulin requirement in both young and old adults with type 2 diabetes (35). In 3,672 newly diagnosed patients in the UKPDS, 34% of those aged 25–34 years and 7% of those aged 55–65 years had GADA (35). Among patients older than 55 years at diagnosis, 34% of those with GADA and 5% with autoantibodies to neither GADA nor islet cell cytoplasm required insulin therapy. In these older patients, only the presence of GADA but not phenotypic features such as BMI predicted insulin requirement. There are no studies comparing insulin combination regimens with insulin alone in these patients, who are often classified as having type 2 diabetes but actually have type 1 diabetes (36). In patients in whom signs of absolute insulin deficiency (rapid weight loss, ketonuria) ultimately develop, the presence of GADA may guide the choice of a basal-bolus–type full insulin-replacement regimen (37).

	PREDICTORS OF A GLYCEMIC RESPONSE TO INSULIN COMBINATION THERAPY

TOP INTRODUCTION GLYCEMIC CONTROL AND INSULIN... WEIGHT GAIN HYPOGLYCEMIAS CHANGES IN SERUM TRIGLYCERIDES... BLOOD PRESSURE SPECIAL QUESTIONS PREDICTION OF INSULIN... PREDICTORS OF A GLYCEMIC... PRACTICAL ALGORITHM TO INITIATE... CONCLUDING REMARKS References

 
In studies in which the insulin dose is titrated aggressively to reach glycemic targets, the decrease in HbA_1c will be directly proportional to its initial level. Of other factors, obesity predicts a poor response to any type of insulin therapy, especially if insufficient doses of insulin are used (30,38). In addition, and as discussed above, GADA may predict poor response to combination therapy.

	PRACTICAL ALGORITHM TO INITIATE INSULIN THERAPY

TOP INTRODUCTION GLYCEMIC CONTROL AND INSULIN... WEIGHT GAIN HYPOGLYCEMIAS CHANGES IN SERUM TRIGLYCERIDES... BLOOD PRESSURE SPECIAL QUESTIONS PREDICTION OF INSULIN... PREDICTORS OF A GLYCEMIC... PRACTICAL ALGORITHM TO INITIATE... CONCLUDING REMARKS References

 
Initiation of insulin therapy on an ambulatory basis in type 2 diabetic patients has been shown to be as safe and effective as an inpatient program (39). Regardless of the insulin treatment regimen chosen, the insulin dose should be adjusted to reach glycemic targets. Considering the large interindividual variation in insulin requirements, it is difficult to define the correct insulin dose by performing dose adjustments only at outpatient visits, unless these are very frequent. In our experience of treating insulin-naïve patients (12,15), the best method of defining the insulin dose is teaching the patient to self-adjust the dose based on results of home glucose monitoring. This is easiest to perform if the dose adjustment is based on measurement of fasting plasma glucose only. Fasting plasma glucose is not influenced by size, composition, or rate of absorption of meals as much as by postprandial glucose levels, and its measurement does not interfere with daily activities. The maximal action of NPH given at bedtime is exerted on fasting glucose, which, therefore, is a particularly suitable target for titration of the dose when insulin combination therapy with NPH or insulin glargine is used. However, because especially NPH insulin is unable to adequately control postdinner glycemia, fasting glucose must be in the normal range (4–6 mmol/l) for average glycemic control, measured using HbA_1c to be <7.5%. A simple method of initiating insulin therapy, developed based on experience from the FINFAT study, is shown in Table 5 (12). The patient is assumed to be insulin-naïve and on maximal doses of sulfonylureas and metformin. The recommendation to discontinue the sulfonylurea (glyburide) but not metformin after insulin combination therapy is started is based on the inability of some patients to adequately titrate the dose of bedtime NPH because of hypoglycemia (12). An increase in mild hypoglycemias was also reported by Riddle and Schneider (25) with glimepiride combined with a single injection of 30/70 insulin at 6:00 P.M. compared with two injections of 30/70 insulin. Hypoglycemias may not be a problem with peakless insulins such as insulin glargine (40). Discontinuation of sulfonylurea when insulin therapy is started may retard achievement of good glycemic control unless the insulin dose is rapidly increased (12,25). Glitazones could be an additional or alternative component in the oral hypoglycemic agent regimen, but there are no studies in insulin-naïve patients.

