All About Diabetes > Diabetes Management > Lifestyle Modification & Pharmacotherapy


Prevention of Diabetes

 

The ADA recommends a variety of lifestyle interventions for the prevention of diabetes.

Individuals at high risk for developing diabetes need to become aware of the many benefits of weight loss and participating in regular physical activity, and counseled on how to initiate these lifestyle changes.

Close attention should be given to, and appropriate treatment given for, other CVD risk factors (e.g., tobacco use, hypertension, dyslipidemia).

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The LOOK AHEAD trial showed that intensive lifestyle modification provided many positive effects that would reduce risk in type 2 diabetic patients. The blue bars shown above show us the weight,A1C% BP, Lipid parameters and others, all had a benefit reduction from their baseline values.

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In the Diabetes Prevention Program, lifestyle changes were shown to dramatically reduce the risk of developing diabetes in patients at high risk for the condition. In the study, 3,234 non-diabetic patients with elevated fasting and post-load plasma glucose concentrations were randomized to placebo, metformin, or a lifestyle-modification program involving at least 7% weight loss and at least 150 minutes of physical activity per week. Follow-up ranged from 1.8 to 4.6 years, with an average of 2.8 years. Shown here is the effectiveness of lifestyle interventions, which reduced the risk of new-onset diabetes by 58% (p<0.001).

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Traditional nutrition advice focused on avoiding sugar & losing weight. Therapy now focuses on other lifestyle strategies (as shown here) that can contribute to improvements in metabolic control. No clear answer regarding which of these should be the first priority, rather, the strategy is to individualize therapy & set goals based on what the client chooses to focus on.

Carbohydrate is the macronutrient with the greatest impact on BG levels. Individuals need to be provided with the basic guidelines for the amount of carbohydrate to eat at meals and snacks, e.g., 3 to 4 carbohydrate choices/meal (60 g/meal plus/minus 15 g) and 1-2 carbohydrate choices (15-30 g) at snacks. With the help of BG monitoring, the amount eaten at a particular meal or snack from day to day can be evaluated and adjustments made accordingly to find the tolerable "carbohydrate load".

Modify calorie and fat content; reduce saturated fat: Calorie and fat content of the diet need to be modified based on individualized treatment goals; due to the increased risk of CVD for those with diabetes, most individuals will benefit by decreasing saturated fat intake

Space meals: Due to a slowed first phase insulin release, spacing meals and distributing food intake throughout the day may be beneficial.

Increase physical activity: The benefits of physical activity for those with type 2 diabetes are well documented. Physical activity is known to enhance blood glucose uptake by the muscle during or shortly after the activity and to improve insulin sensitivity. It is recommended that individuals adopt a lifetime activity model

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Diet and diabetes

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Its very important that Nutrition advice becomes an integral part of Diabetes Management. Many active physicians do not spend much time with their patients in this task. Treating Metabolic disorders relies heavily on controlling what is consumed.

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Though carbohydrates contain glucose and they can lead to hyperglycemia, they still form the basis of energy in our diets. One cannot avoid a total absence of carbohydrates in the body and the recommendation is to consume at least 130 gms per day, which translates to 130 x 4 =520 kcals of energy. On course the quality of the carbohydrate is of value and one must not consume sugary food and drinks but diets that have a low GI index. Trans fats are to be avoided, and an overall decrease in the caloric intake is first recommended.

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Professionals may be need to adjust diets for those who are looking for controlled weight reduction. Modest weight loss can give great benefits all around and thus improve metabolic parameters. Weight loss alone may not be possible with diet therapy only and a proper exercise regime may need to be followed too. For a diabetic, any change in caloric intake affects glucose parameters and thus therapy needs to be readjusted.

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The evidence for omega 3 fatty acids is conflicting but large studies are underway that may shed some light on the exact useful ness of these molecules. Trans fast are to be surely avoided. Red meat has been shown to be a risk factor for development of Diabetes and thus a plant based diets are preferable.

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Proper diabetic management is a team effort. Without proper diet and exercise advice, medicines may not help fully. The multifactorial intensive lifestyle intervention used in the DPP (Diabetes Prevention Program study), which included reduced intake of fat and calories, led to weight loss averaging 7% at 6 months and maintenance of 5% weight loss at 3 years, associated with a 58% reduction in incidence of type 2 diabetes

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The GI is the blood glucose response of a 50-g (or 25-g) carbohydrate portion of food, expressed as a percentage of the same amount of carbohydrate from a reference food- either glucose or white bread Essentially, the GI ranks the glycemic potential of the carbohydrates in different foods, gram for gram of carbohydrate.

