the blood sugar diet “It might also lead to new treatments, if we can find ways to reactivate dormant insulin-producing cells in the older age group. This would be a ...diabetes online community pdf
Department of Endocrinology, Marshfield Clinic-Wausau Center, Wausau, Wisconsin
The incidence of type 2 diabetes mellitus (DM) in the United States continues to grow rapidly, paralleling the overweight and obesity epidemic. For many years the only therapeutic options for type 2 DM were sulfonylureas and insulin. However, over the last 9 years there has been an explosion of new and exciting agents approved for the treatment of type 2 DM. Some of the treatments target insulin deficiency and others insulin resistance, the hallmarks of the disease. Other drugs delay the intestinal absorption of carbohydrate. Recently several combination agents have been released. With these new drugs has come an overwhelming mountain of information, making it difficult for the busy clinician to know how best to manage the ever-increasing portion of patients with type 2 DM.
the blood sugar diet urine test (🔥 treat) | the blood sugar diet wikihow to the blood sugar diet for New questions have arisen: Which agent to start as first line? How much of this drug to use before adding something else? How long for this drug to reach full effect? Which agent to add second? Should a patient uncontrolled on dual therapy begin insulin or start a third oral agent? If insulin therapy is started, what should become of the patient''s weight gain on therapy? These are not easy questions and no review can fully detail all the therapeutic combinations possible. Instead, the practical approach of reviewing the agents in terms of their mechanism of action and critically comparing their dosing, effect and cost, is undertaken herein. Also addressed is the possible niche some newer classes of agents and combination drugs may or may not hold in the management of type 2 DM. The decision of using insulin versus a third oral agent will be looked at from the standpoint of where the patient is on dual therapy in relation to the hemoglobin A1c goal. In this way it is hoped that some clarity will be brought to the dizzying array of information that both the physician and patient have to deal with in regard to the management of this prevalent and serious disease.
Vast amounts of literature have been written about the current and growing epidemic of diabetes mellitus (DM) and its associated complications. The cost of diabetes to the United States healthcare system is staggering, amounting to $100 billion in direct and indirect expenditures annually.1 Currently 15 million Americans have diabetes, one third of whom have yet to be diagnosed. Ninety percent of these cases represent type 2 DM. The incidence of type 2 DM and its precursor (impaired glucose tolerance) continues to rise, paralleling that of overweight and obesity.2 Frighteningly, this is occurring in children and adolescents, as well as adults.3 Over the last 9 years a growing number of oral medications and newer insulin analogs have become available for use in type 2 DM. The optimal use of these agents has become more difficult with the increased complexity a greater number of choices bring. This task is made more challenging with the pharmaceutical industry spending large sums of money annually in direct marketing toward physicians and patients.4 For better or worse, prescribing patterns are affected by this marketing, or obviously such amounts of money would not be so spent.5
It should be stressed that despite the vast literature available, many patients and physicians alike still view type 2 DM as a “less severe” illness than type 1 DM. On the contrary, because of the much greater prevalence of type 2 DM, the great majority of microvascular complications occurs in these patients. The increased risk of cardiovascular disease (CVD) in type 2 DM has led to more stringent goals for the management of cholesterol and blood pressure, in addition to the use of aspirin.6 Therefore, close attention should be paid to the overall cardiovascular health of patients with type 2 DM, not just their hemoglobin A1c (HbA1c).
the blood sugar diet webmd (👍 quick facts) | the blood sugar diet questionnairehow to the blood sugar diet for The optimal management of type 2 DM cannot be discussed by simply outlining what agents are available along with their doses, effectiveness and side effects. More difficult management issues need to be explored as well. Also, as CVD is so prevalent in patients with type 2 DM the potential for non-glycemic benefits of some of the newer agents deserves mention. This review will focus not only on the oral agents per se, but also on their proper use over time and in combination. The potential benefit of non-glycemic effects of some agents will be mentioned briefly. The use of insulin in combination with oral agents will also be described. It is hoped that through a better understanding of these agents providers of care for patients with type 2 DM will be aided in the most difficult task of preventing the complications of the disease.