	CONCLUDING REMARKS

TOP INTRODUCTION GLYCEMIC CONTROL AND INSULIN... WEIGHT GAIN HYPOGLYCEMIAS CHANGES IN SERUM TRIGLYCERIDES... BLOOD PRESSURE SPECIAL QUESTIONS PREDICTION OF INSULIN... PREDICTORS OF A GLYCEMIC... PRACTICAL ALGORITHM TO INITIATE... CONCLUDING REMARKS References

 
Against the emerging epidemic of type 2 diabetes, studies comparing different insulin treatment regimens are sparse and include only a small number of patients treated for a maximum of 1 year (Tables 1 and 2). Data on effects of insulin-combination therapy versus insulin alone on diabetic microvascular and macrovascular complications are nonexistent. The main reason for the paucity of data may be the reluctance of private funding agencies to support studies using pharmacological agents and the reluctance of industry to support studies with established preparations. The development of new agents such as glitazones and insulin analogs have increased the number of patients included in various trials, but many company-initiated trials are designed to fulfill licensing requirements and must be performed in multiple centers to save time. Although some company-initiated trials are of superb quality, others suffer from inadequate glycemic control and may lack the comparisons the clinicians would be interested in. Despite these deficiencies, some conclusions regarding the role of insulin combination therapy in the treatment of type 2 diabetic patients seem justified.

No study reported worse glycemic control with insulin combination therapy than with insulin alone. Glycemic control was better with insulin combination therapy than with insulin alone in most studies of previously insulin-treated patients, but this could be explained by a smaller difference (20% for metformin or sulfonylureas) (Table 2) in the insulin dose between the two modes of treatment than in studies performed in insulin-naïve patients (30–40%, Table 1). Combination regimens allow use of less insulin injections, which may ease titration of the insulin dose and compliance (12,15,41). These benefits must be balanced against the side effects of oral drugs and, in some countries, their cost. Abnormal renal or liver function also limits the use of many oral agents. Weight gain seems proportional to the number of insulin injections used (12,15,31,32) and can be counteracted by inclusion of metformin in the treatment regimen. Metformin also seems to reduce the incidence of hypoglycemias (12), as does the use of the peakless long-acting insulin analog insulin glargine compared with NPH (40). These considerations and the need to treat not only hyperglycemia but also other risk factors in type 2 diabetes support the use of simple insulin combination regimens such as insulin glargine and metformin and or a sulfonylurea (40). The prevailing view that patients who are poorly responsive to such a regimen benefit from adding additional insulin injections is not supported by existing data. Instead, special emphasis should be placed on increasing the dose of the single long-acting insulin to a dose that normalizes the fasting glucose concentration.

	FOOTNOTES

Received for publication 19 October 2000 and accepted in revised form 2 January 2001.

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

	References

TOP INTRODUCTION GLYCEMIC CONTROL AND INSULIN... WEIGHT GAIN HYPOGLYCEMIAS CHANGES IN SERUM TRIGLYCERIDES... BLOOD PRESSURE SPECIAL QUESTIONS PREDICTION OF INSULIN... PREDICTORS OF A GLYCEMIC... PRACTICAL ALGORITHM TO INITIATE... CONCLUDING REMARKS References

 

1. U.K. Prospective Diabetes Study (UKPDS) Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–852, 1998[Medline]
   
2. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR: Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321:405–412, 2000[Abstract/Free Full Text]
   
3. Ryysy L, Hakkinen AM, Goto T, Vehkavaara S, Westerbacka J, Halavaara J, Yki-Jarvinen H: Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes 49:749–758, 2000[Abstract]
   
4. Peters AL, Davidson MB: Insulin plus a sulfonylurea agent for treating type 2 diabetes. Ann Intern Med 115:45–53, 1991
   
5. Pugh JA, Wagner ML, Sawyer J, Ramirez G, Tuley M, Friedberg SJ: Is combination sulfonylurea and insulin therapy useful in NIDDM patients? Diabetes Care 15:953–959, 1992[Abstract]
   
6. Yu JG, Kruszynska YT, Mulford MI, Olefsky JM: A comparison of troglitazone and metformin on insulin requirements in euglycemic intensively insulin-treated type 2 diabetic patients. Diabetes 48:2414–2421, 1999[Abstract]
   
7. Knowler WC, Pettitt DJ, Savage RJ, Bennett PH: Diabetes incidence in Pima Indians: contributions of obesity and parental diabetes. Am J Epidemiol 113:144–156, 1981[Abstract/Free Full Text]
   
