Long-term glycaemic improvement after addition of metformin to insulin in insulin-treated obese type 2 diabetes patients.

AIM: To assess the adjunct effect of metformin to insulin in type 2 diabetes. METHODS: Obese and overweight type 2 diabetes patients treated with insulin for at least 1 year, and with poor glycaemic control (HbA1c > upper reference level + 2%), were included in a randomised, double-blind, placebo-controlled study. Patients were treated for 12 months with either metformin (850 mg b.i.d.) or placebo added to their usual insulin, which was stabilized during a 3-month placebo run-in period, but thereafter attempted to be unchanged. RESULTS: Thirty-seven patients were included. Two patients dropped out during run-in. There were no differences between the metformin (n = 16) and placebo (n = 19) group at baseline. Most patients received multiple insulin injections. Metabolic control was improved by addition of metformin. Mean change in HbA1c from baseline showed highly significant difference between groups at 3, 6, 9 and 12 months. Mean change (percentage units +/- s.d.) at 12 months was -1.1 +/- 0.7% vs. + 0.3 +/- 0.8% (p < 0.001) for HbA1c and -1.4 +/- 2.1 mmol/l vs. + 0.6 +/- 2.2 mmol/l (p = 0.025) for fasting blood glucose. Mean low density lipoprotein (LDL) cholesterol change differed slightly at 6 months, but not at 12 months. There were no changes in insulin dose, blood pressure, body weight, triglycerides, total- and high density lipoprotein (HDL) cholesterol, fibrinogen, C-peptide and laboratory safety variables, including serum B12. Combination therapy was well-tolerated with the same adverse event rate as insulin alone, but more patients with diarrhoea. CONCLUSION: Addition of metformin to insulin induced and maintained clinically significant and consistent long-term reduction of hyperglycaemia in obese, insulin-treated type 2 diabetes patients.

Optimising therapy for insulin-treated type 2 diabetes mellitus.

The purpose of this article is to provide a guide to the optimal use of insulin in type 2 (non-insulin-dependent) diabetes mellitus. Based on pathophysiological considerations and a knowledge of drug actions, an individualised, targeted strategy is selected for obtaining good metabolic control without compromising well-being and quality of life. The treatment should target hyperglycaemia along with other risk factors. Insulin is indicated when adequate glycaemia can no longer be obtained with diet and oral antihyperglycaemic agents. Commonly, the oral drugs are replaced by insulin, but preferably they should be used in combination with insulin. This approach can lead to improved glycaemic control, a reduced insulin dose and counteraction of insulin-associated bodyweight gain. There may also be less hypoglycaemia with combination insulin/oral therapy as compared with insulin monotherapy, as well as other benefits. Optimisation of oral drug therapy should be attempted before initiating insulin. A combination of insulin with a sulphonylurea agent is commonly used: the adjunctive effect of the sulphonylurea is dependent on pancreatic beta cell function. The combination of insulin with metformin or a thiazolidinedione is more logical as insulin resistance is targeted directly. Bedtime insulin plus metformin conferred the most benefits among several options investigated in a randomised 1-year study. The combination of insulin with acarbose is a further option when there is significant postprandial hyperglycaemia. It is recommended to start with a medium- to long-acting insulin preparation at bedtime or premixed insulin before the evening meal. Changes in insulin administration can be subsequently introduced as needed, e.g. use of twice-daily premixed insulin, multiple injections of rapid-acting insulin or insulin analogues. There are many options, but limited clinical data are available to support a number of the regimens.

Effects of antihyperglycaemic therapies on proinsulin and relation between proinsulin and cardiovascular risk factors in type 2 diabetes.