Prior to 1994 selecting an oral agent for the treatment of type 2 DM was as simple as choosing which sulfonylurea (SU) to use. Since then, a variety of newer agents with unique mechanisms of action and even some combination agents have been released for use as monotherapy or in any number of combination regimens. This trend is likely to continue as even newer agents with completely different mechanisms of action are currently under investigation. Along with this explosion of therapeutic options has come uncertainty over how to use these agents effectively. When thought of the 1 last update 06 Jul 2020 simply, there are but three ways in which these agents work toward improving glycemic control: (1) increasing insulin secretion [insulin secretagogues], (2) increasing insulin action [insulin sensitizers], and (3) decreasing insulin need [inhibitors of glucose absorption].Prior to 1994 selecting an oral agent for the treatment of type 2 DM was as simple as choosing which sulfonylurea (SU) to use. Since then, a variety of newer agents with unique mechanisms of action and even some combination agents have been released for use as monotherapy or in any number of combination regimens. This trend is likely to continue as even newer agents with completely different mechanisms of action are currently under investigation. Along with this explosion of therapeutic options has come uncertainty over how to use these agents effectively. When thought of simply, there are but three ways in which these agents work toward improving glycemic control: (1) increasing insulin secretion [insulin secretagogues], (2) increasing insulin action [insulin sensitizers], and (3) decreasing insulin need [inhibitors of glucose absorption].
These agents were first introduced for the management of type 2 DM in the mid-1950s. These were the only oral agents available in the United States until 1994. These drugs work by binding to a regulatory protein (commonly referred to as the SU receptor) on pancreatic β-cells, which in turn, results in closure of ATP-dependent potassium (KATP) channels leading to membrane depolarization and influx of calcium through voltage-dependent channels, which subsequently leads to insulin secretion.7
As the second generation SUs are currently the most widely used, this discussion will be limited to these agents. The dosing, and the cost and effect of the SUs on HbA1c are summarized in table 1. As is apparent, their relative potency is similar. The most common side effect of the SUs is hypoglycemia, the risk of which varies somewhat among the agents. It is generally accepted that glyburide has twice the risk of hypoglycemia compared to the other second generation SUs.8,9 This is due to increased duration of binding to the SU receptor, resulting in fasting hyperinsulinemia with glyburide. This degree of fasting hyperinsulinemia is generally not seen with the other SUs, which are more glucose-sensitive (and thus prandial) in their stimulation of insulin secretion.9 An additional factor in this regard is glyburide''s actual mechanism of action is not fully known, but its main effect is to decrease hepatic gluconeogenesis, thus improving fasting hyperglycemia.25 There is also a peripheral effect of improved insulin action in muscle tissue, which may be related to metformin''s opinion, is more strongly affected by physician-patient discussions that occur (or do not occur) in regard to combination therapy. An informed patient is more likely to comply with therapy than an uninformed or confused patient.
For a combination agent to be useful it should be comparable, if not less, in cost to its components and should involve fewer tablets daily (and/or decreased frequency of dosing). With this in mind, it is interesting to see that the various combination agents available do not fare well (table 2). Indeed, none offer fewer tablets daily than the components taken separately. In reference to cost, only Avandamet (GlaxoSmithKline, Research Triangle Park, NC) offers savings over its components separately (approximately $400 per year less). There is some unpublished, retrospective data suggesting that Glucovance lowers HbA1c to a greater degree than similar doses of metformin and glyburide separately. These results suggest a benefit of 0.13% to 0.6% with Glucovance. Until these results can be confirmed by a prospective, randomized trial, they should be interpreted with caution. Even if confirmed, the cost-effectiveness of this benefit (an additional $700 annually) is unclear.
Cost comparison of combination agents versus component agents separately.
|Agent||Maximum effective dose (mg)||Cost/year ($)a||Pills/day||Component cost/year ($)a||Pills/day|
|Glucovance*||2.5/500, 2 bid||1,400||4||730||3|
|Avandamet*||2/500, 2 bid||2,170||4||2,550||4|
|Metaglip*||5/500, 2 bid||1,400||4||775||4|
aAverage wholesale price for brand name and maximal allowable cost for generic preparations.