8. Bogardus C, Taskinen M-R, Zawadzki J, Lillioja S, Mott D, Howard BV: Increased resting metabolic rates in obese subjects with non-insulin-dependent diabetes mellitus and the effect of sulfonylurea therapy. Diabetes 35:1–5, 1986[Abstract]
   
9. Welle S, Nair KS, Lockwood D: Effect of a sulfonylurea and insulin on energy expenditure in type II diabetes mellitus. J Clin Endocrinol Metab 66:593–597, 1988[Abstract]
   
10. Franssila-Kallunki A, Groop L: Factors associated with basal metabolic rate in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 35:962–966, 1992[Medline]
    
11. Mäkimattila S, Nikkilä K, Yki-Järvinen H: Causes of weight gain during insulin therapy with and without metformin in patients with non-insulin-dependent diabetes mellitus. Diabetologia 42:406–412, 1999[Medline]
    
12. Yki-Jarvinen H, Ryysy L, Nikkila K, Tulokas T, Vanamo R, Heikkila M: Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus: a randomized, controlled trial. Ann Intern Med 130:389–396, 1999[Abstract/Free Full Text]
    
13. O’Brien SV, Mangnall M: Metformin superior to gliclazide when used in combination with NPH insulin in type 2 diabetic patients inadequately controlled on oral hypoglycemic therapy: median follow-up 13 months (Abstract). Diabetes 48:A115, 1999
    
14. Schernthaner G, Biesenbach G, Kacerovsky G, Mihaljevic R, Pieber TR: Evaluation of combination therapy in NIDDM patients with sulfonylurea failure: the Austrian intervention study (Abstract). Diabetes 46 (Suppl. 1):166A, 1997
    
15. Yki-Järvinen H, Kauppila M, Kujansuu E, Lahti J, Marjanen T, Niskanen L, Rajala S, Ryysy L, Salo S, Seppälä P, Tulokas T, Viikari J, Karjalainen J, Taskinen M-R: Comparison of insulin regimens in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 327:1426–1433, 1992[Abstract]
    
16. Chow C-C, Tsang LWW, Sorensen JP, Cockram CS: Comparison of insulin with or without continuation of oral hypoglycemic agents in the treatment of secondary failure in NIDDM patients. Diabetes Care 18:307–314, 1995[Abstract]
    
17. Akazawa S, Sun F, Ito M, Kawasaki E, Eguchi K: Efficacy of troglitazone on body fat distribution in type 2 diabetes. Diabetes Care 23:1067–1071, 2000[Abstract/Free Full Text]
    
18. Kawai T, Takei I, Oguma Y, Ohashi N, Tokui M, Oguchi S, Katsukawa F, Hirose H, Shimada A, Watanabe K, Saruta T: Effects of troglitazone on fat distribution in the treatment of male type 2 diabetes. Metabolism 48:1102–1107, 1999[Medline]
    
19. Mori Y, Murakawa Y, Okada K, Horikoshi H, Yokoyama J, Tajima N, Ikeda Y: Effect of troglitazone on body fat distribution in type 2 diabetic patients. Diabetes Care 22:908–912, 1999[Abstract]
    
20. Balfour JA, Plosker GL: Rosiglitazone. Drugs 57:921–930, 1999[Medline]
    
21. Gillies PS, Dunn CJ: Pioglitazone. Drugs 60:333–343, 2000[Medline]
    
22. The Diabetes Control and Complications Trial 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 329:977–986, 1993[Abstract/Free Full Text]
    
23. Ohkubo Y, Kishikawa H, Araki E, Miyta T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M: Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 28:103–117, 1995[Medline]
    
24. Aviles-Santa L, Sinding J, Raskin P: Effects of metformin in patients with poorly controlled, insulin-treated type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 131:182–188, 1999[Abstract/Free Full Text]
    
25. Riddle MC, Schneider J: Beginning insulin treatment of obese patients with evening 70/30 insulin plus glimepiride versus insulin alone: Glimepiride Combination Group. Diabetes Care 21:1052–1057, 1998[Abstract]
    
26. Stenman S, Groop P-H, Saloranta C, Tötterman KJ, Fyhrqvist F, Groop L: Effects of the combination of insulin and glibenclamide in type 2 (non-insulin-dependent) diabetic patients with secondary failure to oral hypoglycaemic agents. Diabetologia 31:206–213, 1988[Medline]
    