AIM: To assess the effect of oral antihyperglycaemic therapy on fasting proinsulin and the relation between proinsulin levels and cardiovascular risk factors in type 2 diabetes. METHODS: One hundred and sixty-five patients with type 2 diabetes, fasting blood glucose concentration (FBG) > or = 6.7 mmol/l, were recruited from five diabetes outpatient clinics in primary health care. Diet and antihyperglycaemic medication, aiming at FBG < 6.7 mmol/l, was maintained for 6 months after completed dose titration in a randomized, double-blind, double-dummy trial with metformin (M), glibenclamide (G) and primary combination of both drugs (MG). The study compared M, G and MG in low dose (MGL) and also different high-dose regimens, i.e. G added to M (M/G), M added to G (G/M) and primary combination (MGH). Outcome measures were fasting proinsulin, glycaemia, body mass index, blood pressure, lipids, insulin and C-peptide. RESULTS: Lower proinsulin levels were found when therapy was initiated with metformin (M vs. G, p = 0.013 and M/G vs. G/M, p = 0.033). M and G were equally effective on glucose levels. In the group as a whole FBG decreased from (mean +/- s.d.) 10.2 +/- 2.7 to 7.0 +/- 1.2 mmol/l with no change in proinsulin. Proinsulin was associated with cardiovascular risk factors, linking high proinsulin to an atherogenic risk marker profile. Mean proinsulin change from baseline was inconsistently associated with markers of insulin resistance. Meal-stimulated glucose (net AUC) decreased after treatment only in those with low baseline proinsulin levels. CONCLUSION: It may be advantageous to initiate oral antihyperglycaemic therapy with metformin rather than with sulphonylurea. High proinsulin levels are associated with an atherogenic-risk marker profile and an impaired therapeutic postprandial glucose response after treatment in patients with type 2 diabetes. Proinsulin change after therapy is inconsistently associated with markers of insulin resistance and unrelated to fasting blood glucose reduction.

[Combination treatment with insulin and metformin in type 2 diabetes. Improves glycemic control and prevents weight gain]. / Kombinationsbehandling med insulin och metformin vid typ 2-diabetes. Förbättrar blodglukoskontroll och motverkar viktuppgång.

Type II diabetes patients on insulin often show inadequate glycaemic control and weight gain. The rationale for adding metformin in these cases is that it can reduce insulin resistance. The present article reviews the growing body of clinical documentation supporting combination therapy, i.e. placebo-controlled studies in insulin-treated patients and controlled studies with reference therapies in patients not yet treated with insulin. These studies show improvement of glycaemic control and less weight gain. Insulin dosages can be reduced in both type II and type I diabetes. A combination of insulin and metformin is recommended especially for obese type II diabetes patients on high insulin doses.

Irreversibility of the defect in glycogen synthase activity in skeletal muscle from obese patients with NIDDM treated with diet and metformin.

OBJECTIVE: To assess the reversibility of the defect in glycogen synthase (GS) activity in skeletal muscle from obese patients with NIDDM treated with a hypocaloric diet and metformin. RESEARCH DESIGN AND METHODS: Eighteen obese patients newly diagnosed with NIDDM were included in a randomized placebo-controlled double-blind parallel group trial and followed for 3 months. Euglycemic-hyperinsulinemic clamp including indirect calorimetry and biopsy of m. vastus lateralis was performed before and after treatment with a hypocaloric diet plus metformin or placebo. The patients were studied at basal, low, and high insulin concentrations. RESULTS: The impaired GS activity in muscle biopsies was not reversed either by acute normalization of glycemia (for 8 h) or by chronic reduction of hyperglycemia by diet plus metformin. In both treatment groups, comparable effects on glycemic control and weight loss were found together with marked insulin suppression of nonesterified fatty acids and increased glucose oxidation. Total glucose disposal at euglycemic-hyperinsulinemic clamp increased significantly in the metformin group by 25% at high insulin level (259 +/- 31 vs. 207 +/- 21 mg x m(-2) x min(-1), P < 0.05). An insignificant increase by 13% was found in the placebo group. There were no significant changes in nonoxidative glucose metabolism. GS activity and glucose utilization showed no significant differences between the two treatment groups when regression coefficients, expressed as incremental changes by increments of insulin, were compared. CONCLUSIONS: Defective GS activity in obese NIDDM patients is not secondary to hyperglycemia. Metformin and diet had no significant influence on GS activity. The added effect of metformin to that of a hypocaloric diet in improving insulin-stimulated glucose utilization is marginal when blood glucose reduction is obtained by weight loss.