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High GI food would increase sugar levels fast and thus may lead to greater glycemic variability. The slide shows examples of two varieties of foods that can be consumed. Due to a low GI index, it better for a Diabetic to consume the low GI alternative.

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The GI of food are affected by various factors as depicted in this slide. Currently with our existing methods we cannot accurately predict the GI of the food in-vitro, thus we cannot do many tests that can show us the exact response to the carbohydrate meal.

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This slide shows the effects of high GI foods. Not only do they affect glycaemia but also affect other metabolic parameters also. This predisposes a patient to unnecessary CVD risk in time.

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The Diabetes food pyramid displayed above gives us direction regarding the quantity of food that needs to be consumed per group. Starches that are the main source of carbohydrates and that need to provided the maximum are shown at the base. Fats and sweets are at the top intending a very controlled intake. This food pyramid also has an alternative of the plate prepared by the US department of Nutrition

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The USDA has recommended the my plate concept to try and make nutritional requirements and concepts easy to understand for the general public and also aid health care professionals in trying to push diet changes in their patients. Using whole grains, green leafy vegetables, using skimmed milk and avoiding over sized portions are the main mantras.

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Exercise and diabetes

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There is a direct mechanism between exercise and improved blood glucose control. Insulin sensitivity of both skeletal and adipose tissue can improve with or without a change in body composition. Exercise appears to decrease insulin resistance by activating glucose transporters (i.e., Glut 4). This effect is transient and deteriorates within 72 hours. As a result, regular physical activity is necessary to sustain improved insulin sensitivity. Improved lipids including decreased levels of serum triglycerides, VLD, total cholesterol, LDL, and potentially an increase in HDL.

Lowers blood pressure in people with type 2 diabetes. Exercise by itself rarely leads to weight loss. However, 90% of weight maintainers exercise.

In persons with type 2 diabetes, exercise is related to favorable changes in HbA1c and/or glucose tolerance. Exercise appears to be most beneficial in the early stages of diabetes and for individuals with blood glucose levels <200 mg/dL. For persons with type 1 diabetes, a long-term effect of exercise on improving blood glucose control has not been demonstrated. This lack of improvement has been attributed to the increased intake of ~300 to 400 kcal on exercising days. Therefore, the goal for persons with type 1 diabetes is to exercise safely so as to receive the same benefits of exercise that individuals who do not have diabetes receive.

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Patients should choose activities that are appropriate for their lifestyles. Some recommended aerobic exercise are walking, etc.


Weight loss is enhanced if exercise is increased to 5-6 times per week

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This slide discusses the type and intensity of exercise that needs to be done which is recommended by the ADA and ACSM.

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Not all patients can be recommended to start exercising when they come to a doctors consult. They need to be assessed case wise and then the appropriate regime needs to be detailed. Older patients, patients with pre existing complications or comorbidities need to be cardio-assessed.

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Pharmacotherpy

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When considering drug therapy in diabetes, certain goals come to mind. We want therapy that reduces insulin resistance and hence the demands on the beta cell, while at the same time increasing beta-cell function and mass. We want, of course, to sustain glucose lowering. And reducing CVD risk is of tremendous importance. We want therapy that is safe, well-tolerated, and available at low cost. But it's quite unlikely that any existing drug meets all of these criteria.

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Clear messages came out of UKPDS, for example results established that lowering blood glucose levels in type 2 diabetes with intensive therapy conferred clear benefit in retinopathy, nephropathy, and perhaps neuropathy length of time with which the patient lives with hyperglycemia is critically important glycemic control does deteriorate over time. UK Prospective Diabetes Study Group (UKPDS). 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
1998;352:837-53.

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This algorithm considers the various characteristics of each of the interventions, and a more detailed discussion follows. Nathan DM et al. Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2009;52:17-30; Diabetes Care 2009;32:193-203.

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Tier 1 looks at the well-validated core therapies, the best established in helping patients reach their glycemic goals, as well as being most effective and cost-effective.
Step 1 recommends the use of metformin and lifestyle modifications (e.g., weight loss) simultaneously, recognizing that for many patients, lifestyle interventions alone may not be realistic.
Step 2 adds a second medication, when lifestyle interventions and metformin fail to achieve or sustain glycemic levels. This may be basal insulin or a sulfonylurea.
Step 3 recommends that insulin therapy should be initiated or intensified if lifestyle intervention, a sulfonylurea or basal insulin glycemic control is not achieved.

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In some parts of the world, metformin is the only biguanide available.
- typically lowers A1C by ~1.5%
- generally well-tolerated, weight neutral, low cost

Insulin, as the oldest medication available, is the one with which we have the greatest clinical experience. Long-acting and rapid-acting insulins result in A1C reductions of 1.5-2.5%, but can contribute to weight gain and hypoglycemia.