27. Riddle MC, Hart JS, Bouma DJ, Phillipson BE, Youker G: Efficacy of bedtime NPH insulin with daytime sulfonylurea for subpopulation of type II diabetic subjects. Diabetes Care 12:623–629, 1989[Abstract]
    
28. Riddle M, Hart J, Bingham P, Garrison C, McDaniel P: Combined therapy for obese type 2 diabetes: suppertime mixed insulin with daytime sulfonylurea. Am J Med Sci 303:151–156, 1992[Medline]
    
29. Wolffenbuttel BH, Sels JP, Rondas-Colbers GJ, Menheere PP, Nieuwenhuijzen KA: Comparison of different insulin regimens in elderly patients with NIDDM. Diabetes Care 19:1326–1332, 1996[Abstract]
    
30. Yki-Järvinen H, Ryysy L, Kauppila M, Kujansuu M, Lahti J, Marjanen T, Niskanen L, Rajala S, Salo S, Seppälä P, Tulokas T, Viikari J, Taskinen M-R: Effect of obesity on the response to insulin therapy in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 82:4037–4043, 1997[Abstract/Free Full Text]
    
31. Landstedt-Hallin L, Adamson U, Arner P, Bolinder J, Lins P-E: Comparison of bedtime NPH or preprandial regular insulin combined with glibenclamide in secondary sulfonylurea failure. Diabetes Care 18:1183–1186, 1995[Abstract]
    
32. Bastyr EJ, Johnson ME, Trautmann ME, Anderson JHJ, Vignati L: Insulin lispro in the treatment of patients with type 2 diabetes mellitus after oral agent failure. Clin Ther 21:1703–1714, 1999[Medline]
    
33. Groop LC, Widen E, Ekstrand A, Saloranta C, Franssila-Kallunki A, Eriksson JGS-J: Morning or bedtime NPH insulin combined with sulfonylurea in treatment of NIDDM. Diabetes Care 15:831–834, 1992[Abstract]
    
34. Soneru IL, Agrawal L, Murphy JC, Lawrence AM, Abraira C: Comparison of morning or bedtime insulin with and without glyburide in secondary sulfonylurea failure. Diabetes Care 16:896–901, 1993[Abstract]
    
35. Turner R, Stratton I, Horton V, Manley S, Zimmet P, Mackay IR, Shattock M, Bottazzo GF, Holman R: UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes: UK Prospective Diabetes Study Group. Lancet 350:1288–1293, 1997[Medline]
    
36. World Health Organization: Report of a WHO Consultation: Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Part 1: Diagnosis and Classification of Diabetes Mellitus . Geneva, World Health Org., 1999
    
37. Landstedt-Hallin L, Arner P, Lins PE, Bolinder J, Olsen H, Groop L: The role of sulphonylurea in combination therapy assessed in a trial of sulphonylurea withdrawal: Scandinavian Insulin-Sulphonylurea Study Group Research Team. Diabet Med 16:827–834, 1999[Medline]
    
38. Wolffenbuttel BH, Sels JP, Rondas-Colbers GJ, Menheere PP: Prognostic factors for successful insulin therapy in subjects with type 2 diabetes. Neth J Med 54:63–69, 1999[Medline]
    
39. Muller UA, Muller R, Starrach A, Hunger-Dathe W, Schiel R, Jorgens V, Grusser M: Should insulin therapy in type 2 diabetic patients be started on an out- or inpatient basis? Results of a prospective controlled trial using the same treatment and teaching programme in ambulatory care and a university hospital. Diabete Metab 24:251–255, 1998[Medline]
    
40. Yki-Jarvinen H, Dressler A, Ziemen M: Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes: HOE 901/3002 Study Group. Diabetes Care 23:1130–1136, 2000[Abstract/Free Full Text]
    
41. Bergenstal RJM, Whipple D, Noller D, Boyce K, Roth L, Upham P, Fish L, Debold R: Advantages of adding metformin to multiple dose insulin therapy in type 2 diabetes (Abstract). Diabetes 47:A89, 1998
    
42. Relimpio F, Pumar A, Losada F, Mangas MA, Acosta D, Astorga R: Adding metformin versus insulin dose increase in insulin-treated but poorly controlled type 2 diabetes mellitus: an open-label randomized trial. Diabet Med 15:997–1002, 1998[Medline]
    