Combination therapy with insulin and metformin.

OBJECTIVE: To review the clinical usefulness of combination therapy with insulin and metformin. METHODS: Basic considerations about the use of insulin in non-insulin-dependent diabetes mellitus (NIDDM) and the interaction of metformin with insulin are outlined. The clinical documentation of this therapeutic strategy is reviewed, with emphasis on controlled studies. In addition, the use of this drug combination in insulin-dependent diabetes mellitus (IDDM) is briefly addressed. RESULTS: Insulin is used in patients with NIDDM when adequate plasma glucose control can no longer be maintained by orally administered agents. Metformin ameliorates insulin resistance, reduces hyperinsulinemia, and counteracts weight gain. It exerts an insulin-sparing and antihyperglycemic effect and may improve cardiovascular risk factors. Although these effects have been demonstrated consistently in several controlled studies, relatively few patients have been treated with insulin + metformin (with or without sulfonylurea). The combination is well tolerated, commonly used, and approved in several countries. No specific guidelines have been established for selection of patients, but obese patients with NIDDM who are receiving high doses of insulin are likely to benefit. Patients whose diabetes is poorly controlled by sulfonylurea or by combination oral therapy, not previously treated with insulin, may also be suitable candidates. Insulin administered at bedtime is a feasible approach, and a daily dose of 1.5 to 2.5 g of metformin seems adequate. Although the application may be questionable, metformin can also be added to insulin in the treatment of selected patients with IDDM. CONCLUSION: Metformin is effective in conjunction with insulin in NIDDM. Because of its action on insulin resistance, it might be a more suitable adjunct to insulin than sulfonylurea in obese patients with NIDDM who are receiving high insulin doses, but it has been less well studied.

Antihyperglycaemic efficacy, response prediction and dose-response relations of treatment with metformin and sulphonylurea, alone and in primary combination.

The short-term (2-12 weeks) antihyperglycaemic efficacy of metformin (M), glibenclamide (G), and their primary combination (MG) was assessed in a double-blind study including 165 unselected patients with Type 2 diabetes. Patients with diet failure were randomized to M, G or MG. The dose was titrated with a fasting blood glucose concentration (FBG) of < 6.7 mmol l-1 as the target, using at most six dose levels, the first three comprising increasing monotherapy (M or G) or low-dose primary combination (MGL), and the second three add-on therapies (M/G and G/M) and primary combination therapy escalated to high dose (MGH). Success rates were higher on MGL than on monotherapy. The difference in achieving acceptable control (FBG < or = 7.8 mmol 1(-1)) was 70% versus 51% (95% confidence interval 3-36%, p = 0.032). When the drugs were combined, a slightly greater FBG reduction (p = 0.026) was observed, at lower dosage (p = 0.013). The response could not be predicted from body weight, but depended upon initial FBG (p = 0.019) and meal-stimulated C-peptide (p = 0.007). FBG declined progressively with increasing doses of metformin, whereas glibenclamide exerted most of its effect at low dose. Primary combination therapy with metformin and sulphonylurea may be clinically useful.

Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations. A double-blind controlled study.