Sulfonylureas lower glycemia by improving insulin secretion, and are similar in efficacy to metformin. Higher doses should be avoided since effects can generally be seen at half-maximal doses.

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Metformin is one of the oldest drugs used today to manage Diabetes. It is also one of the most extensively studied. It is used as a first line therapy not only for known Diabetics but also recommended for Prediabetics who are at high risk. The side effects of Lactic acidosis though severe is very rare and is not usually seen during routine clinical practice. However, special populations may need to avoid Metformin.

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These special population may need to monitor their Metformin doses.

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Sulphonylureas are also one of the oldest class of drugs used in the management of DM. They have been around for many years. Their main action is stimulating the release of Insulin from the pancreas. They were discovered from antibiotics.

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There are many issues with the use of Sulphonylureas. Weight gain, hypoglycemia, and sustainability are some of the key ones. The newer agents of DPP4 inhibitors seems to be challenging the dominance of sulphonylureas as the second line option for DM mgmt. Combination therapy with insulin, specially Basal insulin needs a relook at the dose of the SU in order to avoid undue hypoglycemia.

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Antidiabetic treatment was shown to protect patients from an adverse MI events than diabetic patients who did not have any treatment. SU and Insulin therapy gave the best benefits. The SU studied here was Glimepiride (Amaryl). No distinction was made between different SUs, but based on pre-clinical results, it might be expected that Glimepiride better inhibits the development of post-MI left ventricular dilatation than other SUs.

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Vascular complications observed in diabetes are often related to altered platelet functions. The most widely used hypoglycaemic drugs for treating Type II (non-insulin-dependent) diabetes mellitus are sulphonylurea derivatives. The purposes of this study were to evaluate the inhibitory effects of hypoglycaemic agents on platelet aggregation, to measure their lipophilicity and identify their structural parameters which assess their antiaggregatory activity. Glimepiride appeared to be a more potent ADP-induced platelet aggregation inhibitor in vitro than gliclazide. Antiaggregatory activity was confirmed for glibenclamide.

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Less well-validated therapies are outlined here, in an algorithm that may be useful in particular clinical settings. If hypoglycemia is particularly undesirable, a second step may involve initiation of a GLP-1 agonist like exenatide, which may also be considered if weight loss is a major consideration. Adding pioglitazone or a sulfonylurea may also be considered if step 1 and step 2 interventions are not effective in getting patients to target A1C.

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As compared to tier one glucose-lowering drugs, tier 2 therapies are more expensive. TZDs do not contribute to hypoglycemia, but are linked to edema, CHF, and bone loss. GLP-1 agonists like exenatide may contribute to weight loss, nausea and vomiting.

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Several studies have looked at the safety of rosiglitazone as regards to cardiovascular disease, with endpoints of myocardial infarction, death, stroke, etc. Some meta-analyses have suggested a relative increase in risk for MI of 30-40%.

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Data like the PROactive study, a randomized clinical trial, suggest that there were no significant effects of pioglitazone as compared to placebo on primary CVD outcome, and meta-analyses have suggested a possible beneficial effect of the drug on CVD risk. However, neither of these TZDs - rosiglitazone or pioglitazone - are recommended, based on their link to increased risk of fluid retention and CHF, and in increased incidence of fracture. Pioglitazone has a further controversy regarding its use and bladder cancer. In fact some countries have already asked a labeling change and have put in a black box warning. Bladder cancer seems to be related to continuous use more than 2 years, and is thus based on cumulative exposure.

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PPAR gamma, many actions, decreases markers of inflammation, decreases small dense ldl, increases HDL, decreases TG, its an insulin sensitizer thus reduces hyperglycemia and hyperinsulinemia, also helps in hypercoagulation by decreasing PAI, thus many benefits.

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Alpha-glucosidase inhibitors are less effective in reducing A1C than metformin or SUs, with a reduction of 0.5-0.8%. Gastrointestinal symptoms sometimes discourage patients from continued use.
Glinides stimulate insulin secretion in the same way as do the SUs, but must be administered more frequently. Repaglinide is almost as effective as metformin or SUs in decreasing A1C levels, on average ~1.5%. Amylin agonists like pramlinitide (available only in the US at present) is administered subcutaneously prior to meals, and inhibits glucagon production in a glucose-dependent fashion. Gastrointestinal side effects have been reported, as has weight loss.
DPP-4 inhibitors like sitagliptin can be used as monotherapy or in combination with metformin or TZDs. They are weight neutral and well-tolerated.