43. Robinson AC, Burke J, Robinson S, Johnston DG, Elkeles RS: The effects of metformin on glycemic control and serum lipids in insulin-treated NIDDM patients with suboptimal metabolic control. Diabetes Care 21:701–705, 1998[Abstract]
    
44. Kyllastinen M, Groop L: Combination of insulin and glibenclamide in the treatment of elderly non-insulin dependent (type 2) diabetic patients. Ann Clin Res 17:100–104, 1985[Medline]
    
45. Lindstrom T, Nystrom FH, Olsson AG, Ottosson AM, Arnqvist HJ: The lipoprotein profile differs during insulin treatment alone and combination therapy with insulin and sulphonylureas in patients with type 2 diabetes mellitus. Diabet Med 16:820–826, 1999[Medline]
    
46. Clauson PG, Linde B: Absorption of rapid-acting insulin in obese and nonobese NIDDM patients. Diabetes Care 18:986–991, 1995[Abstract]
    
47. Kitabchi AE, Soria AG, Radparvar A, Lawson-Grant V: Combined therapy of insulin and tolazamide decreases insulin requirement and serum triglycerides in obese patients with noninsulin-dependent diabetes mellitus. Am J Med Sci 294:10–14, 1987[Medline]
    
48. Gutniak M, Karlander S-G, Efendic S: Glyburide decreases insulin requirement, increases b-cell response to mixed meal, and does not affect insulin sensitivity: effects of short- and long-term combined treatment in secondary failure to sulfonylurea. Diabetes Care 10:545–554, 1987[Abstract]
    
49. Schade DS, Mitchell WJ, Griego G: Addition of sulfonylurea to insulin treatment in poorly controlled type II diabetes: a double-blind, randomized clinical trial. JAMA 257:2441–2445, 1987[Abstract]
    
50. Groop L, Harno K, Tolppanen EM: The combination of insulin and sulphonylurea in the treatment of secondary drug failure in patients with type II diabetes. Acta Endocrinol (Copenh) 106:97–101, 1984
    
51. Groop L, Harno K, Nikkila EA, Pelkonen R, Tolppanen EM: Transient effect of the combination of insulin and sulfonylurea (glibenclamide) on glycemic control in non-insulin dependent diabetics poorly controlled with insulin alone. Acta Med Scand 217:33–39, 1985[Medline]
    
52. Schwartz S, Raskin P, Fonseca V, Graveline JF: Effect of troglitazone in insulin-treated patients with type II diabetes mellitus: Troglitazone and Exogenous Insulin Study Group. N Engl J Med 338:861–866, 1998[Abstract/Free Full Text]
    
53. Rubin C, Egan J, Schneider R, Pioglitazone 014 Study Group: Combination therapy with pioglitazone and insulin in patients with type 2 diabetes (Abstract). Diabetes 48:A110, 1999
    
54. Raskin P, Dole JF, Rappaport EB: Rosiglitazone (RSG) improves glycemic control in poorly controlled, insulin-treated type 2 diabetes (Abstract). Diabetes 48:A94, 1999
    
55. Bachmann W, Lotz N, Mehnert H, Rosak C, Schoffling K: Effectiveness of combined treatment with glibenclamide and insulin in secondary sulfonylurea failure: a controlled multicenter double-blind clinical trial. Dtsch Med Wochenschr 113:631–636, 1988[Medline]
    
56. Quatraro A, Consoli G, Ceriello A, Giugliano D: Combined insulin and sulfonylurea therapy in non-insulin-dependent diabetics with secondary failure to oral drugs: a one year follow-up. Diabete Metab 12:315–318, 1986[Medline]
    
57. Giugliano D, Quatraro A, Consoli G, Minei A, Ceriello A, DeRosa N, D’Onofrio F: Metformin for obese, insulin-treated diabetic patients: improvement in glycaemic control and reduction of metabolic risk factors. Eur J Clin Pharmacol 44:107–112, 1993[Medline]
    
58. Lins PE, Lundblad S, Persson-Trotzig E, Adamson U: Glibenclamide improves the response to insulin treatment in non-insulin-dependent diabetics with second failure to sulfonylurea therapy. Acta Med Scand 223:171–179, 1988[Medline]
    
59. Reich A, Abraira C, Lawrence AM: Combined glyburide and insulin therapy in type II diabetes. Diabetes Res 6:99–104, 1987[Medline]
    