OBJECTIVE: To assess and compare the therapeutic efficacy and safety of metformin (M) and sulfonylurea (glyburide, G), alone and in various combinations, in patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: Of 165 patients (fasting blood glucose [FBG] > or = 6.7 mmol/l) initially treated with diet alone, 144 (FBG still > or = 6.7 mmol/l) were randomized to double-blind, double-dummy controlled treatment with M, G, or primary combination therapy (MG). The dose was titrated, with FBG < 6.7 mmol/l as target, using, at most, six dose levels. The first three dose levels comprised increasing single-drug therapy (M or G) or primary combination at increasing but low dosage (MGL), and the second three levels were composed of various high-dose combinations, i.e., add-on therapy (M/G or G/M) and primary combination escalated to high dosage (MGH). Medication was maintained for 6 months after completed dose titration. RESULTS: The FBG target was achieved in 9% of patients after diet alone. Single-drug therapy was insufficient in 36% and MGL in 25% (NS) of the randomized patients. There was further improvement in glucose control by the high-dose combinations. Mean FBG +/- SE was reduced (P = 0.001) from 9.1 +/- 0.4 to 7.0 +/- 0.2 mmol/l in those maintained on single-drug treatment or low-dose primary combination. Those treated with different high-dose combinations had a large mean FBG reduction, from 13.3 +/- 0.8 to 7.8 +/- 0.6 mmol/l. HbA1c levels showed corresponding reductions, and glycemic levels rose after drug discontinuation. Fasting C-peptide rose during treatment with G and MGL but not with M, while fasting insulin was not significantly changed. Meal-stimulated C-peptide and insulin levels were unchanged by M but increased by G and, to a lesser extent, by MGL. There were no significant insulin or C-peptide differences between the different high-dose combinations (M/G, G/M, and MGH). Body weight did not change following treatment with M or combination but increased by 2.8 +/- 0.7 kg following G alone. Blood pressure was unchanged. Overall effects on plasma lipids were small, with no significant differences between groups. Drug safety was satisfactory, even if the reporting of (usually modest) adverse events was high; the profile, but not the frequency, differed between groups. CONCLUSIONS: Dose-effect titrated treatment with either metformin or glyburide promotes equal degrees of glycemic control. The former, but not the latter, is able to achieve this control without increasing body weight or hyperinsulinemia. Near-normal glycemia can be obtained by a combination of metformin and sulfonylurea, even in advanced NIDDM.

Effects of metformin and glibenclamide alone and in combination on serum lipids and lipoproteins in patients with non-insulin-dependent diabetes mellitus.

Metformin, glibenclamide and their combination were compared in a randomized, double-blind trial in patients with non-insulin-dependent diabetes mellitus (NIDDM) using a parallel group design. The study was performed in primary health care, and the purpose was to assess possible synergistic effects of combination therapy with the two drugs as primary treatment versus conventional oral therapy, starting with one drug and adding the other, if necessary. Lipids and lipoproteins were measured in the study, and preliminary results are reported for one hundred sixteen patients concluding 6 months maintenance therapy. Comparison of mean differences showed that patients randomized to combination therapy (n = 60) demonstrated a greater decrease in total- and LDL-cholesterol levels after 4 and 6 months treatment than patients randomized to conventional therapy starting with either metformin (n = 28) or glibenclamide (n = 28). For LDL-cholesterol a significant difference was also found between patients solely on monotherapy with lower values after treatment with metformin. Triglycerides did not change significantly, and only minor fluctuations were seen in HDL-cholesterol, independent of treatment. Obese patients had significantly higher triglyceride concentrations than the non-obese group, both at baseline and after treatment, as well as significantly lower HDL-cholesterol levels. The mean triglyceride concentration (+/- SD) after 6 months treatment was 2.32 +/- 1.38 mmol/l in the obese group (n = 69) and 1.54 +/- 0.84 mmol/l in non-obese (n = 47). For HDL-cholesterol the corresponding values were 0.83 +/- 0.23 mmol/l in obese and 0.93 +/- 0.29 mmol/l in non-obese patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative efficacy of metformin and glibenclamide in patients with non-insulin-dependent diabetes mellitus.