*Glucophage-XR, Glucovance for 1 last update 06 Jul 2020 and Metaglip (Bristol-Myers Squibb Company, Princeton, NJ); Avandamet (GlaxoSmithKline, Research Triangle Park, NC).*Glucophage-XR, Glucovance and Metaglip (Bristol-Myers Squibb Company, Princeton, NJ); Avandamet (GlaxoSmithKline, Research Triangle Park, NC).
As was shown in the UKPDS, most patients with type 2 DM will eventually require multiple oral agents to maintain optimal glycemic control. With the availability of newer agents that target not only the defect in insulin secretion, but also insulin action, a variety of combination strategies are now possible. A full discussion of these options is beyond the scope of this review, but several excellent summaries are available.56,57 In general, the combination of an insulin secretagogue and sensitizer is most often used and makes intuitive sense given the two major pathogenic mechanisms of type 2 DM (insulin resistance and insulin deficiency). Most often this involves the use of metformin and an SU, as this combination brings together high potency, low cost and a low potential for weight gain. Certainly, a TZD should be substituted for metformin in the case of contraindications to the latter. The use of non-SU secretagogues and/or AGIs brings increased cost, decreased potency, and more potential for side effects (with AGIs).
The potential utility of metformin plus a TZD as dual therapy is interesting. From the standpoint of annual cost, this combination ($2,500) is certainly more expensive than metformin plus SU (∼$800). Metformin plus TZD is also slightly less potent than metformin or TZD plus SU.56,57 However, despite both being insulin sensitizers, this combination still makes good pharmacologic sense, as each improves insulin resistance primarily in a different tissue. Also, there may be some potential for limiting weight gain with TZDs when used with metformin. Furthermore, with the data on preservation of β-cell function, a TZD may help preserve insulin secretory capacity and thus delay secondary failure of oral agent therapy.35,37,38 As well, this combination may allow for tighter glycemic control without the risk of severe hypoglycemia that using an SU might bring. Lastly, the beneficial effects on surrogate markers of CVD cannot help but make one think of the potential benefit of TZDs beyond lowering glucose. What might be the potential cost-benefit of early use of TZD therapy, if they are shown to prevent cardiovascular events and/or deaths?
Perhaps one of the most difficult decisions in the management of type 2 DM has become whether to add a third oral agent or to start insulin therapy in an uncontrolled patient. This has only become an issue since the release of the TZDs several years ago. As mentioned previously, there may be several reasons why these agents should be used earlier in the course of treatment than is typically the case. TZDs have now been primarily used as third line agents and they will be discussed as such in this setting. There are three key issues that need considering when facing this decision.
First, how far from goal is the patient? This is important in terms of both whether to add a TZD or start insulin, also how intense an insulin program to start, if need be. The addition of a TZD as a third agent is beneficial in about 60% of patients.44 In those who respond the effect can be substantial with a mean HbA1c reduction of approximately 2.5% seen in a troglitazone trial.44 When taken as a whole (responders and non-responders alike), the mean reduction in HbA1c by adding troglitazone third line was only 1.4%.58 In the only published trial (in letter form) of the currently available TZDs, rosiglitazone added to glimepiride and metformin therapy,59 led to a 1.4% reduction in HbA1c. Patients whose HbA1c is above 9.5% on dual therapy are unlikely to get to goal by the addition of a TZD. A trial can be given to these patients (especially those particularly averse to insulin therapy), but follow-up for consideration of other options should be scheduled after 3 months at maximal dose. The TZD should be discontinued if the patient does not respond. If the decision to start insulin is made it should be stressed that adding bedtime insulin to daytime oral agent therapy will only lower HbA1c by 2% to 2.5%.60 Therefore, if the HbA1c is above 9.5% on dual therapy, the patient is likely to need a more intensive insulin program. Also, there is no evidence that bedtime glargine insulin results in better glycemic control than bedtime neutral protamine Hagedorn (NPH) insulin, although there is certainly less hypoglycemia with the former.61 Use of glargine insulin increases costs by 65% versus NPH insulin. As is noted in table 3, triple oral agent therapy costs over twice as much as SU and metformin plus bedtime NPH insulin for a similar reduction in HbA1c.