60. Lewitt MS, Yu VK, Rennie GC, Carter JN, Marel GM, Yue DK, Hooper MJ: Effects of combined insulin-sulfonylurea therapy in type II patients. Diabetes Care 12:379–383, 1989[Abstract]
    
61. Osei K, O’Dorisio TM, Falko JM: Concomitant insulin and sulfonylurea therapy in patients with type II diabetes: effects on glucoregulation and lipid metabolism. Am J Med 77:1002–1009, 1984[Medline]
    
62. Feinglos MN, Thacker CR, Lobaugh B, DeAtkine DD, McNeill DB, English JS, Bursey DL: Combination insulin and sulfonylurea therapy in insulin-requiring type 2 diabetes mellitus. Diabetes Res Clin Pract 39:193–199, 1998[Medline]
    
63. Longnecker MP, Elsenhans VD, Leiman SM, Owen OE, Boden G: Insulin and a sulfonylurea agent in non-insulin-dependent diabetes mellitus. Arch Intern Med 146:673–676, 1986[Abstract]
    
64. Casner PR: Insulin-glyburide combination therapy for non-insulin-dependent diabetes mellitus: a long-term double-blind, placebo-controlled trial. Clin Pharmacol Ther 44:594–603, 1988[Medline]
    
65. Kelley DE, Bidot P, Freedman Z, Haag B, Podlecki D, Rendell M, Schimel D, Weiss S, Taylor T, Krol A, Magner J: Efficacy and safety of acarbose in insulin-treated patients with type 2 diabetes. Diabetes Care 21:2056–2061, 1998[Abstract]
    
66. Chiasson J-L, Josse RG, Hunt JA, Palmason C, Rodger NW, Ross SA, Ryan EA, Tan MH, Wolever TMS: The efficacy of acarbose in the treatment of patients with non-insulin-dependent diabetes mellitus: a multicenter controlled clinical trial. Ann Intern Med 121:928–935, 1994[Abstract/Free Full Text]
    

CiteULike

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				M. C. Riddle Combined Therapy With Insulin Plus Oral Agents: Is There Any Advantage?: An argument in favor Diabetes Care, February 1, 2008; 31(Supplement_2): S125 - S130. [Full Text] [PDF]

				M. Massi-Benedetti and M. Orsini-Federici Treatment of Type 2 Diabetes With Combined Therapy: What are the pros and cons? Diabetes Care, February 1, 2008; 31(Supplement_2): S131 - S135. [Abstract] [Full Text] [PDF]

				L. Juurinen, M. Tiikkainen, A.-M. Hakkinen, A. Hakkarainen, and H. Yki-Jarvinen Effects of insulin therapy on liver fat content and hepatic insulin sensitivity in patients with type 2 diabetes Am J Physiol Endocrinol Metab, March 1, 2007; 292(3): E829 - E835. [Abstract] [Full Text] [PDF]

				D. Hinnen, L. L. Nielsen, A. Waninger, and P. Kushner Incretin Mimetics and DPP-IV Inhibitors: New Paradigms for the Treatment of Type 2 Diabetes J Am Board Fam Med, November 1, 2006; 19(6): 612 - 620. [Abstract] [Full Text] [PDF]

				J. Menard, H. Payette, J.-P. Baillargeon, P. Maheux, S. Lepage, D. Tessier, and J.-L. Ardilouze Efficacy of intensive multitherapy for patients with type 2 diabetes mellitus: a randomized controlled trial Can. Med. Assoc. J., December 6, 2005; 173(12): 1457 - 1466. [Abstract] [Full Text] [PDF]

				M C Marshall Jr Diabetes in African Americans Postgrad. Med. J., December 1, 2005; 81(962): 734 - 740. [Abstract] [Full Text] [PDF]

				J. Rosenstock, B. Zinman, L. J. Murphy, S. C. Clement, P. Moore, C. K. Bowering, R. Hendler, S.-P. Lan, and W. T. Cefalu Inhaled Insulin Improves Glycemic Control When Substituted for or Added to Oral Combination Therapy in Type 2 Diabetes: A Randomized, Controlled Trial Ann Intern Med, October 18, 2005; 143(8): 549 - 558. [Abstract] [Full Text] [PDF]

E. Cochran, C. Musso, and P. Gorden The Use of U-500 in Patients With Extreme Insulin Resistance Diabetes Care, May 1, 2005; 28(5): 1240 - 1244.