Metformin and glibenclamide were compared in a randomized, double-blind trial in patients with non-insulin-dependent diabetes mellitus (NIDDM) using a parallel group design. The study was performed in primary health care, and the main purpose was to assess combination therapy with the two drugs as primary treatment versus conventional oral therapy. After a 2 months diet period patients were randomized to commence treatment with either metformin, glibenclamide or the combination of both. Patients randomized to monotherapy received the alternative drug in addition if the maximal dose i.e. 3 g metformin or 14 mg glibenclamide was insufficient to normalize the fasting blood glucose concentration (FBG). Randomization and dose escalation occurred at FBG greater than or equal to 6.7 mmol/l. The titrated dose was continued for 6 months, whereafter placebo was given for 2 weeks. Seventy-two patients were randomized to either the metformin group (n = 38) or the glibenclamide group (n = 34). Fifty-six completed 6 months treatment, twenty-eight in each randomized group. Glycaemic control was unchanged after diet alone in all groups. The improvement during drug treatment was highly significant (p less than 0.001), mean FBG difference (+/- SEM) 3.2 +/- 0.4 mmol/l and mean HbA1c difference (+/- SEM) 1.5 +/- 0.2% (n = 56). There were no significant differences between patients treated solely with metformin (n = 16) and glibenclamide (n = 17) or between patients treated with a combination of glibenclamide added to metformin (n = 12) and metformin added to glibenclamide (n = 11).(ABSTRACT TRUNCATED AT 250 WORDS)

Prospective comparative study in NIDDM patients of metformin and glibenclamide with special reference to lipid profiles.

Twenty-two NIDDM patients completed an open randomized cross-over study comparing metformin and glibenclamide over 1 year. The drugs had an equivalent effect on glycaemic control, but, in contrast to glibenclamide, metformin reduced body weight. Neither drug affected triglycerides, total- and LDL-cholesterol or C-peptide. Metformin caused a slight elevation of HDL-cholesterol (P less than 0.05). No serious adverse effects were observed. The results show that oral hypoglycaemic agents are not associated with undesirable effects on lipids and lipoproteins.

Biguanides and sulfonylureas as combination therapy in NIDDM.

Oral combination therapy with biguanides (metformin) and sulfonylureas is discussed. The rationale for the use of this combination is based on the different sites of action of the two kinds of drugs and the possibility for obtaining additive or potentiating effects and reduced side effects. The clinical usefulness of chlorpropamide and glyburide in combination with metformin has been demonstrated in some clinical trials. The combination may provide satisfactory glycemic control for several years, and possibly insulin therapy can be postponed or even avoided. No special safety problems are encountered with the use of the combination other than those attributed to the use of metformin or sulfonylurea alone, i.e., lactic acidosis and hypoglycemia, respectively. The lethality risks of these associated conditions are comparable. It is concluded that more data are needed to evaluate the full clinical potential and the mechanism of action of oral combination therapy.

Metabolic effects of glucose compared with invertose and a mixture of fructose, glucose and xylitol before and after moderate surgical trauma.

The metabolic and clinical effects of different isocaloric carbohydrate infusions were studied perioperatively in 54 female patients undergoing cholecystectomy. The patients were randomized to six treatment groups, who received infusions only postoperatively (group 1, 2 and 3) or pre- as well as postoperatively (group 4, 5 and 6). One litre was given during 8 h as a 12% infusion solution. Glucose (group 1 and 4) was compared to invertose (group 2 and 5) and to a mixture of fructose, glucose and xylitol 2:1:1 i.e. Triofusin (group 3 and 6). The glycogen content in liver biopsies, taken peroperatively, was significantly higher when infusions were given preoperatively. No significant differences were found between groups, when comparing the different carbohydrate infusions. A minor glucose intolerance was noticed postoperatively, especially in group 4, whereas no fructose or xylitol intolerance was seen. Lactataemia was insignificant and acid-base balance normal in all groups. Serum urea concentrations were lower when preoperative infusions were given but without differences between groups 4, 5 and 6. Electrolytes, creatinine, hemoglobin, hematocrite and liver function tests were unaltered and the clinical course was uncomplicated in all cases. No side effects were observed. It is concluded that the infusion of one litre 12% Triofusin can be used as effectively and safely as 12% glucose and invertose before and after moderate surgical trauma. But no obvious advantage with Triofusin was revealed.

Antihypertensive effect of verapamil in patients with newly discovered mild to moderate essential hypertension.