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Here is a comparison of some of the properties of the incretin mimetics and DPP-4 inhibitors, showing, briefly that insulin secretion and glucagon are glucose-dependent with both, their effect on fasting glucose is the same, and effect on A1C about the same; that exenatide's effect on postprandial glucose is good, while sitagliptin's is modest; dosage with sitagliptin is once-daily (oral) compared to a twice-daily s.c. injection with exenatide.

 

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This slide shows the key differences between the various DPP4 inhibitors that are available in the market today, or which would be in the near future.

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This slide shows the key differences between the various DPP4 inhibitors that are available in the market today, or which would be in the near future.

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This slide shows the key differences between the various DPP4 inhibitors that are available in the market today, or which would be in the near future.

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Insulin is a powerful and effective pharmacological tool for a diabetic . There are many avenues now available. There are many new Insulins. But in spite of these advances, Insulin therapy is usually delayed and control is sacrificed giving rise to bad metabolic memory. There are many barriers to Insulin use, from the patient to the doctor themselves.

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Multiple reasons contribute to patient resistance to insulin therapy, including fear of injections, pain, the complexity of insulin regimens, and psychological resistance to insulin use. Physician resistance to insulin use is based on perceived cardiovascular risks as well as a lack of time and resources to supervise treatment Major medical concerns regarding insulin use include the potential for hypoglycemia and weight gain

Real and/or perceived concerns continue to present barriers to effective insulin use. Many patients fear the pain of multiple daily injections or are uncomfortable with the complexity of their regimens. Some have trouble adjusting to the idea that they require insulin therapy to control their diabetes.

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Clinical inertia is a common phenomenon in which practitioners fail to intensify therapy in response to glycemic levels that are above target

Due to clinical inertia, pharmacologic therapy is not initiated or advanced until patients have A1C levels well above the targets set by the ADA and AACE/ACE

As a result, patients are exposed to high glycemic levels for many years, greatly increasing their risk of diabetes complications

A prospective, population-based study demonstrated that prior to the initiation of insulin, the average patient had had A1C levels >8% for nearly 5 years and had spent approximately 10 years at an A1C >7%. Using retrospective observational data collected from the Kaiser Permanente Northwest Region between 1994 and 2002, the authors identified over 7000 patient records that comprised a complete course of treatment consisting of lifestyle management, sulfonylurea or metformin monotherapy, and combination oral therapy.1

The authors found that from the point of diagnosis, the average patient remained on lifestyle management for

30 months and that when oral agent monotherapy was initiated, the mean A1C was 8.6%. An additional 27 months for those on metformin or 35 months for patients on a sulfonylurea passed before combination therapy was initiated. The mean A1C at this point was 9.1% for sulfonylurea-treated patients and 8.8% for those on metformin (the time span and A1C value shown on the slide are the averages between the 2 monotherapy groups). The mean A1C upon initiation of insulin was 9.6% after an average of 34 months of combination therapy.1

This "clinical inertia" results in unnecessary exposure of patients to glycemic levels well above target, greatly increasing their risk of diabetes complications.
Reference
Brown JB, Nichols GA, Perry A. The burden of treatment failure in type 2 diabetes. Diabetes Care. 2004;27:1535-1540.

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T2DM treatment should be target driven and intensified as diabetes progresses.1 When lifestyle modification and OHAs fail to provide glycaemic control, insulin therapy should be initiated with a basal insulin such as once-daily insulin glargine. If FBG has been reduced to target levels but HbA1c values remain high, insulin therapy can be intensified with the stepwise addition of prandial insulin injections. This is known as the basal-plus approach. A prandial insulin, such as insulin glulisine, should be initiated once daily with the main meal of the day.

A second and third prandial insulin injection can be added as T2DM progresses and tighter glycaemic control is sought. A physiological basal-bolus regimen of 1-2 basal insulin injections and 3 prandial insulin injections daily may ultimately be required by some T2DM patients.

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In terms of safety, all drugs have some 'issue' associated - but drugs like insulin, SUs, metformin have been around 50 years or more, with the others available 10 years or less. Insulin, metformin, and SU are the most effective at lowering A1C. Metformin and SU are the least expensive of the glucose-lowering agents, insulin generally next. Most of the newer agents, are quite expensive. Weight loss and weight gain can be issues with certain of the drugs, as can the risk of hypoglycemia.

In terms of safety, all drugs have some 'issue' associated - but drugs like insulin, SUs, metformin have been around 50 years or more, with the others available 10 years or less. Insulin, metformin, and SU are the most effective at lowering A1C. Metformin and SU are the least expensive of the glucose-lowering agents, insulin generally next. Most of the newer agents, are quite expensive. Weight loss and weight gain can be issues with certain of the drugs, as can the risk of hypoglycemia.

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