Cost comparison of triple oral the 1 last update 06 Jul 2020 therapy (adding thiazolidinediones) versus institution of various insulin programs in patients uncontrolled on sulfonylureas (SU) and metformin combination therapy.Cost comparison of triple oral therapy (adding thiazolidinediones) versus institution of various insulin programs in patients uncontrolled on sulfonylureas (SU) and metformin combination therapy.
|Therapya||Cost/year ($)b||HbA1c reduction (%)||Comments|
|SU maximal dosec +|
|metformin 1000 bid||900||N/A||Baseline|
|SU maximal dose +|
|metformin 1000 bid +||1.4 overall58,59|
|TZD maximal dosed||2,900||2.5 for responders44||∼60% response rate44|
|SU maximal dose +|
|metformin 1000 bid +|
|Bedtime NPHf||1,200||1.5–2.0||20 units/day60|
|NPH and regular bid or||1,400||120 units/daye (70% NPH; 30% short-acting insulin)|
|NPH and Humalog/NovoLog bidg||1,900||Based on dosage|
|metformin 1000 bid +|
|NPH and regular bid or||1,650||82 units/day62,63 (70% NPH: 30% short-acting insulin)|
|NPH and Humalog/NovoLog bid||1,950||Based on dosage|
|SU maximal dose +|
|metformin 1000 bid +|
|NPH and regular bid or||1,600||46 units/day62,63 (70% NPH; 30% short-acting insulin)|
|NPH and Humalog/NovoLog bid||1,800||Based on dosage|
a Insulin doses for oral agents plus insulin regimens represent “insulin-sparing” effects of oral agents as described in references noted.
b Average wholesale price for brand name and maximal allowable cost for generic (oral agents ± insulin vials) (syringes included).
the blood sugar diet epidemiology (👍 zero to finals) | the blood sugar diet bornhow to the blood sugar diet for c SU (sulfonylurea), Glipizide-GITS 10 mg qd or glimepiride 4 mg qd.
d TZD (thiazolidinediones), pioglitazone 45 qd or rosiglitazone 4 bid.
e Insulin dosage assumes a 100 kg patient requiring 1.2 units/kg/day.
f NPH, neutral protamine Hagedorn.
g Humalog (Eli Lilly and Company, Indianapolis, IN ); NovoLog (Novo Nordisk Pharmaceuticals, Inc., Princeton, NJ).
Second, if insulin is started, which oral agent(s) should be stopped? This will depend on the type of insulin program contemplated. If bedtime insulin is chosen, then daytime oral agents should be continued. However, if a more intensive insulin program is started, then three options should be considered: (1) continue both the SU and metformin, (2) stop the SU and continue metformin, (3) discontinue both oral agents. Provided appropriate adjustments in insulin are made, each of these three options will likely result in a similar improvement in HbA1c. The cost is surprisingly similar as well, owing to the differences in total insulin dose that will be needed to achieve control (i.e., continuing oral agents will result in less insulin being needed) (table 3).62,63 Continuation of metformin makes intuitive sense, as its mechanism compliments that of insulin and tends to lessen any weight gain that might occur. On the contrary, an SU works in relatively the same manner as insulin and thus is often discontinued. It should be remembered, that the SU is often still having some, albeit an inadequate, effect on glucose control. If discontinued, the SU effect will dissipate quickly, allowing glucose levels to sometimes rise dramatically. The physician should relay this possibility to the patient so as to not mislead them into believing that the insulin is not working and they were “better off on pills.” This may be particularly important in patients who have been very resistant to insulin and in those who are less likely to be compliant with scheduled follow-up. Continuation of both the SU and metformin may be best in these patients. Interestingly, the incremental cost of using fast-acting insulin analogs versus regular insulin becomes less as one or more oral agents are continued with insulin initiation due to an “insulin-sparing” effect of oral agents (table 3). As β-cell failure progresses, an increase in exogenous insulin will be required, thus rendering the continued use of the SU less cost-neutral.