The antihypertensive effect of verapamil (Isoptin) 120 mg X 3 for four weeks was compared with that of placebo in a randomized, double-blind, cross-over investigation. Twenty patients with newly discovered, not previously treated, mild to moderate essential hypertension were included in the study. Verapamil significantly reduced the diastolic and systolic blood pressure in the supine and standing positions, as well as the heart rate. One patient discontinued the treatment because of rash. Otherwise, only constipation was registered as a side effect of Isoptin. No orthostatic reactions were observed and the PQ-interval was unchanged. Compliance was excellent.

Tromantadine hydrochloride in the treatment of herpes simplex. Results of a double-blind therapeutic trial and an open prophylactic investigation.

In a randomised, double-blind trial on 20 patients with herpes simplex, tromantadine hydrochloride (TH) ointment had a significant therapeutic effect. No side effects were observed. 12 lesions were treated with the active drug and 13 with placebo. In an open study on 19 patients with recurrent herpes simplex, the prophylactic effect of the drug was good in most patients. During long-term treatment, 2 patients developed eczematous lesions. It is concluded that TH is a valuable topical agent for the treatment of herpes simplex.

Lactic acidosis during metformin treatment in an elderly diabetic patient with impaired renal function.

In recent years, lactic acidosis has been described in association with metformin therapy in diabetics. We report a fatal case in an elderly diabetic patient with impaired renal function and cardiac insufficiency. The patient presented with an elevated plasma metformin concentration and a concomitant digitoxin intoxication.

Metformin: a review of its pharmacological properties and therapeutic use.

In a survey, the pharmacological and clinical documentation of metformin is presented and discussed, and the present state of knowledge relating to metformin-associated lactic acidosis is reviewed. The use of metformin in the treatment of diabetes is based on clinical experience over twenty years. It has been well documented that metformin is effective in maturity-onset diabetes both as monotherapy and in combination with a sulphonylurea. An advantage of metformin treatment is the tendency to weight reduction and the absence of significant hypoglycaemia; blood glucose levels are reduced only to normal. The disadvantages are the gastro-intestinal side effects and the potential risk of vitamin B 12 and folic acid deficiency during long-term use. Metformin-associated lactic acidosis is a very rare complication, which has mainly occured in patients with serious renal insufficiency or other contra-indications to the use of metformin. The association between phenformin and lactic acidosis has led to withdrawal of this biguanide in several countries. Metformin differs from phenformin in certain important respects, and the normal use of metformin does not involve the risk of side effects disproportionate to the intended effect. Further experimental studies are required to substantiate pharmacokinetics and metabolic effects of metformin in man.

Influence of phenformin and metformin on exercise induced lactataemia in patients with diabetes mellitus.

The effect of long-term treatment with phenformin and metformin respectively on blood lactate concentrations in relation to submaximal muscular exercise has been examined in 21 maturity-onset diabetics, using a cross-over method. At similar degrees of diabetic control the mean blood lactate concentration during exercise and shortly thereafter was significantly higher when the patients had received phenformin. The mean fasting lactate concentration was 1.07 mmol/l with phenformin and 1.03 mmol/l with metformin and the peak concentration was 2.56 mmol/l and 2.19 mmol/l respectively. The mean fasting blood glucose concentration before the exercise was 11.2 mmol/l with phenformin and 11.3 mmol/l with metformin; the glucose output in the urine during the preceding 24 hours was 93 mmol and 105 mmol respectively. The mean work load during exercise was 60 watts.

The effect of epinephrine and isoproterenol on insulin secretion and glucose utilization in isolated islets of Langerhans from mice.

The effect of epinephrine and isoproterenol in different concentrations and adrenergic blocking agents on glucose induced insulin secretion and glucose utilization was studied in isolated islets of Langerhans from mice. Epinephrine in physiological concentrations significantly inhibited the glucose induced insulin secretion. This effect was not mediated by a change in glucose utilization but involved alpha-adrenergic stimulation. Isoproterenol significantly stimulated the glucose induced insulin secretion but had no effect on glucose utilization. Beta-adrenergic stimulation by isoproterenol at low glucose concentration was not sufficient to stimulate insulin secretion. The results are discussed in relation to current therories on the mechanism of glucose induced insulin secretion.