the blood sugar diet vaccine (👍 treatment and prevention) | the blood sugar diet breakfasthow to the blood sugar diet for Lastly, what type of insulin program should be started? While a complete discussion of insulin options beyond bedtime dosing only is impossible here, one of the most common strategies is to employ a twice-daily regimen of an intermediately-acting insulin mixed with a short-acting insulin (figure 3). Whether self-mixing of insulin or premixed formulations are used is a matter of preference, but the author prefers the former for its greater flexibility, which allows tighter control with less hypoglycemia. However, self-mixing of insulin may result in less accuracy. The choice of regular insulin versus an insulin analog can be debated. Most often this debate centers on cost-benefit issues as each vial of an insulin analog is priced approximately $34 more than regular insulin. As previously mentioned, this incremental cost becomes less of an issue as oral agents are used with insulin. There is good evidence that both insulin analogs result in improvements in HbA1c (Humalog, 0.3% to 0.4% [Eli Lilly and Company, Indianapolis, IN] and NovoLog, 0.12% to 0.16% [Novo Nordisk Pharmaceuticals Inc., Princeton, NJ]) when compared to regular insulin.64 Both analogs have also been shown to reduce hypoglycemic risk (especially nocturnal hypoglycemia) when compared with regular insulin.64 For these reasons the author prefers to use insulin analogs.
Excess body weight and obesity play a large role in the development of type 2 DM. Many patients have struggled unsuccessfully for years to lose weight. Depending on a variety of factors patients might be gaining, maintaining, or even losing weight when they are diagnosed with type 2 DM. The weight gain that often occurs in the first year of treatment can thus be especially frustrating. The propensity for weight the 1 last update 06 Jul 2020 gain differs significantly between treatment options with metformin generally being the most weight-neutral. Insulin and the TZDs are at the other end of the spectrum, being prone to cause the greatest weight gain. The causes of weight gain associated with treatment of type 2 DM are listed in table 4. The distribution of weight gain shows two-thirds representing increased fat mass and one-third lean body mass.65 The weight-neutral characteristic of metformin may be due to its ability to decrease energy intake.66Excess body weight and obesity play a large role in the development of type 2 DM. Many patients have struggled unsuccessfully for years to lose weight. Depending on a variety of factors patients might be gaining, maintaining, or even losing weight when they are diagnosed with type 2 DM. The weight gain that often occurs in the first year of treatment can thus be especially frustrating. The propensity for weight gain differs significantly between treatment options with metformin generally being the most weight-neutral. Insulin and the TZDs are at the other end of the spectrum, being prone to cause the greatest weight gain. The causes of weight gain associated with treatment of type 2 DM are listed in table 4. The distribution of weight gain shows two-thirds representing increased fat mass and one-third lean body mass.65 The weight-neutral characteristic of metformin may be due to its ability to decrease energy intake.66
Mechanisms of weight gain with treatment of type 2 diabetes mellitus.
|Decreased metabolic rate (less gluconeogenesis and proteolysis)65,66|
|Hypoglycemia-induces appetite stimulation57|
|Agent-specific side effects (edema with thiazolidinediones)57|
The contribution of decreased glycosuria to weight gain can be substantial and will be greatest in those with the poorest baseline control. However, those with the poorest baseline control will improve the most with therapy. For every 100 g per day decrease in glycosuria, there is a positive energy balance of 400 kcal per day.57 With 1 kg of adipose tissue representing approximately 7,700 kcal, it can take just 3 weeks to gain 1 kg once glycosuria ceases. Data from the UKPDS demonstrated a 2.5 kg weight gain in the intensively treated group versus the conventional group. The HbA1c difference was 0.9%.14 Thus, one might expect a 2.8 kg (6.16 pound) weight gain for every 1% decline in HbA1c. The increased food intake associated with hypoglycemia may be related to the treatment of overt events, stimulation of appetite by mild hypoglycemia and attempts by the patient to prevent future events. The greater a drug''Young TS, Hazlet TK, Bradley KA, Maynard C, Lessler DS. A physician survey of the effect of drug sample availability on physicians'' therapy of type 2 diabetes - α progressive disease. Diabetes. 1995;44:1249–1258. [PubMed] [Google Scholar]